# I Like to Draw Pictures of Random Molecules



## nuke

This is the official been-up-tweaking-for-two-days-and-though-a-methylenedioxy-ring-on-everything-would-make-a-better-drug thread.

Please put your pretty pictures in here and talk about them so that they do not clutter the rest of the forum.

ModEdit: if all you are doing are structural doodles and silly names, try the Name A Molecule Thread


----------



## Pomzazed

Wee! Great!
So now the random molecule wont spread around all over the topics!

Let me start this (supposedly fun?) topic by this one: 
(Please vote a name for it!)


----------



## perKeceT

nice MDbuckyball


----------



## shishigami

I like to draw pictures of molecules that I know hoping that one day I can make them.

n-(3-hydrogen isocyanide)-butyl-pomzazedene


----------



## skillet

Pomzazed said:


> Wee! Great!
> So now the random molecule wont spread around all over the topics!
> 
> Let me start this (supposedly fun?) topic by this one:
> (Please vote a name for it!)



Dude! That looks so awesome! lol! 

How about MDBA - Methylenedioxybuckminsteramphetamine

(Nice work on the drawing, that can't have been easy!)


----------



## negrogesic

I have a number of compounds I drew that in theory should be either CNS active, toxic, anabolic-androgenic or even high explosives, all while resembling....well........other things.....

I named one "enpenetrate sodium", and a bit more offensive compound called" swastikadolimide' (a theoretical opioid reminiscent of methadone in structure). 

I don't have an chem draw type app for this android, any suggestions?


----------



## FPU4eva

I love the buckeyball compounds wut type of drug is it lol


----------



## skillet

It's MDMA * 10, because there are 10 times as many carbon atoms sticking off the chain, and 10 times as many methylenedioxy groups. But the buckyball isn't aromatic, so maybe MDMA * 5...

^^ lol, enpenetrate sodium!? what does that do, F you in the A?


----------



## negrogesic

Enpentrate sodium is a theoretical barb........and yes, the concept is to facilitate penetration with marked inhibition reduction....(I had to scrath daterapelonape due to lack of gender specificity......a joke, poor taste perhaps).....

Seriously, what is a good chemdraw app, because I have some hilarious theoretical compounds........


----------



## Pomzazed

negrogesic, apart from CambridgeSoft Chemdraw which is a paid application, you can use ACD Chemsketch for free, its a freeware with quite various tools to use.


----------



## Hammilton

a supposedly paid-for application, anyway


----------



## Munroe

Free online ChemDraw software: http://www.emolecules.com/


----------



## nj754

Methylenedioxymichaeljackson (mdmj):






(methylenedioxypropofol)

I like the md-buckyball. That would have quite a bit of ring strain, though.


----------



## ebola?

I prefer the parent compound, for literally tweaking balls:






*groans*

ebola


----------



## freemind

Pomzazed said:


> Wee! Great!
> So now the random molecule wont spread around all over the topics!
> 
> Let me start this (supposedly fun?) topic by this one:
> (Please vote a name for it!)


Would this pass the blood-brain barrier? o.o


----------



## skillet

I dunno, but it would tear your SERT a new ligand entry pathway if it did


----------



## fastandbulbous

Blatent self promotion, I know, but I still like the idea of the benzodifurans that would have to be the duck/duckling series.

Can't be arsed drawing it out again, so here's a link to the thread where I did 

Behold DOM-duck!

http://www.bluelight.ru/vb/threads/300348-Is-ring-substituted-phenmetrazine-derivatives-as-5HT2a-agonists-such-a-daft-idea?p=4881523&viewfull=1#post4881523


----------



## freemind

*5HTP-NBOMe*

Why not 5HTP-NBOMe? =p


----------



## nuke

the md buckyball's p[ic50] for sert-transfected cells is over 9000


----------



## skillet

Haha, I'm sure it is! Do you have data at DAT and NET?


----------



## PsychedelicPeptide

Que "Will it float?" song.  (http://www.youtube.com/watch?v=WfUSyP3gqAw)

Will it float, will it float???


----------



## mr shush

*Phenodihydrochloride Benzelex*

What would this look like and is it even a real drug ?


----------



## sekio

Mr shush, that's a pile of nonsense and not an IUPAC or common name.
Freemind, I believe the 5-MeO-T-NBOMe analog was tested somewhere but the tryptamine analogs are just not as potent or fun.


----------



## freemind

^ Hmm... yeah, the correct wouldn't be 5HTP-NBOMe as I posted, would be 5-HO-T-NBOMe.
Anyway, if it was tested and it's not potent/fun, it's sad.


----------



## nj754

Has anyone tried making cyclohexadiene analogues of amphetamines?


----------



## Pomzazed

I've thought of that many years before, but it is the bad idea. 

Dienes got surprisingly high reactivity and would alkylate things inside your body. Even if it is not for consumption, you can see it decomposes...


----------



## fastandbulbous

^ Alkylate thing like DNA, which isn't a good thing nomatter how you look at it!


----------



## Limpet_Chicken

Unless one markets the new drug specifically at chavs, call it 'burberry speed' or something, then one could stop them from reproducing sucessfully. (or at least give those still alive cancer, I suppose that could be considered a consolation practise, it would keep doctors in work)


----------



## fastandbulbous

I gather your a believer in the Tesco slogan "every little helps"!


----------



## sekio

Alkylating agents are fun.


----------



## nj754

So what if it causes cancer? We'll let Phillip Morris handle the marketing.


----------



## Pomzazed

WHOA! at the chloroalkyls...

*Pomzazed found himself exploded handling the last molecule, 4-Grignardphetamine*


----------



## michael_1992

*.*

im not tweaking, but i do take adderall which causes me to feel that odd need to do something, even if its a complete waste of time.  
i have probably done this so much i have probably been through 1000 pages of paper (ive done this for draw the molecule thing for years). its completely  
pointless, as i have no understanding of what causes a drug to have efficacy at a particular receptor, so i cant even determine if my "theoretical drugs"     are even active. but its strangely fun 

i always wanted to be a chemist, since i loved both quantum mechanics and drug experimentation, i thought id be able to study chemistry in college, then 
buy all the chemicals i need, and then make them at home. then i came to my senses and realized that you literally cant easily buy ANY chemicals from a cchemical supply shop.


----------



## Pomzazed

Hmm.. I forget where my MDStrichnine image is, somewhere in this forum. :/


----------



## Limpet_Chicken

What do you mean by that, fast?

LOL sekio...you are just cruel....hydrazine amphetamine derivatives? probably a MAOI I would guess...instant hypertensive crisis.

And those chloroalkyl whassits...methylenedioxymustardgas?


----------



## polymath

I think the idea behind those alkylating agents is that they would bind irreversibly to receptors or serotonin/dopamine transporters. Compare http://en.wikipedia.org/wiki/Chlornaltrexamine


----------



## sackynut

polymath said:


> I think the idea behind those alkylating agents is that they would bind irreversibly to receptors or serotonin/dopamine transporters. Compare http://en.wikipedia.org/wiki/Chlornaltrexamine


does that produce an ultra long lasting high, does tolerance develop? how exactly does covalent bound ligands work? thanks for any insight. id rather not ever irreversibly bind to any of my receptos, but im curious as to how it works. the wiki is awfully short. would an alkylated SSRI basically be a one-time use SSRI haha


----------



## Nagelfar

sackynut said:


> does that produce an ultra long lasting high, does tolerance develop? how exactly does covalent bound ligands work? thanks for any insight. id rather not ever irreversibly bind to any of my receptos, but im curious as to how it works. the wiki is awfully short. would an alkylated SSRI basically be a one-time use SSRI haha



Methamphetamine permanently alters transporters so the effect would be no different really, excepting possibly the receptors aren't compromised in the same way so are not internalized as quickly (they last even longer), but your transporters and receptors have their own life-cycles, so permanently bound to a receptor doesn't mean a receptor is 'permanently activated in you ever-more'. If a receptor is even chronically used by non-covalent binding agonists the body recycles it faster than normal as 'defective'


----------



## Nagelfar

=




+





...

My question is, where would the nitrogen double bond to sulfur, that makes the phenyltropane RTI-76 covalent binding, go?


----------



## Odd_nonposter

Phenethylamines are probably the easiest.






4-heptafluoropropyl-2,5-dimethoxymethoxy-phenethylamine, or as I like to call it, 2C-Penis, because of the Teflon dildo at the 4-position.

(I've probably drawn and/or named it wrong. Big hairy deal.)


----------



## Roger&Me

^LOL, nice -- I think the steric bulk at the 4 position would hinder its activity, though.


----------



## sekio

I would expect the pentafluoroethyl version to be reasonably active.


----------



## polymath

GHB derivatives:






Note that even though there's three carbon atoms between the hydroxy and carboxyl groups in all of the molecules, the actual spatial distance between them depends on bond angles(size of the ring). What's the optimal distance for receptor binding?


----------



## sekio

Here's a list of GHB derivatives and the corresponding distances from alcohol oxygen to carbonyl carbon in the energy minimized structure. I think the cyclohexanemethanol carboxylic acid has the groups too close together.


> trans 3-OH C7 acid	4.968
> GHB	4.935
> trans 3-OH C6 acid	4.921
> S-4-Me-GHB (S-GHV)	4.914
> GHV	4.912
> cis 3-OH C7 acid	4.824
> t-HCA	4.719
> cis 3-OH C5 acid	4.694
> cis 3-OH C6 acid	4.409
> trans 3-OH C5 acid	4.395
> S-3-Me-GHB	4.382
> S-2-Me-GHB	4.331
> R-2-Me-GHB	4.328
> R-4-Me-GHB (R-GHV)	4.314
> R-3-Me-GHB	4.305


----------



## polymath

When thinking about rings of different sizes, I imagined the ring-expanded fentanyl derivative above... Unfortunately when I did a google search with keywords 'fentanyl' and 'ring expansion', I found out that someone has already made that compound and that it's less potent than fentanyl itself. (but there's lots of new positions to put substituents in)

In TIHKAL, Shulgin writes about N,N-dialkyl substituted tryptamines... Why can't the nitrogen atom be part of a ring, like in the second picture?

EDIT: Maybe expand the piperazine ring in BZP to a seven-atom ring, I don't think anyone has tried that...


----------



## sekio

Shulgin touches on the piperidine analog of the tryptamine - pip-T - and it seems to be a very strange and malicious compound indeed.


----------



## polymath

I often invent 'new' compounds and then find out that someones already made them...

I looked for info about the ring-expanded BZP derivative (N-benzyl homopiperazine), and some chemical company seems to be supplying it. A similar derivative has been made from the antihistamine chlorcyclizine and it seems to retain H1 antagonist activity while also binding to DA and 5HT receptors. Would that ring-expanded BZP be considered a controlled substance analog in USA?


----------



## Swerlz

sekio said:


> Shulgin touches on the piperidine analog of the tryptamine - pip-T - and it seems to be a very strange and malicious compound indeed.



Yeah I was just bout to reference 5-MeO-PyrT


----------



## ebola?

Unsubstituted Pyr-T also appears, with bioassays.

ebola


----------



## mr shush

Sorry its just off a film Withnail and I lol


----------



## Nagelfar

freemind said:


> Would this pass the blood-brain barrier? o.o



Well this does:






...and it's even an SNDRI


----------



## immad

^Beautiful molecule! Has this been bioassayed?


----------



## Nagelfar

immad said:


> ^Beautiful molecule! Has this been bioassayed?



http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=441298


----------



## polymath

I find the compounds of N-benzyl ethylenediamine class interesting. It might first seem that there's no a priori reason to expect them to act as DRIs, but note that they are essentially open-chain versions of benzylpiperazine, without the second ethylene bridge connecting the nitrogens.

The antihistamine tripelennamine(lower picture) has this structure, and it's known to be a weak dopamine reuptake inhibitor... Maybe there's some compound of this class that would have enough DRI potency to be used as an amphetamine-like stimulant.


----------



## nj754

Sorry if this is too newbie-ish, but is it generally understood what makes a drug more or less potent? Why is 4-FA so much weaker than d-AMP or d-methamphetamine? It ought to be roughly as lipophilic as d-AMP, and generally share most chemical characteristics with d-AMP (except the fluorine probably makes the aromatic ring more polar). Would it be that you need a higher concentration in the brain, due to weaker receptor binding? A couple of papers I found put the EC50s for NE release at 7.2e-9 and 3.7e-8 for d-AMP and 4-FA, respectively, in molar, about a 5x difference in favor of d-AMP (rat brain in vitro). For DA it's 8.0e-9 and 2.0e-7, respectively, a 25x difference in favor of d-AMP. Does this account for the whole difference? It seems like there is no amount of 4-FA that will get you as messed up as d-AMP. Is there any way to predict this or account for it based on the structure?


----------



## sekio

4-FA is also a serotonin releaser whereas D-amp is not. It's also worthwhile to note that 4-FA cannot be metabolized via p-hydroxylation unlike D-amp.

The 25x preference for DAT for D-amp over 4-FA is the major issue. Lower EC50s at the transporters = more effective as a monoamine releaser = generally more abusable, euphoric, and toxic.


----------



## nj754

sekio said:


> 4-FA is also a serotonin releaser whereas D-amp is not. It's also worthwhile to note that 4-FA cannot be metabolized via p-hydroxylation unlike D-amp.


Your point about 5-HT is well taken, but 4-FA ought to cause subjective effects even if it's just releasing 5-HT, shouldn't it? I mean, 5-HT release may antagonize the DAergic effects, but it shouldn't necessarily decrease the overall subjective feeling of being high, right? Unless 5-HT release itself causes little or no subjective effects, while still diminishing the DAergic effects. That would help explain why drugs like MDAI are said to not feel like much by themselves.

Wouldn't that difference in metabolism tend to increase the potency of 4-FA relative to d-AMP?



> The 25x preference for DAT for D-amp over 4-FA is the major issue. Lower EC50s at the transporters = more effective as a monoamine releaser = generally more abusable, euphoric, and toxic.


Does that place a ceiling on the effect of a drug like 4-FA, or can you compensate with higher doses?


----------



## Nagelfar

I wonder how effective this would be and how it would metabolize.

This one might be a bit more predictable:






^I wonder how many millions of times this one has been drawn by chemistry student drug enthusiasts?


----------



## polymath

^ 'Speedballamine' lol...


----------



## Nagelfar

polymath said:


> ^ 'Speedballamine' lol...



WF-23 + Acetorphine, super speedballamine:


----------



## polymath

^ In fact, morphinelike compounds need to have the phenolic 3-hydroxy group or they lose potency completely... (thats why codeine or heroin isn't active before it's hydrolyzed in the body) You should connect that tropane part only to the cyclohexene ring.

EDIT: I was talking about the first molecule, where theres a carboxyl at 3-position.


----------



## Nagelfar

polymath said:


> ^ In fact, morphinelike compounds need to have the phenolic 3-hydroxy group or they lose potency completely... (thats why codeine or heroin isn't active before it's hydrolyzed in the body) You should connect that tropane part only to the cyclohexene ring.
> 
> EDIT: I was talking about the first molecule, where theres a carboxyl at 3-position.



Yes, which was why I was wondering how it would metabolize, or if the cocaine part would even be active: I'd like the morphine to come on after the other metabolizes for obvious reasons ;-)

I call this one 'MK Ultra' -p):






Wonder if it'd be more viable somewhere on a PCP ring.


----------



## polymath

If that carbonyl is put to 4-position instead of 2-position on the cyclohexane ring, the compound becomes an opiate AFAIK. (use the search function and look for 4-oxo-PCP) I'm not sure if theres a way to make a drug that's both a strong opiate and a strong dissociative...


----------



## Nagelfar

polymath said:


> (use the search function and look for 4-oxo-PCP)



I'm not getting a match.


----------



## polymath

http://www.bluelight.ru/vb/threads/504286-PCP-analogs-(Cumulative)



> 4-phenyl-4-(piperidin-1-yl)cyclohexanone, 4-Oxo-PCP
> 
> Route/dose: 20mg intramuscularly of HCl salt
> Report:
> This is an interesting compound. It almost completely lost its NMDA blockade effects. Instead it possesses opioid-like activity. Probably PCE analogs of this would yield very strong narcotic-like compounds. But that's just a prediction. PCE analog could still retain NMDA antagonist properties while having strong a narcotic effect similar to that of morphine.



Also look for the "Synthesis and effects of PCP analogs" article in Rhodium's drug chemistry archive at Erowid (I can't give a link because there's drug synth discussion there). There's good basic info about arylcyclohexylamine's SAR and the 4-oxo compounds are also mentioned there:



> Ketamine (1-(2-chlorophenyl)-1-methylamino-(2-cyclohexanone) has a carbonyl substituent at the two-position of the cyclohexane ring. This confers the desirable property of increasing elimination and decreasing the duration of anesthetic action, and may enhancie the analgesic potency. The veterinary anesthetic tiletamine (the N-ethyl 2-thienyl analog of Ketamine) also has a carbonyl group at the same position.
> 
> If the carbonyl group is moved to the 4-position of the cyclohexane ring, compounds that are active analgesics comparable to morphine can result, along with a reduction in PCP-like activity.



Weren't you looking for a compound that's both mu agonist and NMDA antagonist in another thread?


----------



## Nagelfar

polymath said:


> Weren't you looking for a compound that's both mu agonist and NMDA antagonist in another thread?



I wanted a pharmacophore that was a DRI, NMDA antagonist & opioid; all three.


----------



## sekio

3'-OH PCP is a known opioid arylcyclohexylamine (the exp. report notes unconciousness at sub-10mg doses(!!!)), so is bromidol if you want to go that far into left field.

I think your best bet for the Holy Trinity of receptor site occupancy would be a derivative of 3'-OH-PCE. 3' acetyl PCE anyone? Though it does depend on the ratio of effects desired from all 3 sites - you may want to look into meperidine analogs.


----------



## mr shush

What is it called when you change a ketone to an aldehyde, sorry can't use my chem sketch as am a retard. So say with amphetamine, MDMA etc if in stead of putting a ketone in to make a cathone you put an extra carbon coming off where the ketone would (double bonded) and then a double bonded oxygen?

Or what about it you changed the cathone to an ether bond? would it just break up


----------



## sekio

Aldehydes are reactive and will react with amines to form imines (Schiff bases) and water. That's why you don't see beta-carbonyl amphetamine.

The CH2->O version of amphetamine is 1-aminoethanol phenyl ether. I don't know if it would be active.


----------



## Fyasko.

hahahaha so i've drawn sooo many MDMA molecules the past hour.
amph


----------



## mr shush

sekio said:


> Aldehydes are reactive and will react with amines to form imines (Schiff bases) and water. That's why you don't see beta-carbonyl amphetamine.
> 
> The CH2->O version of amphetamine is 1-aminoethanol phenyl ether. I don't know if it would be active.



Thanks for your reply


----------



## Pomzazed

> {1-aminoethanol phenyl ether structure}



No that molecule is UNstable and would cleave back to a phenol, acetaldehyde and ammonia. You do not even need any special conditions in decomposing it apart from "room temp". (or even -78C). Take note at the "aminal" structure and its properties. (not animal xD)


----------



## Nagelfar




----------



## I NUK3D U




----------



## Nagelfar

^lol. Might work on just opposite sides maybe?


----------



## polymath

mr shush said:


> What is it called when you change a ketone to an aldehyde, sorry can't use my chem sketch as am a retard. So say with amphetamine, MDMA etc if in stead of putting a ketone in to make a cathone you put an extra carbon coming off where the ketone would (double bonded) and then a double bonded oxygen?
> 
> Or what about it you changed the cathone to an ether bond? would it just break up


 
What about methyl ester of 2-phenyl-3-aminobutanoic acid? That would be like an open-chain version of methylphenidate.


----------



## Roger&Me

mr shush said:


> What is it called when you change a ketone to an aldehyde



I think you're referring to reduction, but you can't change a ketone to an aldehyde, because an aldehyde is by definition at the end of a carbon chain, and a ketone is by definition in the middle of one (aldehydes and ketones also have the same oxidation state, which is a good clue that neither is accessible through oxidation/reduction of the other). Via reduction, aldehydes are made from carboxylic acids.


----------



## nj754

Roger&Me said:


> I think you're referring to reduction, but you can't change a ketone to an aldehyde, because an aldehyde is by definition at the end of a carbon chain, and a ketone is by definition in the middle of one (aldehydes and ketones also have the same oxidation state, which is a good clue that neither is accessible through oxidation/reduction of the other). Via reduction, aldehydes are made from carboxylic acids.



I think he was talking about inserting an intervening carbon, as if you somehow replaced the carbonyl with formaldehyde. If there is a reaction that does this, it's not undergrad-level chemistry.


----------



## skillet

Wittig reaction can do that, with the phosphonium salt made from MOM-Cl and a trialkylphosphine (I don't know if PPh3 is the best, and they don't work so well on ketones sometimes, so maybe there are better conditions) and is undergrad level.


----------



## Pomzazed

I'd prefer taking this:
dioxygendiyl ,the ground state of molecular oxygen. bearing DOUBLE RADICAL form.


----------



## nj754

skillet said:


> Wittig reaction can do that, with the phosphonium salt made from MOM-Cl and a trialkylphosphine (I don't know if PPh3 is the best, and they don't work so well on ketones sometimes, so maybe there are better conditions) and is undergrad level.



Wouldn't that be a nonstandard use of the Wittig reaction? The wikipedia entry shows the carbonyl being replaced with a C=C double bond, which looks vaguely familiar from o-chem all those years ago. Looks too complex for undergrad.


----------



## nuke

watch the synth discussion


----------



## skillet

I'll give you a clue, that's hopefully vague enough - it's two undergrad level reactions, the first is a normal Wittig.

(I don't see this as being against the rules, but if it is, I apologise and feel free to delete it)


----------



## Nagelfar

How would someone go about drawing different kinds of bridged tropane analogs, like this:






But with the tropane as a cycloheptane ring?


----------



## skillet

Tropanes are bridged cycloheptane rings. I'm not sure what you mean?


----------



## Nagelfar

skillet said:


> Tropanes are bridged cycloheptane rings. I'm not sure what you mean?



Bridged as in the previous examples, a ring as in a literal visual ring depiction, e.g.:

ChemDraw puts out cocaine like figure A:






I want to draw figure C like figure A, not like figure B. So I can modify it in ChemDraw.


----------



## skillet

Like this?


----------



## Nagelfar

So the shaded orbital lobe is unnecessary, the wedge bond comes out from the ring and not to the nitrogen? Thanks


----------



## skillet

The shaded bit represents the nitrogen lone pair, weather you draw it or not depends on what you're trying to show. You can also just draw it as a pair of dots next to the nitrogen (representing the two electrons) like this N: which is easier I think.

I'm not sure what you mean about the wedged bonds, there are several ways you could show the stereochemistry, I just picked the way I thought was best.


----------



## Odd_nonposter

An amateur psychedelic chemist's wet dream






Dimethylenedioxy-dimethamphetamine.

Looks alien, doesn't it? 

I suspect that the double-para configuration has no activity whatsoever. This probably doesn't either.

Edit: Another one:






Lismethylenedioxyamphetamine (LisMDA)

Whenever MDA is approved for long term medical use, it'll probably be in this form. (took the idea from Vyvanse)


----------



## sekio

To discourage abuse, I suppose <g>


----------



## Nagelfar

Prodrugs from stims. That reminded me of phenmetrazine & phendimetrazine....

BTW, could anyone find me a picture of cocaine with all the positions numbered like in this image of morphine?


----------



## Roger&Me

Ah, I didn't realize he was talking about adding a carbon-carbon bond, guess I misread it. 



skillet said:


> I'll give you a clue, that's hopefully vague enough - it's two undergrad level reactions, the first is a normal Wittig.
> 
> (I don't see this as being against the rules, but if it is, I apologise and feel free to delete it)


 
Hmmm, I can definitely see it in three reactions -- but not two, at least off the top of my head. I'll shoot you a PM though so we don't get in trouble.


----------



## sekio

Here you go Nagelfar.


----------



## /navarone/

So far Methoxetamine has been a miracle drug in my opinion, don't ask....though i was wondering if anything could be done to give it come 5-ht activity, and possible decrease duration a little bit.

Would you all think it's methoxy group responsible for the duration, or rather the position on the ring?

The great resemblances with tramadol makes me wasnt to investigate this compound a bit further.


----------



## Solipsis

One day we'll evolve and everyone will see the fundamental love, and have MDNA in their nuclei.


----------



## nj754

skillet said:


> I'll give you a clue, that's hopefully vague enough - it's two undergrad level reactions, the first is a normal Wittig.
> 
> (I don't see this as being against the rules, but if it is, I apologise and feel free to delete it)



The original post asked, "What is it called when you change a ketone to an aldehyde?" That sounded to me like there should be a single named reaction that does this. It would be fun to take up your challenge to figure out a way to do it in 2 or 3 reactions, but I never used my o-chem knowledge after college, so it would require a bit too much re-learning and mental effort for me at this point.


----------



## skillet

Navarone, it is pretty close to tramadol isn't it. I've no idea how you could make a kinda hybrid of the two though. Wouldn't shortening the N-Et to an N-Me as in ketamine reduce the half-life? Or is it the chloro in ketamine that somehow makes the duration so short, seems unlikely I think?

Haha Solipsis, but I think you might need a few more hydrogen bonds for stability, check out the G-C base pair:


----------



## sekio

N-ethyl to N-methyl does reduce potency/duration for arylcyclohexylamines, IIRC.


----------



## /navarone/

From what I've read on Wikipedia, lengthening the N-methyl to a N-ethyl simply increases potency, this was demonstrated on a study about arylcyclohexylamines (eg: PCP) analogues with ethylcyclidine being the most potent out of the classic arylcycloamine.
See:
http://en.wikipedia.org/wiki/Phencyclidine#Structural_analogues
And
http://upload.wikimedia.org/wikipedia/commons/7/78/ACHA_SAR.png
[Note: it pisses me off i cant post .png pictures on bluelight ARGHH]

Tiletamine was one of the newest analogues which seemed to exert more potency and duration than PCE, in fact it also ha a N-ethyl but I guess the rate at which the alkyl is cleaved is just as fast as for N-methyls, it is very likely that the boost in duration and probably also potency was due to the thiophene additin.

In the case of methoxetamine, Rick james would say: "Methoxetamine is one fucking hell of a drug!"

(Ow man I'm craving for some MXE so bad right now...250mg MXE + 3g piracetam + 1mg clonazepam IV was the most mindblowing experience of my life, a mindtrip far above LSD)


----------



## Nagelfar

Solipsis said:


> One day we'll evolve and everyone will see the fundamental love, and have MDNA in their nuclei.


 
Baseline is baseline, my thinking is that fun will still be relative even from there


----------



## altarazims

Nagelfar said:


> Baseline is baseline, my thinking is that fun will still be relative even from there



I have a hope that eventually we'll genetically engineer ourselves off the hedonic treadmill at least, I can dream;p


----------



## Nagelfar

altarazims said:


> I have a hope that eventually we'll genetically engineer ourselves off the hedonic treadmill at least, I can dream;p


 
Is there thriving without striving?

The danger there is that we may stop progressing if we are ever fully contented. Hedonism may be redirected from animalistic pursuits, but could the social implications of such pursuit whatever it may be changed to?


----------



## altarazims

Nagelfar said:


> Is there thriving without striving?
> 
> The danger there is that we may stop progressing if we are ever fully contented. Hedonism may be redirected from animalistic pursuits, but could the social implications of such pursuit whatever it may be changed to?



Well.... I kind of don't really see us evolving much more these days as it is. I mean, natural selection is so much less important for survival, since we can keep everyone alive so easily these days. And less intelligent people are the ones most likely to reproduce the most.

Maybe it doesn't so much have to be that as just evening people out. Some of us really enjoy things like drugs, but I know people who are just so happy and pleased by simple things in life, they never feel the desire to use any drugs. Yet these people are the ones I know that are much more likely to be contributing than someone constantly hampered by negativity.

I would like it very much if we could change to be people that cared more about progressing the quality of all life than our own lives, but I agree it's the sort of thing that is easier said than done, and there is always the issue that something could go wrong, like so many 'failed utopias'. And you wouldn't want to force this on people, in my opinion forcing things on people is immoral. But people just having more emapthy for others would be a nice start, or having the choice to be more empathetic, caring individuals. Maybe if we have this option, eventually we well be a better society.. (shrugs)

For me, in the current direction of hedonism, it looks more and more likely 'Idiocracy' is a movie from the future;p

Eh, forget I said anything, I'm dragging this off topic, and I don't really want to bring up controversial stuff...


----------



## Solipsis

About the MDNA bullshit I posted: yes I'm quite aware of molecular genetics, it happens to be a course I passed. I was just joking around just like a lot of other drawn molecules are surely jokes.


----------



## nj754

altarazims said:


> I have a hope that eventually we'll genetically engineer ourselves off the hedonic treadmill at least, I can dream;p



Even if happiness is genetically-engineered, that may not benefit those of us already living. I'm holding out hope for an intracranial electrode. http://www.wireheading.com/


----------



## skillet

Solipsis said:


> About the MDNA bullshit I posted: yes I'm quite aware of molecular genetics, it happens to be a course I passed. I was just joking around just like a lot of other drawn molecules are surely jokes.



Yeah I figured you were joking, didn't mean to be patronising sorry


----------



## pharmakos

so symmetrical.

2,6-dimethoxy-4-hexafluoroisopropylphenethylamine, or psi-2C-HFIP

i predict that it will hit the market it 2024.


----------



## I NUK3D U

Any takers? It's an N-substituted fuckmeamine, with compulsory MDs wherever possible.


----------



## Swerlz

wasn't there a russian drug like that? Metabolized into amphetamine IIRC


----------



## I NUK3D U

Swerlz said:


> wasn't there a russian drug like that? Metabolized into amphetamine IIRC



Basic structure of α-phthalimidopropiophenone

Edit: Metabolises to cathinone I believe, but same (and interesting) principle. My crazy attempt above would arguably not be a cathinone either.


----------



## Swerlz

I was thinking of this

http://en.wikipedia.org/wiki/Fenethylline


----------



## allium

Yo dawg! So I herd you like rolling! So we put the methylendioxy ring on the methylendioxy ring, so you can roll while you roll.





PS: madskillz


----------



## nuke

but how


----------



## negrogesic

Come on guys, where are the neuroactive steroids? I am looking for a compound exhibiting pronounced AAS properties with modest kainate and GABAergic modulation........stimulants are boring...........


----------



## /navarone/

Theanine has some kainate and GABA activity apart from some other peculiar mechanism...but yeah i would agree that Theanine sucks a little.

Some Ampakines (which seem to relieve anxiety to some extent) have some Kainate activity but unfortunately I read that tolerance buildup to is rather quick, rather sad.

BTW negro, check out this:
http://en.wikipedia.org/wiki/Tezampanel

*Also:* Why da fuck do they always tell me invalid URL when trying to post jpeg or png pictures...i've even used imageshack and it doesn't work!!
Somepne please do something about thi cuz its making my nuts rotate counter-clockwise!


----------



## Swerlz

Nav.. You have to manually put in the image tags..


----------



## /navarone/

Here we go:


----------



## /navarone/

allium said:


> Yo dawg! So I herd you like rolling! So we put the methylendioxy ring on the methylendioxy ring, so you can roll while you roll.
> 
> 
> 
> 
> 
> PS: madskillz



Yo dawg! Since I know u like rolling, I pimped up your ride bitch, lemme just fix a few MDs here and there and you'll be ready to hit the streets son!






_Further note: I think that mol picture is not the original Rice university Nanocar since those dodecane chains are simply absurd..they would obstruct the buckyball wheels preventing the molecule from actually 'rolling'._


----------



## /navarone/

Swerlz said:


> I was thinking of this
> 
> http://en.wikipedia.org/wiki/Fenethylline



A new brand of "ICE-TEA"? LOL

(unfortunately this would hydrolyze into amphetamine, a Xantine and ethylene glycol, rather toxic unless used as an antifreeze car additive..it also has some potential as an ethanol fuel additive, more oxygen, cleaner emission and the C-O bond is very energetic in terms of combustion, ethanol fuel is the way to go)


----------



## Nagelfar

More of my cocaine skeleton fixation. This time partially 'Raclopride', a D2 dopamine receptor antagonist.


----------



## Alcyone

@navarone, I don't believe ethylene glycol toxicity would be much of an issue at recreational or therapeutic doses of fenethylline. Assuming complete hydrolysis, 100 mg fenethylline would yield about 18 mg ethylene glycol and 40 mg amphetamine. That's nowhere near a toxic dose of ethylene glycol. Increasing the dose, you'd OD on amphetamine long before EG toxicity would get at you. Fenethylline is only partly metabolised, and if we trust the Wiki entry claiming that 25.4% ends up as amphetamine and 13.7% as theophylline, the actual figure on EG would be even smaller (you'd probably get some hydroxyethyltheophylline and hydroxyethylamph as well).

Water with less than 7 mg EG per litre is considered safe for drinking. It's probably not healthy, but neither are amphetamines.


----------



## sekio

Ethylene glycol is a natural constituent of e.g. fruit juices and fermented drinks. Just like methanol, it's fine to have traces of it in your food/drink (thats why oxidative metabolism exists) as long as you don't overload your body's pathways for handling the metabolites...


----------



## negrogesic

/navarone/ said:


> Here we go:



Good stuff, definitely something I haven't heard off.......

But, it would be interesting to have a variant along the lines of this existing neurosteroid.........






Yet.......tone, down the GABAergic properties, add some mild pro-anabolic/androgenic qualities......and perhaps, an indirect opioidergic or dare I say, modestly potent opioidergic metabolite (we can dream).........

Or just piece together a hideous beast that is pro-drug for multiple conventional compounds with such properties (requiring a "routine" periodic hepatic transplantation).......


----------



## Vader

May I present the awesome-est drug ever concieved of :




I call it "Extrasy".


----------



## pharmakos

you coulda left the original methylenedioxys too


----------



## Indole

thenightwatch said:


> you coulda left the original methylenedioxys too



Now THAT would be pushing it.


----------



## Vader

1. Any more methylendioxys would actually make it TOO awesome (and also exceed the valencies of the carbon atoms)
2. It does have the original methylenedioxys. Free rotation around single bonds. Of course, you already knew that...


----------



## pharmakos

lol you just gave me two new things to look up :D


----------



## Vader

Glad that this could be educational for you


----------



## /navarone/

Did anyone else here get really exited before trying 6-APB (Benzofury) but was later very dissapointed apart from being fucked up by the harsh comedown?
The molecule looked pretty promising considering the aromaticity/electronegativity around the 4th and 5th position and the avoidance of having a-methyldopamine as a metabolite. It sucked pretty much and the psychotic like comedown was horrible.
I first thought 5-APB would have been better thinking that the oxygen at the 4th position would mimic MDMA even more though I later figured out that it was a less desired substance hence its popularity being below that of benzofury.

I yet have to find or try a decent MDMA substitute with fewer risks of toxicity, an analogue with more reuptake inhibition rather than releasing properties was my first thought but in my honest though limited experience with DNRIs and TRIs, reuptake inhibitors are pretty dissapointing compared to amphetamines reason why I find coke almost worthless as a stimulant.


----------



## pharmakos

would 2-methoxy-4,5-methylenedioxyphenethylamine be worthwhile at all?  6-oh-dopamine would be a metabolite and that shit is nasty right?

i like to think of it as being closely related to both 2C-E as well as MMDA-2...


----------



## Nagelfar

I revamped the "List of Cocaine Analogues" page at Wikipedia quite a bit. It's still far from perfect (or even to holding candles to the Phenyltropane list page)

...and in commemoration of that bit of mental masturbation:






2'-acetoxy-difluro-ethyl-pine

I've always thought cocaine looked too dualistic, with the two rings & two acetyl branches. 2'-acetoxy-cocaine remedies the branches to a nice triad, but the core of two rings are maintained. Difluoropine is the answer for the rings. I turned the methyl into an ethyl for good measure. However, since due to the difluoropine conformation, I had to reverse the stereochemistry for the optimal isomer, with the 2'-acetoxy branch, it's anybodies guess how it may function. (For instance, it may requiring being on the ring with the other fluorine fluorocarbon, which wouldn't alter my aesthetic specifications)

(edit: it looks a bit like those "BromoDragonFly" molecules, doesn't it? With the tropane as the tail, and the 2'-acetoxy as the head.)


----------



## ex-amine

Odd_nonposter said:


> An amateur psychedelic chemist's wet dream
> 
> 
> 
> Edit: Another one:
> 
> 
> 
> 
> 
> 
> Lismethylenedioxyamphetamine (LisMDA)
> 
> Whenever MDA is approved for long term medical use, it'll probably be in this form. (took the idea from Vyvanse)



This one has been opted a few years back among other board (as Lys-MDA) , and has been made.
From what i heard it's orally active but has a delayed come up.

Theoraticly the tripsin-trick seems to work on this compound just as it does on Vyvanse

your Ex.


----------



## Nagelfar

negrogesic said:


> But, it would be interesting to have a variant along the lines of this existing neurosteroid.........



+ Salvinorin A





 =






Holy fuck.. it... it overlays...(!)

Salvinorin A is the most centrally active natural molecule known to man. I just made Salvinorin A on steroids (literally).

It looks like an entirely flipped out Swiss army knife though.


----------



## Munroe

Modafinil inspired MDMA-esque things... Why? Because why not.


----------



## Nagelfar

skillet said:


> Like this?



The above doesn't seem like figure C of the below (the ester bridge on the bridged tropane doesn't look correct):



Nagelfar said:


>



Was it made from one of these? (128?):



Nagelfar said:


>



I'd still like to see someone's hand at "flattening" (the admittedly already 2D) tropane for that specific "bridged" variant (RTI-242).


----------



## shady4091

You guys are awesome! I wish I had the slightest clue what any of this meant...

Yeah... I'll leave now...


----------



## Nagelfar

shady4091 said:


> You guys are awesome! I wish I had the slightest clue what any of this meant...
> 
> Yeah... I'll leave now...



Reading and watching what people said for a few years is how I learned anything

Stick around.


----------



## FlippingTop

Fucking awesome thread!

tweaking balls is the best :D


----------



## pete_gasparino

Nagelfar said:


> ...(the ester bridge on the bridged tropane doesn't look correct)...I'd still like to see someone's hand at "flattening" (the admittedly already 2D) tropane for that specific "bridged" variant (RTI-242).


 
They are the same molecule. The ester has been written in shorthand (CO2Me) in skillet's depiction. If you number the carbons you will be able to see this.


----------



## Nagelfar

pete_gasparino said:


> They are the same molecule. The ester has been written in shorthand (CO2Me) in skillet's depiction. If you number the carbons you will be able to see this.



OK thanks for clarifying, I am not entirely familiar with all of the short-hand. For example, the methyl group in short hand confused me for a while when I couldn't positively charge my carbon-hydrogen to 3 in the chemdraw program I was using when visually copying another drug and was wondering how I did that, was a bit frustrating until I discovered it was a simple methyl which that connoted.


----------



## pete_gasparino

Here is a table of some other functional group abbreviations, that you might encounter - it is in PDF format

http://careerchem.com/NAMED/Acronyms-Groups.pdf


----------



## Nagelfar

pete_gasparino said:


> Here is a table of some other functional group abbreviations, that you might encounter - it is in PDF format
> 
> http://careerchem.com/NAMED/Acronyms-Groups.pdf



Am very much obliged. Thanks.


----------



## Nagelfar

Fentropane Methyl Ester.


----------



## mgrady3

throw a methylenedioxy on that bottom phenyl ring and you've got.... testicular cancer? ... sorry I couldn't resist


----------



## Nagelfar

Cocabogaine.

(I think I had a nightmare about this one last night. Seeing the bridged tropane analogues, I almost take this one seriously)


----------



## InhaleDeep

i don't know where else to ask so might as well try here... sorry if it's the wrong place. does this molecule look familiar to anyone?


----------



## nAON

Looks like one of the cathinone derivatives, not sure which one exactly.

EDIT: looks like 4-MEC, dunno how/if the rotation comes in though.


----------



## Vader

Yeah, it's 4-MEC. Atoms can rotate freely around single bonds. That formula shows the S-isomer.


----------



## InhaleDeep

Thank you guys!


----------



## jaurk

Wow, you guys are good at IUPAC..
I've only just finished grade 11 chemistry, and I only know the alcohol IUPAC names, with extra carbons and stuff.
How many people on here did chemistry through university?
Probably shouldn't ask that.. might put this off track.


----------



## Munroe

This should be a prodrug for 4-MMC if i'm correct?
Could anyone with a bit more knowledge correct me if i'm wrong.


----------



## mgrady3

I'm not well versed on metabolic pathways but is there a simple way to cleave the N-methyl group? if so then yeah it looks like that would metabolize into 4-mmc


----------



## Munroe

dimethylcathinone was apparently a legal high in israel for a while.


----------



## Vader

Dimethylamphetamine isn't primarily metabolised to methamphetamine, only 7.5% of the original dose is, so I imagine that you'd get about that percentage of mephedrone from your compound. btw, "prodrug" is used only for drugs that aren't active _per se_.


----------



## Munroe

I thought i'd heard codeine refered to as a prodrug as its converted to morphine in the body? I assumed the same would apply to this as it's metabolised into 4-mmc in the body?

Regardless, the poor conversion rate would mean you need more than 10x the dose?


----------



## Steps

I have a question
It has to do with molecules but mostly affinity

What are the 5-HT, DAT, and NET affinities for the D, L, and Racemic Methamphetamine and Amphetamine
Why are the affinities so different from each other (molecule-wise)
What makes meth so much more neurotoxic than amphetamine (molecule-wise)


----------



## Nagelfar

Munroe said:


> I thought i'd heard codeine refered to as a prodrug as its converted to morphine in the body? I assumed the same would apply to this as it's metabolised into 4-mmc in the body?



Codeine itself is, for instance, inactive. Which is what I believe Vader meant. Anything from an active drug is a metabolite, rather than that drug being 'a prodrug to', etc.



Steps said:


> I have a question
> It has to do with molecules but mostly affinity
> 
> What are the 5-HT, DAT, and NET affinities for the D, L, and Racemic Methamphetamine and Amphetamine
> Why are the affinities so different from each other (molecule-wise)
> What makes meth so much more neurotoxic than amphetamine (molecule-wise)



Somewhat derailing this thread, but it's not a very "serious" thread now anyhow, is it?



> D-(+)-Methamphetamine NET release EC50: 12.3 ± 0.7 DAT release EC50: 24.5 ± 2.1 SERT release EC50: 736 ± 45
> L-(–)-Methamphetamine NET release EC50: 28.5 ± 2.5 DAT release EC50: 416 ± 20 SERT release EC50: 4,640 ± 243


----------



## Nagelfar

Tolazoline + Pyrovalerone. The idea, a MAT inhibitor with reduced NE effect profile. (NDRI + α-blocker)


----------



## SerotonergicHaze

Here is my crappy idea. An amide of amphetamine + phenidate. Not sure what Phenidatic acid does it self, but is probably just a NDRI like methylphenidate. As far as I know, DRIs attenuate the effects of DRAs, but I may be mistaken






Here is my idea of a supertoxic drug 4-methyldeprenyl, a heart attack in a pill


----------



## Nagelfar

SerotonergicHaze said:


> As far as I know, DRIs attenuate the effects of DRAs, but I may be mistaken



Apparently, "Exo-2-phenyl-7-azabicyclo[2.2.1]heptane" is both a DARA & a DARI, but my understanding is that those mechanisms are mutually exclusive depending on what confirmation they bind. e.g. they do not 'attenuate' one another. Phosphorylated DAT (acting in the manner of a releasing agent) cannot be bound by the reuptake inhibitors at DAT, and when DARIs are bound to DAT they cannot be phosphorylated by DA releasing agents (which is my understanding of why DARIs are neuroprotective & DARAs neurotoxic).

I, however, would think something that acted as a releasing agent at VMAT but a pure reuptake inhibitor at plasmalemmal MAT (without phosphorylation at plasmalemmal) would be the ideal of both modes of action for purposes of CNS stimulation.


----------



## irobeth

this is stuck in my head for some reason






obligatory misunderstanding of SAR


----------



## polymath

SerotonergicHaze said:


> Here is my idea of a supertoxic drug 4-methyldeprenyl, a heart attack in a pill



4-methoxytranylcypromine has been synthesized and has MAO inhibiting activity similar to tranylcypromine itself... I don't know what the subjective effects would feel like.

http://www.ncbi.nlm.nih.gov/pubmed/1353376


----------



## SerotonergicHaze

Here are my stupid ideas 





Another MPH amide, could be used as an "anti abuse" version of ritalin.

Here are some esters and amides of amphetamine and ephedrine





N-Acetylamphetamine, inactive prodrug someone else has likely thought of





Ephedrine Acetate





Weird drug, likely an antipsychotic 





Probably an SSRI


----------



## Nagelfar

Steps said:


> I have a question
> It has to do with molecules but mostly affinity
> 
> What are the 5-HT, DAT, and NET affinities for the D, L, and Racemic Methamphetamine and Amphetamine
> Why are the affinities so different from each other (molecule-wise)
> What makes meth so much more neurotoxic than amphetamine (molecule-wise)



I personally, would be interested in knowing the difference in monoamine affinities for N-*Ethyl*amphetamine.

...






Perhaps a non-cardiotoxic/non-anesthetic cocaine analogue which doesn't have the reduced SERT affinity of the basic phenyltropanes?

...






I find this configuration curious.


----------



## Yellobello

Presenting the one and only:




Cyclomethane!

Not sure about its pharmacology, but I painted it on one of the toilets at my former university´s organic chemistry building, and it became 
kinda famous!


----------



## pharmakos

^^^ perhaps if you could come up with some way to fold the carbon atom in one of the higher dimensions (i.e. the 4th or 5th dimension)?


----------



## Pomzazed

LOL...Cyclomethane?

Isnt that a carbene anyway


----------



## pete_gasparino

Nagelfar said:


> I find this configuration curious.



The second molecule is a very unlikely but interesting structure, specifically I'm talking abut the sulfur. You have a tetrahedral hypervalent sulfur atom. It is an interesting but untenable situation: the SR4 compounds are called 'sulfuranes'. The prototypical sulfurane is SH4 and is square pyramidal.

Pentavalent carbon sulfuranes (ie :SR4 where R=alkyl) with four C-S bonds are extremely uncommon but, owing to some ingenious chemistry, and some low temperatures, have been identified spectroscopically - some have even been isolated. 

(A compound called Martin's sulfurane has been used in synthesis, dehydrating tertiary and secondary alcohols to alkenes, but it has two bonds to -O-Ph-CF3 ligands, and two to phenyl groups)

Here's a link to the image from Sigma-Aldrich, or just search Sigma for 'Martin's sulfurane'.

http://www.sigmaaldrich.com/medium/structureimages/62/mfcd00010662.png





Search google for "First Preparation of a Sulfurane with Four Carbon-Sulfur Bonds" and you'll find an article on the preparation of diphenyl bis(2,2'-biphenylylene)sulfurane, which is the compound the article title refers to (the Royal Society has a free version of the article online).

The S is psuedo trigonal bipyramidal, and you can see immediately that the biphenyl ligands confer some level of optical stability in rotation around the C-S bonds is hindered: that is, theoretically the compound would show atropoisomerism (like some of the molecules I mentioned in the other post here).





Possibly you saw the configuration (S with four sigma bonds) as curious, which it is - a more likely linkage would be the thioester, that is R-S-R' (ie if you removed the methyl and hydrogens on the sulfur).

As to other curiosities with representation: in American conventions the narrow end of the wedge bond points away from the central atom, and in European conventions, the narrow end of the wedge bond points to the central atom. They are best used to denote stereochemical configuration and they can be misleading: for example in your molecule, the cycloheptane scaffold in the bicyclic compound I believe you've referred to as a tropane analogue, appears flat (in the same plane as the paper).

In reality it adopts a much different conformation. But for convenience we may use the flattened structures, especially where mechanisms are concerned. 

But back to the wedge bonds for a minute: you must be careful with their use, in that you don't confuse yourself with the shape of a particular molecule. It is conventional to use wedge bonds for tetrahedral or near tetrahedral atoms. Two bold wedge bonds coming from a carbon atom would only be possible if the other two bonds were both line, or both hashed wedge (if one was a hashed wedge and the other a line, the structure would not appear tetrahedral).

Since you're using the American convention, the nitrogen can have two wedge bonds attached: one from the ring-carbon (pointing to the nitrogen), and one from the nitrogen (pointing to another ring carbon). This is clear because the N has both narrow, and broad bold wedge bonds attached.

If it had two bold wedge bonds depicted as emerging from the nitrogen (narrow ends pointing at the N), it would be a confusing structure (in terms of this molecule).

Lastly, this paper addresses optical activity in sulfuranes, and the stereochemistry of various sulfuranes:

Stereochemistry of spirosulfuranes and their oxides: Static and dynamic aspects


----------



## Cydroxy

So I came up with this about a week ago, after reading on wiki about the variations in the phethylamine fly series. Theoretically it would create less visuals and more euphoria then mmda.

The idea is that with a 5-furan ring instead of a methoxy it still hits the same receptor (5-th2a). But when you bring it out to a 5-pyran ring, it now increases selectivity for 5-th2c instead of 5-th2a thus making it more euphoric rather then visual.

What do you guys think?


----------



## SerotonergicHaze

Chemsketch + boredom


----------



## Solipsis

I used to be fan of the record label ID&T, not in the time they were known for hardcore music releases but rather around 2000 when they started hosting the biggest indoor dance event of the world (I think): Sensation. This is their logo:






So when I started spinning records, I built myself a huge DJ booth and using serigraphy (screen printing), I made the following molecule in orange fluorescent paint about 1.5-2 ft across:


----------



## irobeth

Solipsis said:


> I used to be fan of the record label ID&T, not in the time they were known for hardcore music releases but rather around 2000 when they started hosting the biggest indoor dance event of the world (I think): Sensation. This is their logo:
> 
> 
> 
> 
> 
> 
> So when I started spinning records, I built myself a huge DJ booth and using serigraphy (screen printing), I made the following molecule in orange fluorescent paint about 1.5-2 ft across:


 
idiantine?


----------



## rakketakke

Awesome


----------



## /navarone/

Sup..
I wa looking for your opinion on 3 ketamine like substances that I came up with during my long and harsh methoxetamine intake.

Basically I was hoping for some lqualified info on the SAr and other potential properties of the following:






In my opinion the first 2 shold have a high activity, though im dubious abouth the third one.

Thanks in advance. anyways.

Peace!


----------



## SNR

/navarone/ said:


> Sup..
> I wa looking for your opinion on 3 ketamine like substances that I came up with during my long and harsh methoxetamine intake.
> 
> Basically I was hoping for some lqualified info on the SAr and other potential properties of the following:
> 
> 
> 
> 
> 
> 
> In my opinion the first 2 shold have a high activity, though im dubious abouth the third one.
> 
> Thanks in advance. anyways.
> 
> Peace!



You're right. I'm not an expert, but the first two do look more active than the third. Third one looks a little.. eh. Not sure if any would match any of the current arylcyclohexylamines though. Really cool "triflu" section in the second one..


----------



## /navarone/

the 3' one actually fits prety well with metoxetamine on a 3D model though it this is only possible with one of the 2 isomers from what I undestood.

Could anyone advice me a better program than ACD to depict molecules and ther 'natural' comformation?
On ACD chemsketch the molecule seems plausible though i have doubts about that program a lot.

Neways here is what I managed to post in 3D so far to compare between methoxetamine, ketamines and my so called 'ponticlidine' (_from italian 'ponte' which means bridge_).






the general comformation of the molecules don't seem to alter that much so I would gues some activity....plus longer duration since the ethyl grouo is bonded between an amine an an oxygen making enzymatic brakedown moew difficult.

What do you think?
(ps sorry for the typos...im a lil bit drunk right now)


----------



## Steps

Lol, tell an uneducated person "I'm about to drink some dihydrogen monoxide"

The responses I get are like "DUDE DON'T KILL YOURSELFFFF"

Its H2O... god damn hippies...


----------



## pharmakos

but dhmo is the number one cause of drowning amongst all age groups!


----------



## SNR

It's a neuroactive steroid, alphaxolone, combined with a morphine molecule. Does anyone know if either of these combinations would be possible / efficacious?


----------



## polymath

What about this kind of a cyclized amphetamine molecule (2,3-dihydro-2-methylindole) ?






This seems to be available from chem suppliers but I couldn't find any pharmacological data... Also, are there any better known amphetamine derivatives where there is an amino group on the aromatic ring?


----------



## nAON

EDIT: derp


----------



## YellowPolkaDotHalo

polymath said:


> What about this kind of a cyclized amphetamine molecule (2,3-dihydro-2-methylindole) ?
> 
> 
> 
> 
> 
> 
> This seems to be available from chem suppliers but I couldn't find any pharmacological data... Also, are there any better known amphetamine derivatives where there is an amino group on the aromatic ring?


 
I reckon I could draw that.


----------



## cannibalsnail

Its  3,4-methylenedioxy-N-methylcathinone-4-acetoxy-N,N-tripropyltryptamine

or

BK-MD-4-ACO-ATPT for short.

Yeh what a gangsta chemical. 

Its street name would have to be "tentacle rape".


----------



## /navarone/

^^ Very potent though somehow unpleasant from what I've heard.
BTW it is funny we haven't heard of any aryl substituted phenylethylamines....like para-amino or meta-amino.
Is there a reason behind this?


----------



## /navarone/

cannibalsnail said:


> Its  3,4-methylenedioxy-N-methylcathinone-4-acetoxy-N,N-tripropyltryptamine
> 
> or
> 
> BK-MD-4-ACO-ATPT for short.
> 
> Yeh what a gangsta chemical.
> 
> Its street name would have to be "tentacle rape".



Then why not this:






C'mon guys let's kep it serious a bit, my ketamine proposition had some insight in it....playing with molecules wike they are lego is just a waste of time.


----------



## cannibalsnail

Okay I agree that is ridiculous. Heres what I was going for before I got carried away:






Trying to make a novel entactogen/psychedelic. I'm hoping the alpha-ethyl combined with the MD ring should retain some affinity for SERT pathways while the dimethyltryptamine buried in there provides some 2A affinity. The Alpha-ethyl substitution should also stop metabolization by MAO-A.


----------



## /navarone/

In that case the amine conjugations would almost abolish activity, this is a common between all alfa-alkyltryptamines. Also the lower methoxy group makes no sense at all.

Regarding the methylenedioxy moiety, it would be MUCH more reasonable to put it betweeh the 4th and 5th position (1 step up).
I assume this from the psychedelic profiles of 5-MeO-DMT and psilocin. Though maybe 2 indipendent methoxy grouos or 2 halogens might be somehow more efficient and probably more neurotoxic.


----------



## cannibalsnail

/navarone/ said:


> In that case the amine conjugations would almost abolish activity, this is a common between all alfa-alkyltryptamines. Also the lower methoxy group makes no sense at all.
> 
> Regarding the methylenedioxy moiety, it would be MUCH more reasonable to put it betweeh the 4th and 5th position (1 step up).
> I assume this from the psychedelic profiles of 5-MeO-DMT and psilocin. Though maybe 2 indipendent methoxy grouos or 2 halogens might be somehow more efficient and probably more neurotoxic.


 
Excluding the methylenedioxy and lower methyl group (it got put in by accident, I was adapting previous drawings) would an alpha-ethyl position substituent on the DMT (or 4-ho-dmt) molecule create monoamine release properties? AFAIK AMT is the only monoamine releasing psychedelic and I think it would be interesting to explore more.


----------



## randomer945

hi everyone, i was always interested in dragon-fly derivities. anyone have any idea on this





the x represents an alkyl or halo substituet. my reasoning was that if a furan group substituts fairly well for a methylene dioxy group (eg in 6-apb and mda) then the reverse could be applicable for the dragonflys.


----------



## Dysphoric

How would you go about naming the molecule you made?


----------



## Dysphoric

negrogesic said:


> stimulants are boring...........



Blasphemy!


----------



## SNR

ktp said:


> wakofly, the most potent 5ht-2a agonist:


Why would that be the most potent 5-HT2A agonist? Any info to back that up? Just wondering I'm interested ;-)






This would be an ACh releasing agent along with an AChE inhibitor. Hopefully it will kill >;-)






This here is a weird methylphenidate analogue I made.. It is based on a few other MPH analogues and in theory, it would be a potent DA reuptake inhibitor, and maybe even have decent affinity for the other monoamine transporters.. either that or that C-Fl chain in the front would be impossible 






And this guy here is just a product of boredness in Anatomy and Physiology class. An MDMA analogue with some neat stuff!

~snr

EDIT: Sorry for the huge images, from now on I'll use a smaller rendering size.


----------



## Solipsis

randomer, I don't think you can use such methylenedioxy substitutions on two sides of the ring AND a 4-substitution. The starting position of the idea would be that there would be 4 times a methoxy group on all those positions and I think existing molecules indicate that this is too much. It should not be that much electronegativity - it probably couldn't bind correctly. Though I do wonder, with the dragonfly series there are pi orbitals in those areas so who knows.

SNR about the compound with the chloro's that are triple bonded, Cl doesn't do that unless perhaps in special inorganic configurations, if that. It's not nitrogen. Yes it does have extra electron pairs but I think the atom is just too big and negative for one, a second bond would already be far too unstable let alone a third one.

Is this just random? Because that word is in the thread title so in that case I will leave you to it. :D


----------



## skillet

randomer945 said:


> hi everyone, i was always interested in dragon-fly derivities. anyone have any idea on this
> 
> 
> 
> 
> 
> the x represents an alkyl or halo substituet. my reasoning was that if a furan group substituts fairly well for a methylene dioxy group (eg in 6-apb and mda) then the reverse could be applicable for the dragonflys.



An oxygen at the 3-position of 2CD-FLY reduces affinity slightly (2C-MeTriox in Bradens thesis, Ki 10.35nM vs 6.22 for 2CD-FLY). I don't know what effect adding the 6-oxygen would have, but it could be an interesting compound, as could the 2C-MeTriox.



ktp said:


> wakofly, the most potent 5ht-2a agonist:



The brominated, alpha-methylated, non N-benzylated version of that was published by Nichols, same affinity as DOB-FLY but with higher intrinsic activity. So Br-DFLY is still more potent, but who knows when you put the N-benzyl on...


----------



## SNR

Solipsis said:


> SNR about the compound with the chloro's that are triple bonded, Cl doesn't do that unless perhaps in special inorganic configurations, if that. It's not nitrogen. Yes it does have extra electron pairs but I think the atom is just too big and negative for one, a second bond would already be far too unstable let alone a third one.
> 
> Is this just random? Because that word is in the thread title so in that case I will leave you to it. :D



Yes, that particular molecule was pretty random


----------



## Rand0mX1985

/navarone/
You asked about better molecular design software.
*Avogadro* is freeware and can do 2d and 3d editing.



we don't allow torrent site discussion or links on Bluelight. Please read the BLUA Thanks..


----------



## SerotonergicHaze

1,1,1-trifluroethyl-FLY-NB-1,1,1-trifluroethane

My idea of a very potent 5-HT2A agonist 






MethoxyFLY-NBOMe
Another Fly, probably very toxic. I'm a bit of a noob when it comes to these things, but would this substance also have some MAOI activity?


----------



## Munroe

Not got the energy to draw it, but cut off the methoxy and tape on a methelynedioxy.


----------



## BLreturn11

*How about DIPT / DALT combinations, there seems to be little info on these*

Of all the Tryptamine DIPT seems to stand out as a atypical (Quite powerful auditory changes): Wonder if DALT/DIPT combinations have been looked in to ? Seems like a logical one for the legend shulgin (maybe unpublished?) 






steric hinderance might prove problematic in the above but maybe the simplest DIPT / DALT crossbread might be interesting....






-Opinions? 

BL11


----------



## Nagelfar

SNR said:


> This here is a weird methylphenidate analogue I made.. It is based on a few other MPH analogues and in theory, it would be a potent DA reuptake inhibitor, and maybe even have decent affinity for the other monoamine transporters.. either that or that C-Fl chain in the front would be impossible


 
It looks like it would have serotonin affinity. Possibly an antidepressant type action.


----------



## SNR

Nagelfar said:


> It looks like it would have serotonin affinity. Possibly an antidepressant type action.



Any NE or DA activity? Because it's based off of a methylphenidate analogue.


----------



## cannibalsnail

Why the chlorines?


----------



## basement_shaman

Doesn't matter, the bonds are impossible anyway.


----------



## SNR

cannibalsnail said:


> Why the chlorines?


It's based of a MPH analogue I saw before. Had the chlorines and the analogue was supposedly more potent than MPH. 



basement_shaman said:


> Doesn't matter, the bonds are impossible anyway.


How about if the flourines are removed?


----------



## pharmakos

halogens are sorta dead ends as far as SARs are concerned, can't really lengthen them into a chain or anything...


----------



## Astavats

@SNR

The Cl-F might end up as a fluorinating agent which isn't going to be safe. Removing the fluorines you'd still need to replace it with another group to avoid a charge but none the less I'd be surprised if the cyclical organochlorine is stable on the bench let alone within body. The closest I can think of to your drawn structure would probably be R-S-R as both will have similar sizes and two lone pairs, however I'd imagine it's still prone to ring-opening as well (to a lesser extent). If you wanted to tack on a electron withdrawing group (analogous to F) you could try  S=O though without understanding _why_ the parent was more effective it'd be nothing more than blindly guessing.


----------



## nuke

SNR said:


> It's based of a MPH analogue I saw before. Had the chlorines and the analogue was supposedly more potent than MPH.
> 
> 
> How about if the flourines are removed?


 
Three bonds to a chlorine 8(

Start here: http://www.chemguide.co.uk/


----------



## nAON

I was just reading through this thread, thinking 'wow, these ADD guys really know their stuff, I wish one day I could be this knowledgeable'... then I saw that C-Cl(F)-C molecule 


gonna give this a go myself, just trying to figure out how to use chemdraw..


----------



## nAON

Right, here are my attempts, now i just need someone to tell me how horrifically broken and non-viable these will be 

no.1






no.2


----------



## pharmakos

^^ for no.1, that much bulk at the 4-position of the phenyl ring probably would eliminate activity.  all the simple 4-substituted PCx analogues that i am aware of already have drastically reduced potency(4-MeO-PCP is like 100x less potent than PCP) .  what was your reasoning behind that group?   everything else on the molecule makes sense to me.  i woulda made it an N-Ethyl though.

no.2 could possibly be an interesting molecule.  the 4,5-methylenedioxy tryptamines are largely unexplored as far as i know.


----------



## cannibalsnail

Any Tryptamine with an MD ring is a risky prospect because it falls so close to 6,7,dihydroxytrytpamine which is a neurotoxin.


----------



## nAON

cannibalsnail said:


> Any Tryptamine with an MD ring is a risky prospect because it falls so close to 6,7,dihydroxytrytpamine which is a neurotoxin.



just looked this up, actually its this:







which looks disturbingly similar to many other common trypts. that said, i havent seen -OH that often on either trypts or phens




EDIT: just found the phen equivalent of the selective neurotoxin:







it seems indeed a good idea to steer clear of anything with -OH. not sure about how the dioxane rings would affect toxicity, i think the -OH would make it toxic either by oxidative damage or radicals being formed, i dunno if C-O-C would be metabolised that far. 

that said, i mostly have no idea wtf im talking about, someone tell me if im making any sense


----------



## Indole

Your methylenedioxy ring above will be metabolised into the 6,7 dihydroxy compound. I feel like we have talked about the neurotoxic potential of such a compound before, maybe even in this very thread...


----------



## SNR

Astavats said:


> @SNR
> 
> The Cl-F might end up as a fluorinating agent which isn't going to be safe. Removing the fluorines you'd still need to replace it with another group to avoid a charge but none the less I'd be surprised if the cyclical organochlorine is stable on the bench let alone within body. The closest I can think of to your drawn structure would probably be R-S-R as both will have similar sizes and two lone pairs, however I'd imagine it's still prone to ring-opening as well (to a lesser extent). If you wanted to tack on a electron withdrawing group (analogous to F) you could try  S=O though without understanding _why_ the parent was more effective it'd be nothing more than blindly guessing.


 


nuke said:


> Three bonds to a chlorine 8(
> 
> Start here: http://www.chemguide.co.uk/



Thank you both for the feedback, you've given me some things to learn from.


----------



## SNR

Indole said:


> Your methylenedioxy ring above will be metabolised into the 6,7 dihydroxy compound. I feel like we have talked about the neurotoxic potential of such a compound before, maybe even in this very thread...



I believe neurotoxicity was the goal of that compound.


----------



## i are spectre

oh come on this isnt any fun without the IUPAC name that goes with it...  and fuck fluorinated compounds.  actually fuck anything with a HALOGEN.

C N O H is all i usually like in my drugs...


----------



## Nagelfar

nAON said:


> EDIT: just found the phen equivalent of the selective neurotoxin:


 
Does anybody have the know-how to elucidate the exact method of action of this compound? It destroys the neurons from uptake into MAT according to that article? Does it internalize MAT like amphetamine and if so is it like a greatly exagerated DRA-type of neurotoxicity? If so, it seems to be a good example of using DRIs to prevent DRA-like toxicity.


----------



## polymath

^ The exact mechanism of 6-OHDA neurotoxicity is not known, but in a simplified model it enters the dopaminergic cells via the DA transporter and once inside, it causes production of hydrogen peroxide which oxidizes the shit out of cell structures and causes apoptosis (programmed cell death). This model is supported by the fact that in _in vitro_ cell culture experiments, incubation with enzyme catalase which destroys hydrogen peroxide, prevents the 6-OHDA toxicity.


----------



## Nagelfar

polymath said:


> ^ The exact mechanism of 6-OHDA neurotoxicity is not known, but in a simplified model it enters the dopaminergic cells via the DA transporter and once inside, it causes production of hydrogen peroxide which oxidizes the shit out of cell structures and causes apoptosis (programmed cell death). This model is supported by the fact that in _in vitro_ cell culture experiments, incubation with enzyme catalase which destroys hydrogen peroxide, prevents the 6-OHDA toxicity.


 
So its a contrast of transporter damage through oxidization over phosphorylaton? I'm assuming then most chemical causation on dopaminergic neurons is mediated through DAT for the whole system regulation versus for instance their respective receptor condition. (at least for induced toxicity)


----------



## SerotonergicHaze

Here is something a bit new to this thread





O-Methyl-N-Methyl-Muscimol


----------



## pharmakos

^^^ any reasoning behind the alterations?


----------



## SerotonergicHaze

The reason for the N-Methyl addition is to reduce polarity and increase lipophilicty to increase bbb crossing. 
The O-Methylation simply to see what it would do, going all shulgin


----------



## pharmakos

^^ you should only make one variation at a time.  test the n-methyl, the o-methyl, and only then the n,o-dimethyl


----------



## flaming

I was in the process of brainstorming some new various N-benzyl 2C derivatives when I came across this article: http://molpharm.aspetjournals.org/content/70/6/1956.long . Seems like I'm not so original after all... They've already tested N-napthyl, N-benzylmethylenedioxy, just about everything you could think of.


----------



## SNR

Above image is broken. I want to see it too! Please repost!


----------



## flaming

SNR said:


> Above image is broken. I want to see it too! Please repost!


I don't remember whether he drew the aromatic or saturated hemifly, but here's a guess anyway. edit: ignore that first image, I made it a phenmethylamine instead of a phenethylamine :/ It's correct now, SMILES: C13=C(C(=C(C2=C1[C@@H](C2)CN)OC)Br)CCO3


----------



## SNR

Man.. even if it was a phenethylamine it's still a really crazy looking molecule. Any ideas on activity? Not sure I've seen any compound that looks like that haha


----------



## flaming

That _is_ a phenthylamine. It just has a beta-methyl which is also bonded to the 6-position on the phenyl ring. The phenethylamine backbone is still there, even if it is distorted a little bit by chirality along the ethylamine part.

And as for activity, TCB-2 definitely had activity (0.26nM @ 5HT2A), so even if this compound had a tenfold decrease in potency then it would still be quite active.


----------



## i are spectre

hey what do you guys use to draw these compounds on the computer?

i had some software from biorad who makes all kinds of lab shit for schools and stuff (dehydrated enzymes, blood, all kinds of crap).  it was ok, but academic version kind of sucked.

i know there are a ton of programs out there, but what are some good ones more attuned to say structure drawings and nomenclature?  nothing crazy...


----------



## flaming

i are spectre said:


> hey what do you guys use to draw these compounds on the computer?
> 
> i had some software from biorad who makes all kinds of lab shit for schools and stuff (dehydrated enzymes, blood, all kinds of crap).  it was ok, but academic version kind of sucked.
> 
> i know there are a ton of programs out there, but what are some good ones more attuned to say structure drawings and nomenclature?  nothing crazy...


http://en.wikipedia.org/wiki/Molecule_editor

I use PubChem sketcher, it's an online applet that's super simple and can export in a lot of formats, e.g. PNG, SVG, SMILES, etc. Very useful.


----------



## Cortexiphan

flaming said:


> I was in the process of brainstorming some new various N-benzyl 2C derivatives when I came across this article: http://molpharm.aspetjournals.org/content/70/6/1956.long . Seems like I'm not so original after all... They've already tested N-napthyl, N-benzylmethylenedioxy, just about everything you could think of.


This paper is getting old and I for one don't understand why there hasn't been more research into N-benzyls. The N-benzyl substituent hasn't exactly been explored in great detail (6 variations using 3 different phenethylamine scaffolds). I honestly don't understand why nobody has picked up the ball on this.


----------



## i are spectre

flaming said:


> http://en.wikipedia.org/wiki/Molecule_editor
> 
> I use PubChem sketcher, it's an online applet that's super simple and can export in a lot of formats, e.g. PNG, SVG, SMILES, etc. Very useful.



yeah thanks mate, but im asking what program on that list really, out of curiosity.  an online applet sounds ideal though.  something simple that will just do structures.

the program from bio-rad named the compounds for you though which was sick.  only problem was the academic version didn't get into stereochemistry and only allowed 6 or 8 atoms besides the standard organics C N O H

their site is down now for maintenance, ill try and find the program.  http://www.bio-rad.com


----------



## SNR

Cortexiphan said:


> This paper is getting old and I for one don't understand why there hasn't been more research into N-benzyls. The N-benzyl substituent hasn't exactly been explored in great detail (6 variations using 3 different phenethylamine scaffolds). I honestly don't understand why nobody has picked up the ball on this.



Not sure. It could be that these drugs are insanely potent, and safety concerns? But on the other hand, underground chemists don't usually care about safety..

I did read that the N-benzyl substituents of DOI are not active.


----------



## flaming

Cortexiphan said:


> This paper is getting old and I for one don't understand why there hasn't been more research into N-benzyls. The N-benzyl substituent hasn't exactly been explored in great detail (6 variations using 3 different phenethylamine scaffolds). I honestly don't understand why nobody has picked up the ball on this.


Hahaha, your assertion is so incorrect that it makes me laugh. Clearly you haven't read Michael Braden's 176-page paper entitled "Towards a Biophysical Understanding of Hallucinogenic Action" :D


----------



## SNR

I know the N-benzyl part is drawn ugly, I know I know.
Anyways, removed the iodo from 25I-NBOMe and replaced it with a benzofuran group. Any ideas on activity? Reuptake inhibition? Strong 5-HTx agonism?


----------



## randomer945

I know that amphetamine SAR isn't necessarily applicable to nbomes so I'm not saying it would be some sort of MDA replacement, I’m just curious about its possible activity/effects. I'm guessing the alpha methylated derivative would be of decreased potency with respect to MDA, if active at all?


----------



## cannibalsnail

randomer945 said:


> I know that amphetamine SAR isn't necessarily applicable to nbomes so I'm not saying it would be some sort of MDA replacement, I’m just curious about its possible activity/effects. I'm guessing the alpha methylated derivative would be of decreased potency with respect to MDA, if active at all?



Very likely to be no activity. 2Cs work because the majority of visual effects occur in the left hand part of the molecule. With releaser molecules you block the part of the molecule that is used to access the SERT/DAT.


----------



## pharmakos

randomer945 said:


> I know that amphetamine SAR isn't necessarily applicable to nbomes so I'm not saying it would be some sort of MDA replacement, I’m just curious about its possible activity/effects. I'm guessing the alpha methylated derivative would be of decreased potency with respect to MDA, if active at all?



i bet this would be active at a lower dose than MDA, with MDA like effects... more hallucinogenic than stimulatory/empathogenic though

EDIT -- whoops i meant to say *lower* dose than MDA, not higher


----------



## SNR

How about these things..


Had this in my head all day. I'm thinking that with the N-Benzyl, my (Originally DMT, now NMT) molecule will remain sigma agonistic properties, while being a strong 5-HT2A antagonist. Antidepressant effects?





And if MAO devours that compound, how about an ethyl instead of the methyl?


----------



## flaming

^ You may be interested in this paper, I haven't looked through it completely but it may actually cover these compounds. (in German)


----------



## pharmakos

^^^ thats almost starting to look like a cannabinoid


----------



## negrogesic

This is the perhaps one of the most interesting ongoing thread here, I wish to contribute some of my humble doodles (enpenetrate sodium, etc). However, I need a chemdraw app for this new android device; any suggestions? On my last device, I failed to find an app the worked well, so I ended up using a CAD program designed for engineering.....


----------



## skillet

ktp said:


> maybe u can close the ring



Not like that - hemiaminal --hydrolysis--> 5-MeO-T-NBOH


----------



## skillet

Those are not amine nitrogens though, delocalisation of the lone pairs into the C=N should make the hemiaminal type things more stable.


----------



## SNR

How about leaving the ring open, like in the original compound posted?


----------



## randomer945

Would something like this be active? Not that i would want to try it anyway, the thaught just occured to me. Also any other beta-ketones were the carbonyl group is replaced with a thioketone group. Maybe the compound would be unstable, thioketones dont tend to be the most stable compounds.


----------



## pharmakos

might be the anti-insufflation version of mephedrone, bet its smelly as hell


----------



## negrogesic

Any recommendations for android-device molecule drawing apps?


----------



## basement_shaman

http://www.chemdoodle.com/
click on "Mobile tools" in the menu.

But it's not free


----------



## SerotonergicHaze

The Indole counterpart of MPH 

I call it tryptalin


----------



## Epsilon Alpha

SerotonergicHaze said:


> The Indole counterpart of MPH
> 
> I call it tryptalin


 
Had a combination lol and nerdgasm right there :D


----------



## pharmakos

tryptalin would be the tradename for methyltryptidate, no?  (or methylindolidate perhaps)

instead of that methyl "up top" you could have that oxygen connect to the "4 position" on the phenyl, for obvious reasons IMO 

lol thats a structural analogue of 4-AcO-MPT if i am looking at it right   (with a bit of shuffling of the carbons/bonds)


----------



## Nagelfar

SerotonergicHaze said:


> The Indole counterpart of MPH
> 
> I call it tryptalin



The tryptamine is the wrong way around on the MPH skeleton for there to be activity as a DRI: compare O-2172.

It reminds me of the difference between the morphinan skeleton and the mitragynine skeleton however.


----------



## Nagelfar

Anybody care to use their imagination on one of these from my thread on DRA DAT modulators (I have the upper right, SoRI-20041, in mind the most)...






...on ways of making them into functioning DA releasing agent as well?

An allosteric modulator of DAT of this type that is also a DA releaser may just be an optimized abusable dopaminergic.


----------



## cannibalsnail

Its a shot in the dark but would adding Nitrogen to the ring affect 5HT2A docking that much? If not then you have 2CBCB-Fly.


----------



## Astavats

cannibalsnail said:


> http://i.imgur.com/3n7q2.png



Nitrogen cannot have five bonds because it cannot have an expanded octet. Phosphorus may though the phosphabenzene analogue of what you have drawn would most likely be very contorted/skewed whereas a fairly planar parent is believed to be preferred by the 5HT2A receptor for agonism. I'd recommend reading introductory general and organic chemistry texts.


----------



## /navarone/

A modified version of bupropion with probably more activity on serotonin and a metabolite resembring phenmetrazine:





what do you think


----------



## cannibalsnail

It only has 4 bonds...


----------



## Sturnam

cannibalsnail said:


> It only has 4 bonds...



Double bonds count as 2.


----------



## cannibalsnail

My bad, forgot about the saturation in the ring.


----------



## Transform

navarone:

I can't tell you much about SAR, but:

That's more of what I'd call a distant ethcathinone analogue - flourine is more like hydrogen than methyl.

Also, you can be pretty damn sure it won't metabolise like that without some funny business going on.


----------



## nuke

ktp said:


> maybe instead of this N, put an O inside the ring: (with the only argument that many substitutions on 3 and 4 start with O anyway)
> 
> 
> 
> 
> 
> 
> the ring is not completely flat, but looks closer to benzene than MPA's tiophene-ring:


 
I have wondered about the pyrone analogues of amphetamine myself (as they are planar). I know a couple of routes that would probably work, but they're not terribly cheap and of course I can not discuss them here. Pyrones are fairly stable, certainly enough so to last long enough in the body to be active. I should double check scifinder and see which of these have been made.


----------



## Nagelfar

nuke said:


> I have wondered about the pyrone analogues of amphetamine myself (as they are planar).



Is the term "planar" in chemistry here one the same with that of geometry? This thought comes to mind as ktp says its not completely "flat", and my having seen dopamine as "flat ringed" in comparison to n-methyl amphetamine. Might this answer the question I have for DA releaser + DA agonist relative to SE releaser/agonists such as ecstasy? I would assume the two hydroxys would interfere but they seem not to be included with other such DA agonists.


----------



## Nagelfar

I took the phenyltropane idea to dimethocaine. It appears to be a very simplified DRI with no reason why it shouldn't work. Has this molecule ever been made? It is much like a cross between this and this. (If information is unavailable on my above posted image, does anybody have information for either chemical at either of those links?)


----------



## dip12

^anyone know of any drug compounds with a pyran ring?

Reckon this could be interesting:






Thieno-midazolam! Water soluble maybe?


----------



## Enix150

^ Looks to be a little less soluble than midazolam itself (ClogP: 3.66 vs. 3.42 so it should still be water soluble), but that centre nitrogen has too many bonds! Taking a second look I realized that you just rotated those double bonds in the imidazole ring.


----------



## SNR

How's this? Might this be a cannabinoid or have 5-HTergic activity? 

Really random "in the margin of my anatomy and physiology class notes" type drawing.


----------



## /navarone/

The sulphur is in the opposite side of the 'ring'.
Thienodiazepinez are good enoguh as they are at the moment. they have opened a new world to GABA subunit affinity thogh they differ from one another because of their half life.
Etizolam dissapointed me a lot, brotizolam on the oher hand is an amazing drug, still it has a quite short half-life (still i think it would get hydroxylated on te diazepine ring just as diazepam does giving a still active metabilite.


----------



## /navarone/

How about this amphetamine analogue.
In £D it looks slightly non-planar compared to conventional amphetamines but considerinf the reputation of beta methoxy amphetamines (eg: phenmetrazine) and some of the reported apreciations of 2' substituted amphetamines. I thought this was a good analogue. I called it Furanamine.




What do you think?


----------



## Transform

Something else to note about S replacing O - it can be a non-reversible enzyme substrate which can be really dangerous.


----------



## Nagelfar

/navarone/ said:


> ...In £D it looks slightly...
> 
> Location: Under your bed, masturbating...



There I caught you, navarone. My bed is no where near the British Isles.


----------



## cannibalsnail

With the recently demonstrated psychoactivity of 5-API (http://en.wikipedia.org/wiki/5-(2-Aminopropyl)indole) and the success of the 5/6-APB chemicals, perhaps a hybrid will produce a viable entactogen?

The compounds on the right are a theory, will the double bonds saturating the nitrogen molecule improve or worsen activity?


----------



## /navarone/

LOL! Your bed is on the other side of the atlantic compared to mine....I'm in hte middle of the mediterrean sea. My location joke was just a spookish was to fool around.
Anyway what do you thing of my Furanamine (BTW i meant 3D by £D, lil typo)


----------



## dip12

Enix150 said:


> ^ Looks to be a little less soluble than midazolam itself (ClogP: 3.66 vs. 3.42 so it should still be water soluble), but that centre nitrogen has too many bonds! Taking a second look I realized that you just rotated those double bonds in the imidazole ring.



Midazolam is unique in that the imidazole ring can open in solution (creating a highly soluble temporary form) but closes at physiological pH (7.4). Thus also demonstrating high lipid solubility (fast onset past BBB). Don't think this effect would be represented in the ClogP value. An effect very unique to midazolam.

Good point centre Nitrogen is incorrect - double bond is part of imidazole ring.


----------



## SNR

/navarone/ said:


> How about this amphetamine analogue.
> In £D it looks slightly non-planar compared to conventional amphetamines but considerinf the reputation of beta methoxy amphetamines (eg: phenmetrazine) and some of the reported apreciations of 2' substituted amphetamines. I thought this was a good analogue. I called it Furanamine.
> 
> 
> 
> 
> What do you think?



That's really interesting looking!


----------



## atara

I think acetylindolin-5-yl-propan-2-amine would be kind of interesting. Too lazy to draw. Also N-(N,N-diethylpropanamid-3-yl)-N-methyl-2-(indol-3-yl)-ethanamine.



dip12 said:


> ^anyone know of any drug compounds with a pyran ring?[/IMG]



THC comes to mind.


----------



## polymath

Pyran ring is a six-membered heterocycle with two double bonds and an oxygen atom. There's no pyran in THC.


----------



## Nagelfar

/navarone/ said:


> (BTW i meant 3D by £D, lil typo)



Yes I know. ;-j

I think any attempt to get something along the lines of Phenmetrazine is admirable. It'd be great to get some information about what it would do.


----------



## /navarone/

Yep, also considering that some 2' substituted amphetamines (eg:2-FA) where ery appreciated bu many users.... beta methoxys are hard to synth and the obly one famous so far is phenmetrazine.
My only doubt on the substance it's compformation. It would be a bendodehydrofuran molecule with and ethanamine sticking sideways....so somehow far from the classic planar structure of ordinary phenyethylamines.
But who knows..this drug could become the drug of the year especially with some wacky substitution on the 4th carbon like fluorine a la 4-FA.


----------



## hx_

This one looks very interesting but could be quite hard to handle and crystallise.


----------



## Nagelfar

hx_ said:


> This one looks very interesting but could be quite hard to handle and crystallise.



Aesthetically I really like it. The two acetyl groups call to mind cocaine, to me the other three oxygens appear functionally odd however, the rest beside looking much like the amphetamine/dopamine type skeleton. What about it personally looks interesting to you? Did you base it off of a combination of any other specific compounds?


----------



## Pomzazed

^
Eh? Thats just a triglyceride...
fat anyone?


----------



## Nagelfar

Pomzazed said:


> ^
> Eh? Thats just a triglyceride...
> fat anyone?



Of a rather stimulant shadow casting form. However that is not to claim anything of its potential outside of cargo cult molecular biology. The only type of which I have any schooling in.


----------



## dip12

thioPV


----------



## hx_

Nagelfar said:


> Aesthetically I really like it. The two acetyl groups call to mind cocaine, to me the other three oxygens appear functionally odd however, the rest beside looking much like the amphetamine/dopamine type skeleton. What about it personally looks interesting to you? Did you base it off of a combination of any other specific compounds?



Haha no, it's olive oil ripped straight from wikipedia, was wondering how many people would think it to be a drug!


----------



## hx_

Nagelfar said:


> Aesthetically I really like it. The two acetyl groups call to mind cocaine, to me the other three oxygens appear functionally odd however, the rest beside looking much like the amphetamine/dopamine type skeleton. What about it personally looks interesting to you? Did you base it off of a combination of any other specific compounds?



Haha no, it's olive oil ripped straight from wikipedia, was wondering how many people would think it to be a drug!

What about this deliriant/depresant?


----------



## cannibalsnail

hx_ said:


> Haha no, it's olive oil ripped straight from wikipedia, was wondering how many people would think it to be a drug!
> 
> What about this deliriant/depresant?


 
3-Quinuclidinyl benzilate. :D


----------



## hx_

cannibalsnail said:


> 3-Quinuclidinyl benzilate. :D



Yeah it'll get you "well fucked up"


----------



## Vader

> Aesthetically I really like it. The two acetyl groups call to mind cocaine, to me the other three oxygens appear functionally odd however, the rest beside looking much like the amphetamine/dopamine type skeleton. What about it personally looks interesting to you? Did you base it off of a combination of any other specific compounds?





> Of a rather stimulant shadow casting form. However that is not to claim anything of its potential outside of cargo cult molecular biology. The only type of which I have any schooling in.


Hook, line and sinker :D

hx_, if you're interested, that's not specifically olive oil, it's the basic backbone of all edible fats and oils, those "R"s are placeholders, indicating that different hydrocarbon chains can be in those positions. Olive oil isn't a pure chemical, it's a mixture of different chemicals with the basic structure you've shown, plus various other tasty/colorific compounds. Of course, you probably don't give the slightest fuck, but just wanted to troll the thread, in which case, job well done.


----------



## dip12

Inspired by MMDA, desoxy, 6-APB, MMDA-2 equivalent & PEA (equivalent to desoxy) possible...

http://en.wikipedia.org/wiki/MMDA_(psychedelic)


----------



## hx_

Vader said:


> Hook, line and sinker :D
> 
> hx_, if you're interested, that's not specifically olive oil, it's the basic backbone of all edible fats and oils, those "R"s are placeholders, indicating that different hydrocarbon chains can be in those positions. Olive oil isn't a pure chemical, it's a mixture of different chemicals with the basic structure you've shown, plus various other tasty/colorific compounds. Of course, you probably don't give the slightest fuck, but just wanted to troll the thread, in which case, job well done.



Yeah I thought it wasn't likely to be the one chemical, almost all organic and natural things are complex compounds n admixtures. Didn't know about the placeholder thing, you learn something new every (or most) days. Regardless it doesn't look like a very "rigid" molecule so I assumed it wouldn't be able to bind to any significant receptors.


----------



## Nagelfar

hx_ said:


> Haha no, it's olive oil ripped straight from wikipedia, was wondering how many people would think it to be a drug!



I assumed with the R¹, R² & R³ substitutions that it was a definite postulation. I knew it couldn't be anything "specific" (as already stated, it's a lipid back bone)

It does look like it has some phenethylamine backbone (minus the oxygens etc.) So that was a good one to select.

Good show, hah.


----------



## SerotonergicHaze

Since I seem to have a fetish for the MPH molocule






the C=O looks a bit out of place, so perhaps drop that? stim me thinks





opiod?





strange thing 





canabiniod?


----------



## SNR

^^ I doubt any of the structures you made will have the effects you think. The "strange thing" molecule doesn't have any phenyl rings, and I'm pretty sure that the second phenyl ring is important for DAT binding (Someone correct me if I'm wrong). 

However, I'm definitely not saying they are completely inactive. Your "opioid" structure looks like it could have antagonistic action at NMDA receptors if you had a nitrogen coming from the cyclohexylamine ring. 

~snr


----------



## dip12

Thiosilocin


----------



## SNR

Not sure how that would work, but the fact that theres no indole backbone makes me think it wouldn't work.


----------



## Astavats

dip12 said:


> Thiosilocin



The closest analogue I could find removed the hydroxyl, added a 1-phenylsulfonyl group and mentioned 5-HT6 receptor activity (see the patent plain text or w/images). However, sifting through drugs that  work at this site it seems removing the phenylsulfonyl group might reduce or abolish such activity. As for 5-HT2A it might work though I personally wouldn't count on it.


----------



## randomer945

How about something like this. A bit strange looking i know, but i was reading an old post by fastandbulbous ( http://www.bluelight.ru/vb/threads/167978-Acid-dragonflies-and-the-5HT2A-receptor ) about how having an electronegative substituent on the beta position increases activity. So the molecules has electronegative substituents at the 2 and 5 positions similar to the 2c's. There is then also the electronegative substituent at the beta position, and all the substituents are members of a ring to keep the molecule more planar ( i know the dioxane ring isn't perfect but its an improvement on having the substituents free to rotate). Also the molecule could have a halo, alkyl thioalkyl ect substituent at the 4 position. Any feedback? My pharmacology knowledge is very limited as you can probably tell!


----------



## dip12

THIODAFINIL (thiophene analogue of modafinil)..........






.........because the smell of asparagus just isn't strong enough!


----------



## pharmakos

dip12 said:


> Inspired by MMDA, desoxy, 6-APB, MMDA-2 equivalent & PEA (equivalent to desoxy) possible...
> 
> http://en.wikipedia.org/wiki/MMDA_(psychedelic)


 
3C-E with the 4-ethyl wrapped around to one of the meta oxygens, no?


----------



## dip12

thenightwatch said:


> 3C-E with the 4-ethyl wrapped around to one of the meta oxygens, no?


 
your forgetting the methyl from the methoxy group,  still similar I agree.


----------



## dip12

http://en.wikipedia.org/wiki/Ivabradine

The above image is Ivabadrine, heart medication but it certainly has one interesting structure. In particular the TCB-2 style (substructure) conformationaly-constrained PEA. 

Makes me think does the unsubstituted conformationally constrained (as in TCB-2 style) version of PEA / Amphetamine exist?






Not sure if the PEA or Amphetamine would work better? Amphetamine alpha-methyl looks like it might change orientation.


----------



## skillet

Well you could call it DESOXY (3C-E has a methoxy at the 4-position btw) with the 4-methyl cyclised onto the 3-methoxy. I can see that actually working, Nichols made fly analogs of mescaline (with the 3-methoxy cyclised to the 2-position and the 5-methoxy cyclised to the 6-position and they weren't very good IIRC, this might be better.


----------



## pharmakos

it is closer to DESOXY than it is to 3C-E, my bad =p


----------



## dip12

skillet said:


> Well you could call it DESOXY* (3C-E has a methoxy at the 4-position btw) *with the 4-methyl cyclised onto the 3-methoxy. I can see that actually working, Nichols made fly analogs of mescaline (with the 3-methoxy cyclised to the 2-position and the 5-methoxy cyclised to the 6-position and they weren't very good IIRC, this might be better.


 
3C-E has an ETHOXY at the 4 position 






http://www.erowid.org/library/books_online/pihkal/pihkal025.shtml


----------



## skillet

dip, oh yeah, derp


----------



## dip12

*cyclobutane rings to the left*

switching the cyclobutane to the left you get a DMMC analogue (top) and an compound somewhat similar to IAP (maybe with more stimulant effects due to decreased size?)


----------



## Enix150

^ Oh man that bottom one would have been a much better idea than MDPV.. too bad it'd be scheduled as an analog over here now.


----------



## pharmakos

when mephedrone got banned, everyone started adding carbons to the mephedrone molecule in an attempt to make a viable legal alternative.... afaik most of them pale in comparison to mephedrone....

instead of adding atoms though, they should have taken atoms away... mephedrone without the beta-keto would be uncontrolled, and looks a hell of a lot tastier as a stimulant....   riskier legally perhaps.


----------



## dip12

doppelgänger said:


> Any guesses what this might be like?



(from top to bottom) 
1st:  Probably active, if you take away the methylenedioxy it is a documented stimulant I believe - cant remember the name, it was on wiki, predict a DRI?
2nd: Not sure, ritalinic acid (similar isn't active although more polar), maybe weak, ultimately don't know
3rd: fairly sure that will have be made and active



> Instead of adding atoms though, they should have taken atoms away... mephedrone without the beta-keto would be uncontrolled, and looks a hell of a lot tastier as a stimulant.... riskier legally perhaps.



Well it's automatically illegal (more so in some respects as the PEA catch'all predates cathinone catch'all) in the UK. The UK was one of the biggest markets so it's no surprise the PEA wasn't looked at. ALSO highly likely such compounds were made at some point clandestinely, it's possible it was no good.


----------



## Alcyone

thenightwatch said:


> instead of adding atoms though, they should have taken atoms away... mephedrone without the beta-keto would be uncontrolled, and looks a hell of a lot tastier as a stimulant....   riskier legally perhaps.


Riskier in every respect, if you ask me. Mephedrone without the beta-keto would be 4-methylmethamphetamine; one of the nastiest stimulants ever made, according to some. It circulated in Russia and Ukraine a couple of years ago. Never touched it myself, but I've heard plenty of horror stories.

The second structure proposed by doppelgänger is 2-(3,4-methylenedioxybenzoyl)piperidine. It's new to me, but the straight 2-benzoylpiperidine was mentioned by f&b in one of the stims of the future threads. I don't believe it was ever assayed. 2-_Benzyl_piperidine, lacking the keto function, is listed by Wiki as a weak SNRI with little recreational potential. I wouldn't have high hopes for the proposed compound.

The third is methylenedioxypyrrolidinepropiophenone (MDPPP). It's already hit the RC scene. It's claimed to be a decent stimulant, comparable to MDPV albeit less potent, active in the ~50 mg range.
EDIT: I'm being silly. Of course it's not MDPPP, there's no beta-keto. A prolintane analogue, not sure if this one's been made.


----------



## Vader

4-methylmethamphetamine is class A in the UK, which was presumably the primary intended market for the meph replacements.


----------



## Enix150

If cathinones weren't covered by the PEA ban or the amphetamine ban, then would a beta-methoxy amphetamines or even a beta-methoxy phenethylamines like BOD be covered?


----------



## Transform

Also, not having the beta-keto makes them more prone to neuronal uptake, where those para substituents wreak havoc. para-methylamphetamine is quite neurotoxic, if I recall.


----------



## Enix150

dip12 said:


> 1st:  Probably active, if you take away the methylenedioxy it is a documented stimulant I believe - cant remember the name, it was on wiki, predict a DRI?







Benzphetamine looks pretty similar.. but not exact. Is that the one you were thinking of?


----------



## pharmakos

Alcyone said:


> 4-methylmethamphetamine



well i wasn't gonna say it out loud =p


----------



## dip12

Enix150 said:


> Benzphetamine looks pretty similar.. but not exact. Is that the one you were thinking of?








*phenylmethamphetamine*
http://en.wikipedia.org/wiki/Beta-Phenylmethamphetamine


----------



## Alcyone

Transform said:


> Also, not having the beta-keto makes them more prone to neuronal uptake, where those para substituents wreak havoc. para-methylamphetamine is quite neurotoxic, if I recall.


Indeed it is. I'm not sure whether 4-methylmethamphetamine (4-MMA) has ever been properly studied in animals or humans. Its non-N-methylated counterpart 4-methylamphetamine (4-MA) has been claimed to be a near-perfect MDMA subsititute in terms of receptor binding profile and monoamine releasing activity, and in theory, the higher lipophilicity of 4-MMA should make it even better. Ironically, it also appears to be a near-perfect neurotoxin, capable of bitch-slapping serotonergic neurons in a fashion comparable to 4-chloro- and 4-bromoamphetamines, while at the same time royally pissing off dopaminergic neurons by forming a reactive 4-carboxy metabolite in-vivo. Additionally, there is the issue of cardiotoxicity mediated by 5-HT2b agonism, as suggested in early research papers, which fortunately led to the quick demise of 4-MA and xylopropamine as appetite suppressants.

4-Methylamphetamine and 4-methylmethamphetamine were all over Moscow for a brief period in 2007. I lived there at the time (well, stayed there is a better term) and I met with a lot of people who used these drugs recreationally. Not tweakers or junkies, but students and scholars, mostly bright people who didn't mind a bit of a party. A frightening proportion of these people quickly developed serious psychiatric disorders. We're not talking tuesday blues, but anything from severe and persistent depression to catatonic states and parkinson-like dyskinesia. The majority eventually recovered, but more times than I care to count, I've heard people say that 4-MA/4-MMA turned them into a different person, that they were never really the same afterwards. The less lucky ones remain permanent inhabitants of psych wards to this day. I never touched this shit myself, thank fuck, not that I'm such a prude but because I was trying for a baby at the time.

I'm not completely sure whether 4-MA or 4-MMA (or perhaps both) was the main culprit, as there was no way of knowing what people were getting. There were two distinct designer amphetamines making the rounds; both were subjectively very similar to MDMA, but one was about half the potency and twice the duration of the other. Contrary to what one might expect, I'm fairly certain that the less potent one was the N-methylated compound, but I'm not absolutely positive. It was mostly this one which fucked peoples lives.

4-Methylmethamphetamine is a very, very nasty substance. I would urge everyone to stay well clear of ring-substituted amphetamines in general, and 4-methylated ones in particular. Even the fluoroamphetamines scare the crap out of me.


----------



## hjalmar

Hi all, recently I was reading up on melatonin receptor agonists and noticed that a common MT1&2 agonist, agomelatine, is essentially melatonin with a naphtyl ring instead of indole.

Now the obvious question occured to me, if anything is known about the activity of the naphtyl analogs of the common psychedelic simple tryptamines?


----------



## dip12

hjalmar said:


> Hi all, recently I was reading up on melatonin receptor agonists and noticed that a common MT1&2 agonist, agomelatine, is essentially melatonin with a naphtyl ring instead of indole.
> 
> Now the obvious question occured to me, if anything is known about the activity of the naphtyl analogs of the common psychedelic simple tryptamines?



Agomelatine has the alkylamino chain one higher - although both variations might be active.






Agometatine is a 5ht2c antagonist so could be logical to epect similar effects in related compound maybe.


----------



## Nagelfar

Good God! Is this thread actually finally becoming serious?



dip12 said:


> *phenylmethamphetamine*
> http://en.wikipedia.org/wiki/Beta-Phenylmethamphetamine



Would this function as a DRI rather than a DRA? That would be my guess.


----------



## Alcyone

^ That would be my guess as well. It's essentially just a ring-opened homologue of desoxypipradrol and 2-(diphenylmethyl)pyrrolidine, which have been shown to act as NDRIs (and highly potent ones at that).


----------



## SNR

Well now that this thread is getting serious, here's something silly. 

A constrained (?) methamphetamine analogue. Or 2,5-dimethoxymethamphetamine. I went all out with this lil diagram lol


----------



## Pomzazed




----------



## dip12

ktp said:


> ritalin-meph-hybrids:



Not necessarily the 4-methyl BUT would be interested to see if the structurally simplified version of methylphenidate (like the bottom chemical) would still hold true as a dopamine reuptake inhibitor(maybe by even using alpha-ethyl). Reminiscent of tramadol to tapentadol simplification.


----------



## QuasiModo

*Dreamt up this molecule, can anyone tell me if it sounds promising? 5-methyl-MDE*

or 5-methyl-3,4-Methylenedioxy-N-ethylamphetamine

Basically the same reasoning behind 5-methyl-MDA with n-ethylamphetamine rather than n-methylamphetamine. Are there any obvious flaws in my reasoning? 5-me-MDA was around 5x more potent than MDA if IIRC read that on wikipedia.. Wondering if it would fall victim to steric hindrance?


----------



## nuke

merging with the random molecules thread


----------



## QuasiModo

Cool thanks  didn't notice dat


----------



## polymath

I found this structure in this article: http://murphylibrary.uwlax.edu/digital/jur/2001/prescher.pdf

The molecule is hypothesized to bind selectively to 5-HT2A without having 5-HT2C affinity. I'm not sure if this has been discussed here before.


----------



## dip12

Not necessarily 'fun' compound but would be intersted to see what a 4-methylmethcathinone - bupropion hybrid would result in (more for curiosity) - aside from possible lowering of seizure threshold






Might increase monoamine releasing properties


----------



## QuasiModo

What are you guys using to draw these?


----------



## irobeth

QuasiModo said:


> What are you guys using to draw these?


 
http://metamolecular.com/chemwriter/

is my personal favorite, quick and nothing to install


----------



## atrollappears

How about these guys? Apparently electronegative beta substituents are well tolerated. They've been synthesized (a quick google of beta-fluoroamphetamine will tell you that) but not tested as far as I can tell.


----------



## pharmakos

could the metabolites potentially be more dangerous than other flourinated amphetamine analogues, due to the flourines being attached to the alkyl group?


----------



## sekio

Fluorine-carbon bonds are relatively stable unless you start incinerating the compounds in question.


----------



## atrollappears

Found a study on the difluoro variant in rats. Acted as a stimulant, half-life a little over a third that of amphetamine, higher dosage.
http://www.sciencedirect.com/science/article/pii/0006295272902912

Edit: Found a citation for "Tissue distribution and metabolism of amphetamine, β-fluoro-amphetamine and β, β-difluoro-amphetamine in the rat" by RW Fuller et al. in the Pharmacologist, 1971. The article is nowhere to be found on the web.

What about alpha fluoro? Probably wouldn't ionize at all at physiological pH, would it?


----------



## nuke

er, don't know. Fluoroalkenes are very dangerous, fluoroalkanes and aryl are not very dangerous... Benzyl fluorides might be somewhere in between due to resonance of the ring? It's probably ring substituent dependent, too.


----------



## atrollappears

nuke said:


> er, don't know. Fluoroalkenes are very dangerous, fluoroalkanes and aryl are not very dangerous... Benzyl fluorides might be somewhere in between due to resonance of the ring? It's probably ring substituent dependent, too.



Mmm I don't see why a benzyl fluoride would be more dangerous than a fluoroalkane or a fluorobenzene.
Just speculation though, hard to predict this stuff 

Gah, if only I still had access to webMO.


----------



## Roger&Me

atrollappears said:


> Mmm I don't see why a benzyl fluoride would be more dangerous than a fluoroalkane or a fluorobenzene.



You get a resonance stabilized cation that could alkylate DNA. I'm not sure to what degree this happens, though, as fluorine is a terrible leaving group.


----------



## atrollappears

Roger&Me said:


> You get a resonance stabilized cation that could alkylate DNA. I'm not sure to what degree this happens, though, as fluorine is a terrible leaving group.



Uh oh. Ok, I'll keep my fluorines to the ring.

How about some aMT analogues?






From left to right, top down: 6-fluoro-aMT, 7-fluoro-aMT, 6-methyl-aMT, 7-methyl-aMT, and my personal favorite, bk-aMT


----------



## Vader

Not sure how stable that ketone will be, cathinones with a primary amine group quickly degrade to the beta-alcohols, have a feeling that one would behave similarly. Those fluorinated aMT's were the kind of thing that Gordon Skinner and Leonard Pickard were developing, 6-fluoro-aMT is described here as being "a beast".


----------



## ebola?

Is there anything suggesting anything about how ring halogenation (or even small alkyl substitutions) affects tryptamines; do we have any bases to speculate about SAR?

ebola


----------



## atrollappears

Vader said:


> Not sure how stable that ketone will be, cathinones with a primary amine group quickly degrade to the beta-alcohols, have a feeling that one would behave similarly. Those fluorinated aMT's were the kind of thing that Gordon Skinner and Leonard Pickard were developing, 6-fluoro-aMT is described here as being "a beast".



Cool shit! I was trying to preserve the entactogen action though with these substitutions, note that they aren't jutting off at awkward angles so it can fit through the transporter easily 
Yes, the beta-keto will likely not be too stable, but cathinone manages to last for long enough for someone to extract/synthesize it and ingest it xD



ebola? said:


> Is there anything suggesting anything about how ring halogenation (or even small alkyl substitutions) affects tryptamines; do we have any bases to speculate about SAR?
> 
> ebola



The other ring-halogenated aMTs (from what wikipedia says) are more psychedelic, and 5-fluoro is an MAOI.


----------



## Vader

> cathinone manages to last for long enough for someone to extract/synthesize it and ingest it xD


Does this actually happen? Khat has a shelf life of a few days, do people really use synthetic cathinone? It seems like a lot of hassle for a drug that can't be all that great.


> Is there anything suggesting anything about how ring halogenation (or even small alkyl substitutions) affects tryptamines; do we have any bases to speculate about SAR?


lmgtfy 


> A series of fluorinated analogues of the hallucinogenic tryptamines N,N-diethyltryptamine (DET), 4-hydroxy-N,N-dimethyltryptamine (4-OH-DMT, psilocin), and 5-methoxy-DMT was synthesized to investigate possible explanations for the inactivity of 6-fluoro-DET as a hallucinogen and to determine the effects of fluorination on the molecular recognition and activation of these compounds at serotonin receptor subtypes. The target compounds were evaluated using in vivo behavioral assays for hallucinogen-like and 5-HT1A agonist activity and in vitro radioligand competition assays for their affinity at 5-HT2A, 5-HT2C, and 5-HT1A receptor sites. Functional activity at the 5-HT2A receptor was determined for all compounds. In addition, for some compounds functional activity was determined at the 5-HT1A receptor. Hallucinogen-like activity, evaluated in the two-lever drug discrimination paradigm using LSD-trained rats, was attenuated or abolished for all of the fluorinated analogues. One of the tryptamines, 4-fluoro-5-methoxy-DMT (6), displayed high 5-HT1A agonist activity, with potency greater than that of the 5-HT1A agonist 8-OH-DPAT. The ED50 of 6 in the two-lever drug discrimination paradigm using rats trained to discriminate the 5-HT1A agonist LY293284 was 0.17 μmol/kg, and the Ki at [3H]8-OH-DPAT-labeled 5-HT1A receptors was 0.23 nM. The results indicate that fluorination of hallucinogenic tryptamines generally has little effect on 5-HT2A/2C receptor affinity or intrinsic activity. Affinity at the 5-HT1A receptor was reduced, however, in all but one example, and all of the compounds tested were full agonists but with reduced functional potency at this serotonin receptor subtype. The one notable exception was 4-fluoro-5-methoxy-DMT (6), which had markedly enhanced 5-HT1A receptor affinity and functional potency. Although it is generally considered that hallucinogenic activity results from 5-HT2A receptor activation, the present results suggest a possible role for involvement of the 5-HT1A receptor with tryptamines.


http://pubs.acs.org/doi/abs/10.1021/jm000339w
Looks like you could be on to something with that 6-fluoro-aMT, if that fluoro group knocks out any psychedelic activity but doesn't affect monoamine release then it seems like an analogy could be drawn with N-methylation of MDA, you might be left with a very nice entactogen.


----------



## atrollappears

Vader said:


> Does this actually happen? Khat has a shelf life of a few days, do people really use synthetic cathinone? It seems like a lot of hassle for a drug that can't be all that great.



Maybe not worth synthesizing, but perhaps worth extracting 
http://www.erowid.org/experiences/exp.php?ID=58757


----------



## Vader

I was under the impression that hagitat was the name under which mephedrone (or some blend of substituted cathinones or somesuch) was sold in Israel, rather than cathinone itself. The media reports are rather confused (unsurprisingly), but I don't think that those capsules contained cathinone itself, especially given that it's controlled under the Convention on Psychotropic Substances.


----------



## mad_scientist

6-fluoro-AMT is reportedly active and has been rarely sold as an RC, though I've never seen a trip report. 7-methyl-AMT is a known compound but I'm not aware of anyone trying it.


----------



## atrollappears

Vader said:


> I was under the impression that hagitat was the name under which mephedrone (or some blend of substituted cathinones or somesuch) was sold in Israel, rather than cathinone itself. The media reports are rather confused (unsurprisingly), but I don't think that those capsules contained cathinone itself, especially given that it's controlled under the Convention on Psychotropic Substances.



Oh well you seem to know more about this than me. But in any case, I'm pretty sure that non-methyl cathinones can be synthesized or extracted and used before they degrade too much. There are articles in which methylenedioxycathinone is studied, as well as syntheses/extractions described for cathinone itself.

Also, would N-methylation abolish the releasing activity of aMT?


----------



## EncryptiC

Mescofen 






...the mescaline - baclofen cross.


----------



## Mr Smokes Blunts.

Vader said:


> I was under the impression that hagitat was the name under which mephedrone (or some blend of substituted cathinones or somesuch) was sold in Israel, rather than cathinone itself. The media reports are rather confused (unsurprisingly), but I don't think that those capsules contained cathinone itself, especially given that it's controlled under the Convention on Psychotropic Substances.


 
The Designer Drugs episode of "Drugs Inc" led me to believe hagitat was originally cathinone, then that got banned, and there were several different tweaks made before they landed on mephedrone? Whether they are right or wrong I have no idea!


----------



## Alcyone

Vader said:


> I was under the impression that hagitat was the name under which mephedrone (or some blend of substituted cathinones or somesuch) was sold in Israel, rather than cathinone itself. The media reports are rather confused (unsurprisingly), but I don't think that those capsules contained cathinone itself, especially given that it's controlled under the Convention on Psychotropic Substances.


Oh, well... Isolating cathinone is a bitch due to the dimerisation issue, but the original hagigat (not hagitat btw.) was in fact cathinone HCl. Shortly after, there was rakefet, which was N,N-dimethylcathinone. I know because I was somehow (and kinda unknowingly) involved in the hagigat/rakefet business.

Then came the 2006 ban, followed by the (somehow logical) appearance of mephedrone. By the time meph was banned in Israel in 2008, it was hitting the global RC scene big time. These days, anything sold as hagigat in Israel could very well be meph or one of the fluoromethcathinones (or pretty much anything else; I don't really know because I've lost track).


----------



## SNR

EncryptiC said:


> Mescofen
> 
> 
> 
> 
> 
> 
> ...the mescaline - baclofen cross.




Mescofen 

Very clever...


----------



## sekio

Beta carboxymethyl would make it too polar to be active at 5-ht2a I bet


----------



## SerotonergicHaze

A real energy drink :D


----------



## Burn it up

Unfortunately nucleoside triphosphates have no effect when administered exogenously... You have to wait till the body does it's thing 

http://www.ncbi.nlm.nih.gov/pubmed/15179168


----------



## Pomzazed

*POOF*


----------



## Alcyone

@SerotonergicHaze, I think it's pretty cool. "Theophyllosine triphosphate"? 

I wonder if it would be active in any way? I guess it would be pretty much inactive if taken orally, judging from how fast oral ATP is chopped to pieces by various gastrointestinal enzymes. I don't think theophylline or caffeine would be formed as metabolites, but perhaps 7-hydroxytheophylline (don't know whether that one is active).

With its similarity to ATP/GTP, I bet it would have some kind of activity if administered by the IV route. IV ATP is active and does have some clinical applications, e.g. in pain management. But this beast could be anything from a competitive adenosine receptor antagonist to a really nasty enzyme inhibitor. Fortunately, it's entirely hypothetical anyway.


----------



## SerotonergicHaze

Was playing in chemsketch




Above:
Based on my vague memory of what SSRIs are meant to look like. I could postulate arbitrarily would be most likely a 5-HT and NE reuptake inhibitor, possibly with some sigma agonistic activity

Below: Speaks for it self really


----------



## SNR

The top one almost looks like methylphenidate.


----------



## pharmakos

SerotonergicHaze said:


>



i don't think that much bulk on the phenyl ring will work out... (that is, guessing that you're trying to make something like a dissociative)  who knows though.


----------



## SerotonergicHaze

Yeah, I was hoping for a long lasting NMDA antagonist, perhaps one to utilize the other propitiates drugs like ketamine have such as low dose antidepressant effects. The N-iPR group would likely get cleaved off, and your left with this bulk chain, increasing lipophlicity. The fact it has a phenylethylamine backbone may make it more active at the NE sites, but I think it's lack of alpha substitution would mean it gets killed by MAO-A

I really need to put more thought into these, It's basically just drawing pretty pictures at the moment rather than drug design


----------



## pharmakos

also, i believe you have an extra carbon atom between your rings in that molecule.

have you seen this thread? http://www.bluelight.ru/vb/threads/504286-PCP-analogs-(Cumulative)


----------



## sekio

While we are on the topic of novel dissociatives & chemical masturbation, why have I not heard more on the potent NMDA-blocker etoxadrol & derivatives?


----------



## Raihiar

i can't seem to get it to work, but could someone draw "MD-MPA" (methylendioxy-methiopropamine)
this just keeps popping into my mind

could anyone see this working?


----------



## sekio

I don't expect it to be very stable. Or fun.

There were, however, DMT analogues that look scarily like this in a recent Nichols paper.


----------



## toastmann

I have no idea what I am doing.




Anyone have some good source (website/(e)Book) where I can learn what different groups and parts do ? I have some basic chemistry knowledge but zero drug-related.


----------



## sekio

> Anyone have some good source (website/(e)Book) where I can learn what different groups and parts do ?



It's called "structure activity relationships", and many chemists spend their whole lives trying to figure it out. Start by reading PihKAL and TiHKAL by Sasha Shulgin, then read a bunch of David Nichols' papers too while you're at it.


----------



## toastmann

I started reading PiHKAL some weeks ago, primarily just the chems. TiHKAL is waiting here too


----------



## glenjih

I literally just downloaded chemsketch, and henceforth I will be ruining this nice thread with my amateurish rubbish. I present:






aaaand...






You may begin swearing at me in anger now.


----------



## Vader

Well, for a start, you've got one too many carbons on the sidechain of the first one.


----------



## glenjih

How so? (That's a genuine question, not me being an asshole). Should it look like this instead?






I lifted most of the structure from bk-MDMA


----------



## Enix150

^Phen*ethyl*amines only have two carbons before the nitrogen. It's not that you were _wrong_ per se, it's just that when you're trying out several novel substitutions at once, it can get a lil confusing. 



polymath said:


> atara said:
> 
> 
> 
> 
> 
> dip12 said:
> 
> 
> 
> ^anyone know of any drug compounds with a pyran ring?
> 
> 
> 
> THC comes to mind.
> 
> Click to expand...
> 
> Pyran ring is a six-membered heterocycle with two double bonds and an oxygen atom. There's no pyran in THC.
Click to expand...

There is in CBN though.



atrollappears said:


> How about some aMT analogues?


Haha I smiled when I saw your bk-version, you definitely inspired *pyr-αMT*! Wish I could say more about it...


----------



## Transform

Enix150 said:


> Haha I smiled when I saw your bk-version, you definitely inspired *pyr-αMT*! Wish I could say more about it...



That's an interesting one. I expect it would be active.

Glenjih - your second one, based on the fact the n-methylated version is ok, would probably be ok too.  http://www.erowid.org/library/books_online/pihkal/pihkal110.shtml


----------



## atrollappears

glenjih said:


> How so? (That's a genuine question, not me being an asshole). Should it look like this instead?
> 
> 
> 
> 
> 
> 
> I lifted most of the structure from bk-MDMA



Turns out that for an amphetamine to be active, it has to be basic, i.e., it has to be able to grab another hydrogen and put it on the nitrogen. Unfortunately, putting an electronegative fluorine near that nitrogen really limits the compound's ability to do that. So, this would probably not be active 



Enix150 said:


> Haha I smiled when I saw your bk-version, you definitely inspired *pyr-αMT*! Wish I could say more about it...



Hehe why thank you


----------



## glenjih

Thanks guys for your seemingly endless reserves of patience. I know it must get frustrating having people like me roll up with their fancy useless molecules, but I am hoping to steal nuggets of knowledge from you where possible.


----------



## Enix150

^Actually, (and some of the ADD crew may disagree) I think that the molecules that don't work are the ones that I've learned the most from! Everytime someone posts an inactive structure here, it seems that everyone jumps on to teach us all why it won't work. The more "useless" ones that get posted, the more we subscribers to this thread get to learn! 

On that note, I've wondered how 5-HTP analogs would be metabolized:


 

 
*5-MTP* ~ ~ ~ ~ ~ *4-HTP*


----------



## atrollappears

glenjih said:


> Thanks guys for your seemingly endless reserves of patience. I know it must get frustrating having people like me roll up with their fancy useless molecules, but I am hoping to steal nuggets of knowledge from you where possible.



Not at all. I love blabbering about SAR stuff 
Edit: By the way, most of the molecules we are drawing are just completely random crap. There's very little method to our madness, so don't be intimidated.



Enix150 said:


> On that note, I've wondered how 5-HTP analogs would be metabolized:
> 
> 
> 
> 
> 
> *5-MTP* ~ ~ ~ ~ ~ *4-HTP*



Try this one on for size 




5-hydroxy-N-acetyltryptophan, possible precursor to the grand-daddy of endogenous antidepressants: N-acetylserotonin
http://en.wikipedia.org/wiki/N-acetylserotonin


----------



## Enix150

^Haha I like it! Being a huge proponent of psilocin, I always find myself hydroxylating the 4-position...



 


*N-acetyl-4HT* ~ ~ *4-hydroxy-N-acetyltryptophan*

I was even thinking about going for 4-AcO-N-acetyltryptophan, but it seemed a bit.. _ketotic_. 

EDIT:



*N,N-DMTP*

reEDIT: ^Or I guess not for that last one... www.cognitiveliberty.org/shulgin/adsarchive/dmt.htm

v4.0: ^Haha I spoke too soon, apparently its pharmacology remains untested! Also, take a look at these: http://en.wikipedia.org/wiki/Plakohypaphorine

Final Take: Tomorrow I want to start taking substitutions from various MT_n_-agonists to see how they'll fit on some phenethylamines, and maybe vice-versa?


----------



## glenjih

Sweet. In which case, I will take full advantage of your hospitality. 






I was aiming for a beta-ketone analogue of 4-MAR, but I was a little unsure of where that extra oxygen atom should go. Did I do it right this time?

Also, any reason why a BK version would be a bad idea? I know the beta-ketones have a tendency to be less...good....than their parent compounds- bk-MDMA being a prime example. If the same relationship applies here, is there a substitution that could be made to increase the serotonin fun times, and _then_ make it a beta-ketone? Is there any point?


----------



## atrollappears

glenjih said:


> Also, any reason why a BK version would be a bad idea? I know the beta-ketones have a tendency to be less...good....than their parent compounds- bk-MDMA being a prime example. If the same relationship applies here, is there a substitution that could be made to increase the serotonin fun times, and _then_ make it a beta-ketone? Is there any point?



Well that's not always the case... mephedrone is certainly better than 4-methylmethamphetamine, and I'd actually be more interested in trying methcathinone than methamphetamine. (I hear that methcathinone does nothing for focus, and I find that the focus strongly detracts from the recreational potential of amphetamine. Accordingly I've heard methcathinone described as an excellent party drug, even better than MDMA according to some.)
As far as the aminorex family goes, I don't think we know much about their structure activity relationships. Note that it will almost certainly not display the same patterns as amphetamines', e.g. there's little reason to think that slapping a methylenedioxy on it would make it more "rolly" or something. Anecdotally, 4-MAR produces somewhat of an MDMA-like high, and I've not heard the same for aminorex. Perhaps if you wanted to maintain that you could try some subtle substitutions on the 4-MAR molecule, or some different substitutions in the 4 position (one of which you've already done). So overall we don't know much about aminorexes, but I have no reason to think that the molecule you drew wouldn't work (although I honestly don't know that much about SAR stuff), it seems at least worth testing on a few guinea pigs 

How about this one?




4-Methyl-5-phenyl-2-amino-furan (I think?)
The electron donating capability of the furan oxygen should create a very stable conjugate acid I think... and in tryptamines the nitrogen in the indole ring doesn't really do anything at all (at least for agonist activity), maybe it's the same for aminorexes? If so this could be very potent...


----------



## Steps

Kinda.. a double methamphetamine

Can anyone tell me what this would actually do?


----------



## Pomzazed

^ Chiral Copper Ligand? :D


----------



## Steps

Pomzazed said:


> ^ Chiral Copper Ligand? :D



define chiral copper ligand?


----------



## MattPsy

A compound that can form copper complexes with different shapes depending in the chirality (3d configuration) of the stereocentres of the molecules (of which there are two)

Anyway, your double meth probably wouldn't do anything, except perhaps act as a a2 adrenergic agent, as it probably wouldn't be able to be taken up into the presynaptic cell to act on VMAT2, nor would it have the same effect once it got there.


----------



## Steps

What about... 2,3,4-trinitro-amphetamine

I'm very inexperienced with the SAR


----------



## Astavats

Steps said:


> What about... 2,3,4-trinitro-amphetamine



2,3,4-TNA sounds like a blast. How about DHNCT (N,N-di(heptanitrocubanyl)tryptamine)? A reliable source says it's "explosively good" and that I'll "blow right through the stuff".


----------



## Limpet_Chicken

I would not touch that trinitroamphetamine. Aromatic nitro compounds are often highly toxic. 

Di-nitro compounds in particular, such as dinitrophenol. DNP has been used by fat buggers who want to get slim, although its banned, and rightly so. It works by uncoupling oxidative phosphorylation, so the body burns ATP yet gaining less energy. Calories intaken get used up, but without giving the energy they usually would. Not good at all, for mitochondria etc. And it raises body temperature massively, literally turning up the heat on the oven. Sometimes lethally so. Its unpredictable, and noxious stuff. It has been known to cause cataracts also, along with other side effecs.

Not sure if tri-nitro aromatics possess the same sort of ability to fuck with the proton gradient within mitochondria, but I would NOT touch this one. It is likely to be nice and colorful though. Bright yellow I bet. Nitro compounds are often yellow. Such as DON, and having seen the nitrostyrene that corresponds when reduced with LAH, Al/Hg amalgam, zinc/GAA etc to 2C-D (2,5-dimethoxyphenyl-4-methyl-beta-nitrostyrene), before recrystallization from first water, then boiling MeOH it was a lurid shade of bright orange, but post-rxtylization it appeared in the form of purrty clearish golden-yellow crystals.

Aromatic nitro compounds in general are bad news for the body, especially dinitro compounds like DNP, which act as proton ionophores. I would take DON, or 2C-N, but I find them only acceptable due the small amounts needed to produce the intended effects, by weight.

Do tri-nitro aromatics possess the same degree and/or types of toxicity as DNP and its ilk?


----------



## sekio

I think anyone dumb enough to make tetranitrostyrenes needs to be shot before they blow their lab sky-high.


----------



## Limpet_Chicken

It would certainly have to be done bloody carefully


----------



## sekio

Considering the likely precursors for trinitro amphetamine are trinitrobenzenes, I would suspect that even handling the precursors would land you in an "explosive situation" shall we say.


----------



## Limpet_Chicken

Depends, TNT needs some force to set it off, its stable enough to be hot melt casted into bomb cases for military applications, etc. . Not too far removed from trinitrobenzenes. I'd be a bit leery of the tetranitrostyrene though. 

I sure as hell wouldn't be taking any of the resultant amphetamine. Would possibly be an amusing lab exercise, ala Shulgin with his comments on the hypothetical 2C-Po and 2C-At. but just the same, the potential toxicity of trinitroamphetamine would completely rule it out though. I imagine that could cause a serious case of explosive diarrhea, to say the least


----------



## SNR

glenjih said:


> Sweet. In which case, I will take full advantage of your hospitality.
> 
> 
> 
> 
> 
> 
> I was aiming for a beta-ketone analogue of 4-MAR, but I was a little unsure of where that extra oxygen atom should go. Did I do it right this time?
> 
> Also, any reason why a BK version would be a bad idea? I know the beta-ketones have a tendency to be less...good....than their parent compounds- bk-MDMA being a prime example. If the same relationship applies here, is there a substitution that could be made to increase the serotonin fun times, and _then_ make it a beta-ketone? Is there any point?



Found a compound that looks like yours. 
http://en.wikipedia.org/wiki/Pemoline


----------



## Steps

I think this is best suited for ADD, instead of getting possible pseudo-science BDD guesses as answers
Is there a way to calculate or get a good estimate on how much your metabolic rate has increased while under the influence of amphetamine(s)


----------



## pharmakos

?


----------



## sekio

^ Ring-contracted arylcyclohexylamines (arylcyclopentylamines?) are considered to be inactive, the ring has to have 6 and exactly 6 members for good NMDA effects.

I do want to see N-ethyl-norketamine.


----------



## /navarone/

A putative DRI/dopamine D1,D5 agonist with AMPA/Kainate/NMDA antagonism and GABAa agonism.
Inspired by GYKI-52466, GYKI-52895, Fenoldopam and obviously a fluorophenylbenzodiazepine:





Could it work out?


----------



## sekio

Who knows? Send it to GSK for tests


----------



## Transform

Is there a reason why we only see propyl - pentylpyrovalerone derivatives and not any longer chains?

Is there an alpha-propylphenethylamine? What's the SAR like here compared to amphetamines?


----------



## doppelgänger1

And why aren't there any pyrovalerone-derivates of tryptamines?


----------



## pharmakos

Transform said:


> Is there an alpha-propylphenethylamine?



would "1-phenylpentan-2-amine" be the proper name for that stuff?

barely anything online about it, though a few of the big chemical supply houses seem to have it...


----------



## Transform

Yeah that would be the proper name. It's a pretty simple derivative of prolintane so I'm certain it'd be active, I just wonder about its potency. Prolintane was sold as catovit in 10mg tablets I think, so it could potentially be a bit more potent than amphetamine. The butyl analogue is mainly just an NE releaser though so maybe it's a dead end. Especially when you consider that prolintane is an NDRI.

Still, it's interesting for me to see how versatile that prolintane structure is - lots of our favourite amphetamine modifications could probably be applied to it. It'd be interesting to see what the expert's favourite addition p), an MDO ring would do to prolintane. An SRI NDRI or an SRA NDRI?

Edit: Apparently Shulgin talks about alpha alkyl lengthening in pihkal. It'll only be relevant to psychs but I'll see what he had to say.


----------



## glenjih

So I was trying to draw a methylhydroxy- version of Oxilofrine, and ended up with this instead:






Can someone explain what I did wrong? I was trying to follow roughly the difference between MA/MDMA, but obviously I've cocked it up somewhere.

Also, is the above compound feasible? I think oxilofrine is a fairly good NE/DA releaser, and I was shooting for some SE action too.


----------



## sekio

glenjih, that compound is beta-hydroxy-MDMA, aka methylenedioxyephedrine. It is a known metabolite of methylenedioxymethcathinone (bk-MDMA, Methylone).

Generally beta-hydroxy phenethylamines are poor releasing agents of DA/5HT, they are OK NE releasers and adrenergic/5HT agonists though. They also have consideraly more action at adrenergic (peripheral) receptors.

Oxilofrine looks to me like it's a para-hydroxy ephedrine, and woud make for a relatively poor stimulant.


----------



## pharmakos

Transform said:


> Edit: Apparently Shulgin talks about alpha alkyl lengthening in pihkal. It'll only be relevant to psychs but I'll see what he had to say.



http://www.erowid.org/library/books_online/pihkal/pihkal001.shtml

i'm not sure if he tried alpha-ethyl versions of all of his sub-classes though.  shulgin seemed to be very quick to call something a dead end.  i think alpha-ethyl psychedelics might work if you tinker around with the other parts too.

p.s. that link doesn't really say much about stims.


----------



## sekio

As far as I know, alpha-alkylation of phenethylamines beyond a-methyl greatly decreases potency at serotonin receptors. Compounds with long chains do retain activity at NET/DAT though (prolintane).
Even highly potent compounds like DOM/DOB lose hallucinogenic activity when the amphetamine is changed to an alpha-ethyl, see commentary for ARIADNE. At best they could be mild anti-depressants, or so Shulgin speculates. I feel this is probably due to f/x at NET/DAT or other non-%HT targets.


----------



## pharmakos

shulgin only tried alpha-ethylating a few compounds.  

suppose DOI-NBOMe was made and not found to be very potent, so the scientists assumed that 2C-I-NBOMe must be less potent...

i think shulgin was too quick to call certain roads dead ends

there is only so much time to test and taste though


----------



## sekio

'A few"? He at least produced alpha-ethylated DOM (ARIADNE), DOB, AMT/tryptamine (AET), MDMA/MDA (MBDB/BDB), mescaline (AEM), and probably more.

I'm all for 'make em and taste em' but SAR does have its place too.


----------



## pharmakos

i'm not sure we should include AET, tryptamine SAR is fairly different than phenethylamine SAR

DOM/DOB are pretty closely related, as are MDA/MDMA.  and then AEM... he basically alpha-ethylated in three directions only, not five.

as just one quick one off the top of my head, perhaps alpha-ethyl Ganesha analogues are actually more potent?  SAR is weird between 2C-G-X/(DO)G-X

[[lol DOG, no wonder he went with just G as the acronym for Ganesha :D]]

...then again, who would even want a more-potent or longer-acting analogue of Ganesha.  =p

perhaps it is a dead end. i still have a hunch that direction could potentially have some gems, though.  *shrugs*


----------



## SerotonergicHaze

Doubt this compound would be active, but I like its structure


----------



## Sturnam

I've recently been thinking about some LSD analogues, particularly with respect to opening up the rings a little. It seems most modifications have been of the diethyl amide, the 9,10 double bond, 2,3 double bond, on extensions on the 1 or 2 position of the indole. I've preserved the C5 and C8 stereochemistry, as alteration of those abolish all psychedelic actvitiy.






Also, a modification where I took out the carboxyl group of Lysergic acid. I have a feeling that this one, if it is a 5-HT2A agonist, won't be psychedelic though.











Another open ring LSD analogue, but with an oxygen substituted off the 4 position, a la psilocin, but incorporated it into the ring. However, this eliminates the 9,10 double bond, which abolishes psychedelic activity. I wonder if this one might retain some activity though.

Edit: Better pictures uploaded.


----------



## sekio

8-Descarboxy-lysergic acid is apparently active at 5-ht2a as a hallucinogen with something like 1/10 the potency of LSD in mice.

I think the problem with ring-opened ergolines is that part of the reason that the ergolines are effective _at all_ is their flat, planar configuration granted by the ring systems constraining each other. Opening the rings of LSD leads to greatly reduced activity/potency as far as I know, because the molecule rapidly becomes less planar as you break the rings apart.

The 9,10 double bond in particular has been implicated in the high affinity of ergolines for 5-HT receptors - loss of pi bonding at this site causes a dramatic drop in potency (see: lumi-LSD vs LSD). I don't think your 3rd compound will be active for this reason.

I think there may be some existing research on 1- or 3- piperidinyl indoles as agonists at 5-HT. I remember there was at least one - possibly the stericalyl hindered version of AET - that had a reasonable potency.


----------



## Sturnam

sekio said:


> 8-Descarboxy-lysergic acid is apparently active at 5-ht2a as a hallucinogen with something like 1/10 the potency of LSD in mice.



I actually read this in a Nichols review shortly after posting. I was suprised, especially given how slight changes to the diethylamide can drastically reduce potency.

I figured that the flat, planar nature of LSD might be required to adequate binding and activation of 5-HT2A, I was just wondering what other 'skeletons' of 5-HT2A agonists might be buried in there, considering that both phenethylamine and tryptamine skeletons are embedded in LSD. Maybe something incorporating the diethylamine moiety?


----------



## webbykevin

Sturnam said:


> I've recently been thinking about some LSD analogues, particularly with respect to opening up the rings a little. It seems most modifications have been of the diethyl amide, the 9,10 double bond, 2,3 double bond, on extensions on the 1 or 2 position of the indole. I've preserved the C5 and C8 stereochemistry, as alteration of those abolish all psychedelic actvitiy.
> 
> 
> 
> 
> 
> 
> Also, a modification where I took out the carboxyl group of Lysergic acid. I have a feeling that this one, if it is a 5-HT2A agonist, won't be psychedelic though.
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> Another open ring LSD analogue, but with an oxygen substituted off the 4 position, a la psilocin, but incorporated it into the ring. However, this eliminates the 9,10 double bond, which abolishes psychedelic activity. I wonder if this one might retain some activity though.
> 
> Edit: Better pictures uploaded.




Is there not a way to add the 4 position psilocin but still retain the 9,10 double bond ?

That would be worth a bioassay .


----------



## lsd-NBOMe

Facts :
- Substitutions on the 6-position in ring D of LSD creates some magic. In particular, ETH-LAD (cf. TIHKAL) seems roughly twice as potent as LSD-25 (true in humans cf. Shulgin, and rats cf. Nichols).
- LSD is a tryptamine, but it also contains the PEA skeleton, which share that same 6-position-in-ring-D nitrogen.
- NBOMe substitutions on PEAs multiply their potency by roughly 40 and adds a lot of magic to 2C-Xs.

Therefore, I give you:






LSD-NBOMe.

This has the potential to be active in the nanogram range. Could it be the carfentanil of psychedelics?


----------



## JBrandon

I'm talking out of my ass here but I don't think this would be active at excitingly small levels. 

Look at phenethyl-LAD...
http://www.erowid.org/library/books_online/tihkal/tihkal51.shtml

"Something" at half a mg. In addition the NBOMe-tryptamines were all failures, and they share the indole structure with LSD. 

Also I believe Nichols or any of the other real scientists who have studied LSD and the NBOMe series would have jumped on this immediately if there was reason to believe it would be exciting.


----------



## sekio

Doubtful, the size of the amine substituent on LSD seems correlated to activity -by the time you get to PARGY-LAD there is a pretty obvious drop in activity

I don't expect NBOMe to become a popular motif in drug design. It doesn't seem to work with anything but phenethylamines.


----------



## pharmakos

sekio said:


> Doubtful, the size of the amine substituent on LSD seems correlated to activity -by the time you get to PARGY-LAD there is a pretty obvious drop in activity



there was a time when it was thought that any n-substitution on a phenethylamine was considered to be a bad idea =p  the size of a particular group is not the whole story.

besides PARGY-LAD is still active at under a milligram 

i think NBOMe-LSD might work out


----------



## sekio

Don't count on it - the NBOME trytamines never panned out.


----------



## Transform

Aye, but ergolines are at least a bit special, having chemical features of both tryptamines and phenethylamines?


----------



## sekio

Not neccesarily. 

Even Shulgin himself pointed out, SAR is not always as simple as "Compound X plus group Y makes super potent compound XY, so compound Z plus group Y makes super potent compound ZY".

There is also the problem of diminishing returns one runs into. Compounds can only be made to bind so tightly before any changes you make to them decrease activity.

A huge part of LSD's activity comes not from the fact that it's "both a phenethylamine and a tryptamine" - that's mostly just fun trivia - but from the fact that the whole molecule is almost entirely flat and planar.

Another curio is that any modification of the amide seems to greatly decrease activity.

Another other thing to notice is the "phenethylamine" in LSD is a tertiary amine, a sure sign of doom in the traditional PEA world.


----------



## countyourculture

These were posted to Sasha's facebook page.






Thoughts?


----------



## Sturnam

countyourculture said:


> These were posted to Sasha's facebook page.
> 
> 
> 
> 
> 
> 
> Thoughts?



If I'm reading those letters correctly, none of those are even phenethylamines....not a single one has a nitrogen. And without that, no activity. Plus, for the second one, tert-butyl groups in the 4 position makes it inactive, and having hydroxyl groups instead of methoxies greatly reduces activity, although a 2-hydroxy might be ok.

So, no, no, and no. For several reasons.


----------



## countyourculture

I don't see an amine either. I'm interested simply because of the source.


----------



## Epsilon Alpha

Maybe they're prodrugs? I know he mentioned some compounds in nutmeg being activated by that mechanism. Or, they're just some random reagents he had laying around.


----------



## sekio

Jar on the far right is trans-isoapiole.

Other two are substituted hydroquinones


----------



## F1n1shed

um , que?


----------



## sekio

trans-isoapiole is a precursor for DMMDA
The other two are closely related to antioxidants like BHT & the quinones


----------



## Limpet_Chicken

Hydroquinones can also serve as start points in preparing such things as the 2Cs, etc.


----------



## Transform

If I recall, The Shulgin Index has information about quinones so it may be related to that.


----------



## cannibalsnail

Didn't he theorise about a new structure for hallucinogenic drugs derived from tetrahydroquinolines?


----------



## 2CBCB

2c-b-fly-bro(madol)
I doubt it'd be active, but oh... if it were :3


----------



## cannibalsnail

You could create an unstable peroxide group by the amine which would cleave to an oxygenated amine leaving bromadol behind. The 2C-B-FLY-OH would metabolize to 2C-B-FLY. But the synthesis would be near impossible and for what reason?


----------



## Transform

So that you could OD while you enjoy your threshold dose of 2C-B-FLY, of course.


----------



## 2CBCB

You guys had to ruin my fun 

here's something a little more do-able, and potentially actually quite interesting.


----------



## sekio

Fairly sure the hydroxymethyl-BOMamines aren't active.

The FLY-NBOMe compounds, if I remember right, are actually less potent than the plain NBOMes.


----------



## cannibalsnail

Correct. The NBOMes were chosen BECAUSE they were the most active.


----------



## 2CBCB

I screwed up and tacked the oxygen in the wrong place, meant for it to be NBOMe.  I've had a severe lack of sleep this past week (_broken mains-attached fire alarm bleeping every minute of every night and day, I cant rip it off the wall because the fucking thing will alert the local fire dept_).

Didn't realize the FLY-NBOMe's were _less_ potent though.  Seen a few people attempting to put in for 2c-b-fly-NBOMe recently, their reasoning now eludes me if 2c-b-fly would simply be more potent and cost-effective... and it's legal, so its not an issue like that.


----------



## irobeth

I'm not good at SAR but I get impulses when I see molecules to make others





I don't know why I wanted a fluorine here










A symmetric conformationally restricted pregabalin?


----------



## sekio

oxymorphone analogue


----------



## pharmakos

@ all the random molecules on this page:  what was the SAR reasoning behind these structures?


----------



## Hammilton

Sekio, I don't know about the ketone on that, but I'm pretty sure molecules based on that design were active opioids and quite potent.


----------



## sekio

Hammilton, after posting here I did some scouring and all I could find was syntheses - no actual tests of the compound. The dehydro analog has been made (double-bond a la morphine & no tertiary OH) as well as a dimethoxyphenyl variant (to simulate the epoxy bridge) but I haven't actually found any data on tests in vivo.

Definitely interesting compounds. I bet they would have activity as SNRI's or maybe even NMDA antagonists.


----------



## monad

This one has piqued my curiosity for an extensive period of time. I welcome thoughts from the more chemically literate individuals on bluelight as to the expected activity of this compound. Like, the 2c series, if this one has interesting activity, other similar substituted compounds exist, that may also have interesting profiles. I give you :: d-thio-LSD! Edit: New here so I still can't upload images. Also, attached image in web link does not show. Follow link for visual clarification. http://imgur.com/D8Y69


----------



## sekio

Thioamides aren't known for their stability.

Also they stink, I would bet.


----------



## Hammilton

sekio said:


> Hammilton, after posting here I did some scouring and all I could find was syntheses - no actual tests of the compound. The dehydro analog has been made (double-bond a la morphine & no tertiary OH) as well as a dimethoxyphenyl variant (to simulate the epoxy bridge) but I haven't actually found any data on tests in vivo.
> 
> Definitely interesting compounds. I bet they would have activity as SNRI's or maybe even NMDA antagonists.



Sorry, it took me a while to see this.  I found these two pretty quickly.  I'm sure there's more, but I've got two kids bugging me.  First one isn't too promising.  Well, actually, they're pretty potent.  I'm thinking that either that 8a-methyl substitution is the problem or maybe the trans isomers are agonists.  Not sure



> N-Substituted cis-4a-(3-Hydroxyphenyl)- 8a-methyloctahydroisoquin olines Are Opioid Receptor Pure Antagonists
> Authors: F. Ivy Carroll, Sachin Chaudhari, James B. Thomas, S. Wayne Mascarella, Kenneth M. Gigstad, Jeffrey Deschamps, and Hernán A. Navarro
> J. Med. Chem. 48(26), 8182-8193 (2005)
> ISSN: 0022-2623 00222623  DOI: 10.1021/jm058261c



N-Substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines (6a-g) were designed and synthesized as conformationally constrained analogues of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4) class of opioid receptor pure antagonists. The methyloctahy-droisoquinolines 6a-g can exist in conformations where the 3-hydroxyphenyl substituent iseither axial or equatorial, similar to the (3-hydroxyphenyl)piperidines 4. The 3-hydroxyphenylequatorial conformation is responsible for the antagonist activity observed in the (3-hydroxyphenyl)piperidine antagonists. Single-crystal X-ray analysis of 6a shows that the3-hydroxyphenyl equatorial conformation is favored in the solid state. Molecular modelingstudies also suggest that the equatorial conformation has lower potential energy relative tothat of the axial conformation. Evaluation of 6a-g in the [35S]GTP-γ-S in vitro functional assayshowed that they were opioid receptor pure antagonists. N-[4a-(3-Hydroxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinoline-6-yl]-3-(piperidin-1-yl)propionamide (6d) with a Ki of 0.27 nM at the κ opioid receptor with 154- and 46-fold selectivity relative to those of the µ and δ receptors, respectively, possessed the best combination of  κ potency and selectivity.  
http://www.scribd.com/doc/43821646/...ntagonists-J-Med-Chem-48-2005-8182-8193-J-Med


Slightly more promising, but of significantly less value.  I hope the NSFW tag works...


If might be worthwhile for someone to pull the following refs:
Boekelheide et al., JACS 72, 712 (1950)
Eddy, "J. of the Am. Pharm. Assoc.", May 1950, pp. 245ff
Finch et al., "J. Org. Chem" 39, No. 8, 1118-1124, Apr. 19, 1974

These are all real old, obviously!

Patent 4150135
4A-Aryl-cis-decahydroisoquinolines, such as N-phenethyl-4a-(m-hydroxyphenyl)-cis-decahydroisoquinoline, useful as analgesics.

*NSFW*: 





> BACKGROUND
> 
> This invention concerns the discovery that a selected group of 4a-aryl-cis-decahydroisoquinolines are useful as analgesics, many with little or no addictive properties.
> 
> Boekelheide and Schilling, J. Am. Chem. Soc. 72, 712 (1950), disclosed the compound N-methyl-4a-phenyl-cis decahydroisoquinoline, (naming it "N-methyl-10-phenyldecahydroisoquinoline") and indicated that it had low analgesic activity.
> 
> The present invention results from efforts to develop new compounds with high analgesic potency and low abuse liability.
> 
> SUMMARY
> 
> According to this invention there is provided novel compounds of formula I and their suitable pharmaceutical salts, processes for their manufacture, pharmaceutical compositions containing them, and methods of using them to produce analgesia inmammals. ##STR1## where R1 is hydrogen; C1 -C6 alkyl; --CH2 Y where Y is C2 -C6 alkenyl or C2 -C6 alkynyl;
> 
> --(CH2)m ##STR2## WHERE M IS 1 TO 4, X is Cl, Br, F, CF3, OCH3, CH3, isopropyl, --NH2, or --N(CH3)2, a=0, 1 or 2;
> 
> --(CH2)m ##STR3## --(CH2)m ##STR4## or cycloalkylmethyl of the formula --CH2 CH<(CH2)n, where n is 2-5;
> 
> R2 is divalent oxygen (=O), ##STR5## R3 is --OH, --OCH3, ##STR6## or F; R4 is --H, --OH, --OCH3, ##STR7## with the proviso that when R3 is --F, R4 must be --H.
> 
> DETAILED DESCRIPTION
> 
> Representative R1 groups are methyl, ethyl, propyl, butyl, hexyl, allyl (--CH2 CH=CH2), 2-butenyl, 3-butenyl, 4-heptenyl, 3,3-dimethylallyl [--CH2 CH=C(CH3)2 ], propargyl (--CH2 .tbd.CH), phenylpropargyl, heptynyl, benzyl, phenethyl, 4-phenyl-n-butyl[--CH2 (C2)3 C6 H5 ], cyclopropylmethyl [--CH2 CH<(CH2)2 ], cyclobutylmethyl [--CH2 CH<(CH2)3 ], cyclohexylmethyl [--CH2CH<(CH2)5 ], furylmethyl ##STR8## 2-furylethyl ##STR9## 2-thienylethyl ##STR10## p-methylphenethyl ##STR11## p-fluorophenethyl, ##STR12## p-methoxyphenethyl ##STR13## p-chlorophenethyl ##STR14## p-aminophenethyl ##STR15##p-dimethylaminophenethyl, and cinnamyl (--CH2 CH=CHC6 H5).
> 
> Representative Ar groups are 3-hydroxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-acetoxyphenyl, 2,3-dihydroxyphenyl, 3,4-dimethoxyphenyl, 3,4-diacetoxyphenyl, 3-hydroxy-4-methoxyphenyl, 2-methoxy-3-acetoxyphenyl, 3-fluorophenyl and4-fluorophenyl.
> 
> The 4a-aryl-cis-decahydroisoquinolines of formula I include various stereochemical isomers stemming from substitution at position 6, and from optical asymmetry of the whole structure. When monovalent R2 substituents at position 6 aredifferent (e.g., when ##STR16## spatial considerations require the existence of axial and equatorial isomers. In the molecule as a whole, spatial considerations require the existence of d and l optical isomers. These are normally present as racemicmixtures which can be resolved by known methods (Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill, 1962, p. 31).
> 
> Pharmaceutically suitable acid addition salts of these compounds include those made with physiologically acceptable acids that are known in the art; such salts include hydrochloride, sulfate, phosphate, nitrate, citrate, maleate and the like.
> 
> PREFERRED COMPOUNDS
> 
> The analgesic compounds preferred because of their high level of activity are those where
> 
> R1 is ##STR17## X=H or CH3 with CH3 being more preferred; R2 is ##STR18## being more preferred; R3 is m-OH or m-OCH3 ; and
> 
> R4 is H.
> 
> Most preferred because of their activity are N-(p-tolylethyl)-4a-m-hydroxyphenyl-6β-cis-decahydroisoquinoline and N-(phenethyl)-4a-m-methoxyphenyl-cis-decahydroisoquinoline.
> 
> Synthesis
> 
> The multi-step processes of the invention start with 2-cyano-3-aryl-3-carbalkoxymethylcyclohexenes which can be obtained according to procedures disclosed by Boekelheide and Schilling (loc. cit.) with respect to2-cyano-3-phenyl-3-carbethoxymethylcyclohexene (cf, Example 1, Part A). Reaction of a 2-cyano-3-aryl-3-carbalkoxymethylcyclohexene with hydrogen chloride in a lower alkanol such as ethanol forms a4a-aryl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline (cf, Example 1, Part B). These 1,3-diketo-octahydroisoquinolines possess a conformational arrangement of the fused rings which requires formation of trans-decahydroisoquinoline structures whenthe 8,8a- double bond is converted to a single bond (cf, Example 1, Part D; Example 6, Part A). A key step in the invention is the novel isomerization of a 1,3-diketo-trans-decahydroisoquinoline to the cis isomer in the presence of a relatively strongbase (cf, Example 1, Part E; Example 4, Part A).
> 
> The selection of specific preparational steps following the initial formation of a 1,3-diketo-1,2,3,4,4a,-5,6,7-octahydroisoquinoline depends upon the specific 4a-aryl-cis-decahydroisoquinoline derivative that is desired. The sequence involvesat least three steps, A, B, and C, which are illustrated below. Compounds having no unsaturated carbon to carbon bonds in R1 (R1a in process steps) are prepared by steps A, B-1, and C. Compounds having saturated or unsaturated carbon to carbonbonds in R1 are prepared by steps A, B-2, and C. ##STR19##
> 
> R1a in path B-1 is the same as R1 except that it does not include unsaturated groups such as alkenyl or alkynyl. These groups appear to undergo reduction to alkyl, simultaneously with the reduction of the 8,8a bond, in going fromcompound (3) to compound (4). Thus to obtain compounds of formula I where R1 has alkenyl or alkynyl bonds, path B-2is followed. In this path the 8,8a bond of compound (2) is first reduced and then the resulting trans product (6) is reacted withR1 Br, R1 I or mesylates to form the cis product (5) in which R1 has alkenyl or alkynyl groups. Path B-2 includes the possibility of isolating the N-unsubstituted cis imide followed by normal N-alkylation with either a saturated orunsaturated R1 group. ##STR20##
> 
> In the foregoing formulas (1) through (8), the groups R1 have the values given previously. R5 is ##STR21## R6 is C1 to C4 alkyl. Ar1 is ##STR22## in which R7 is hydrogen, F or methoxyl;
> 
> R8 is H or methoxyl; provided when R7 is F, R8 is H.
> 
> In Step A reactant R6 OH, which is also the reaction medium, is generally used in excess, but to insure maximum yield it should be used in an amount of at least one mole per mole of cyanoester. Likewise, the HCl reactant can be used inexcess but to insure maximum yield it should be present in an amount of at least one mole per mole of cyanoester. The reaction is run in the liquid phase under anhydrous conditions. The reaction temperature should be in the range of about 50° to about 120° C. The reaction pressure is not critical, ordinarily being atmospheric for convenience, but should be consistent with achievement of the stated reaction temperature.
> 
> In step B-1 for the conversion of (2) to (3), or in step B-2 for converting (6) to (5), any reactive alkylating agent can be used, such as hydrocarbyl iodide, bromide, mesylate, tosylate, azide, and the like. Alkyl iodides, bromides, mesylates,tosylates, and azides are included and the hydrocarbyl group corresponds to R1 in general formula I. Any base capable of extracting a proton from the imide is satisfactory. Exemplary are alkali metal hydrides (sodium hydride or potassium hydride)in aprotic media (dimethylformamide, hexamethyl phosphoramide, dimethylsulfoxide); alkoxides in aprotic or alcoholic solvents, as, for example, sodium ethoxide in ethanol and potassium t-butoxide in ethanol. Mesylates (Ms=mesyl group=methanesulfonylgroup) are described in Fieser and Fieser, Advanced Organic Chemistry, 1961, pp. 292, 293 and 319. Hydrocarbyl bromides, iodides or mesylates are readily available, as indicated in the following table (Table I).
> 
> In paths B-1 (4) to (5a) and B-2 (6) to (7) a relatively strong base, with or without an inert solvent, is used. Representative strong bases include alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide, and lithium hydroxide;alkali metal alkoxides in which the alkoxide group contains 1-4 carbon atoms, such as sodium methoxide, potassium ethoxide, lithium propoxide, and the like. An inert solvent can be used if desired; included are lower alkanols, e.g., methanol, ethanol,t-butanol and the like. The reaction temperature can range from room temperature to reflux temperature of the reaction mixture.








Oops, I had to read this one really carefully because I think they're using a different numbering scheme.  Today, I'm pretty sure that where the phenyl group is attached it's called 4a-phenyl-decahydroisoquinoline.  This patent talks about 3a-phenyl-decahydroisoquinolines, which made me think they were a bit like methopholine but when I read the abstract, it says, "[the structure can be described] as a decahydroisoquinoline with an hydroxyphenyl group substituted on a ring junction carbon atom para to the isoquinoline nitrogen."  Based on that it seems we're talking about the same structure, especially considering that he references the same Boekelheide paper from 1950.

http://www.patentgenius.com/patent/4001247.html


> BACKGROUND OF THE INVENTION
> 
> It has long been known that slight chemical modifications of the morphine molecule lead to analgesic agonists of widely differing potency and addictive properties. For example, codeine, the methyl ether of morphine, is a relatively mildanalgesic agonist having slight dependance (addiction) liability. On the other hand, heroin, the diacetyl derivative of morphine, is a powerful agonist with extremely high addiction potential. In addition, as long ago as 1915, Pohl found that when theN-methyl group of codeine was replaced with an allyl group, the resulting compound, N-allylnorcodeine, was an opiate antagonist. In 1940, N-allylnormorphine or nalorphine was synthesized and was shown to have a highly specific ability to reverse thedepressant effects of morphine. Other simple chemical modifications of the morphine molecule have yielded many interesting drugs. Thus, one fruitful research area in the search for improved analgesics of high potency and/or lower dependence (addiction)liability has been the chemical modification of the morphine molecule.
> 
> In addition to modifying the morphine ring structure by chemical means, chemists have developed a second related field of research--the preparation of certain morphine partstructures--with the same end in mind as above; i.e., the synthesis ofimproved analgesic agonists and/or analgensic antagonists of improved properties. For example, meperidine, a widely used analgesic, can be written as a morphine part-structure. Many other morphine part-structures have been prepared, some of which haveimproved analgesic agonist properties and others, particularly those with an allyl group attached to a ring nitrogen, have opiate antagonist properties. It had been hoped that morphine part-structure research would produce a compound having both opiateagonist and antagonist properties since the opiate antagonist property would assure a user that the compound would have a greatly reduced dependence liability. Two recently marketed analgesics, pentazocine and phenazocine, have been found to be bothantagonists and agonists although they still retain a certain degree of opiate dependance liability.
> 
> One potential morphine part-structure can be written as a decahydroisoquinoline with an hydroxyphenyl group substituted on a ring junction carbon atom para to the isoquinoline nitrogen. An attempt to prepare such a compound was described by Boekelheide in a paper appearing in J. Am. Chem. Soc., 69, 790 (1947). This paper set forth the preparation of what, according to the numbering system then in vogue, were 10-phenyldecahydroisoquinolines. It was the author's conclusion, however, thatthe compound (IX) had a cis configuration and (footnote 5) showed low analgesic activity. The synthesis itself is cumbersome and not free from ambiguity. Sugimotp et. al., J. Pharm. Soc. Japan, 75 177 (1955), C.A. 1956 1814b described the synthesisof 8 or 10-alkylated decahydroquinolines. The reference also shows the morphine part-structure, 10-(m-hydroxyphenyl)-3-methylisoquinoline [presently named as 1-methyl-3a-(m-hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a, 8-decahydroisoquinoline] but withoutfurnishing a synthesis for it. These authors do not, in fact, describe the preparation of any decahydroisoquinoline, but describe only the preparation of the decahydroquinoline analogs.
> 
> Belgian Pat. No. 802,557 issued Jan. 19, 1974, discloses a general method of preparing N-substituted 3a-phenyldecahydroisoquinolines and specifically discloses 3a, phenyl-3a-(m-methoxy phenyl) and3a-(m-hydroxyphenyl)-1-methyldecahydroisoquinolines, 3a-(m-methyoxyphenyl) and 3a-(m-hydroxyphenyl)-1-phenethyldecahydroisoquinolines. and 1-cyclohexylmethyl-3a-phenyldecahydroisoquinoline.




edit, again: actually he's citing a Boekelheide paper from three years earlier.  Based on the description, though, I'm still pretty sure these are from the same family.  Someone better at reading chemistry patents should give it closer look.

Personally, I still think that 4a-(3-hydroxyphenyl)-2-(2-phenylethyl)-decahydroisoquinolin-6-one will be a potent opioid, whether an agonist or an antagonist.  I dunno about the ketone, though.  It serves a purpose on true morphinans, but these more stripped down fellas don't necessarily follow that closely. 

Don't think it's an analogue of anything scheduled, so these could be a fruitful place to work.


----------



## vvViolet

came across this recently (quality; sorry).  have no idea.  curious.  please help.


----------



## polymath

^ that's serotonin


----------



## vvViolet

^ ah!  for whatever reason i kept seeing 11 carbons.  my monitor is probably totally broken or something.  anyway, thank you muchly!


----------



## doppelgänger1

What do you think?


----------



## Roger&Me

halogenated amines are explosive.


----------



## Transform

Fluorinated analogues of existing drugs offer a great way to circumvent legislation while retaining a very similar effects profile to the originals. With the exception of things like those above, I think as fluorine chemistry becomes easier and more accessible, we will hopefully start seeing some pretty brilliant analogues.


----------



## doppelgänger1

Actually no random molecule, i saw it somewhere on the internet. What is this?


----------



## JackiesBabyy

Roger&Me said:


> halogenated amines are explosive.



So why is my 2-FMA not exploding in my face when I smoke it?


----------



## polymath

doppelgänger said:


> Actually no random molecule, i saw it somewhere on the internet. What is this?



That looks similar to the antidepressant venlafaxine, but the 1-hydroxycyclohexyl group is connected to alpha-carbon instead of the beta-carbon.

Some alpha-cyclohexyl-phenethylamines have opioid activity, see http://www.scribd.com/doc/48177527/...S-and-R-1-Cyclohexyl-and-1-Cyclohexenyl-2-phe .

EDIT: Oh, you corrected the structure. Then it's venlafaxine.


----------



## ebola?

> So why is my 2-FMA not exploding in my face when I smoke it?



The halogen substitution is on the ring, not the amine.

ebola


----------



## sekio

Even the haloamines that aren't explosive are not things I would want to put in my body - they are freakishly similar to nitrogen mustards (alkylating agents)

See also chloramine


----------



## gladiolus

*2-benzylpyrrolidine*

basically methamphetamine with the n methyl wrapped around to join the alpha methyl carbon, forming a terminal pyrrolidine ring.
I'm having difficulty with my chemsketch program at the moment.
similar terminal structure to the highly active lucigenol tryptamine.
Any thoughts on theoretical activity of these 2 compounds?


----------



## polymath

You mean this?

I can't find any info about 2-benzylpyrrolidine (the compound above), but the structurally similar 2-benzylpiperidine is a shitty stimulant with mainly noradrenergic effects, which doesn't sound promising...


----------



## pr0d1gy

polymath said:


> You mean this?
> 
> I can't find any info about 2-benzylpyrrolidine (the compound above), but the structurally similar 2-benzylpiperidine is a shitty stimulant with mainly noradrenergic effects, which doesn't sound promising...



Based on the OPs description it sounds like the the heterocycle would be azetidine rather than pyrrolidine. It is rather late so I may have misread :S


----------



## Cone

*MDMA - Substituting the Oxygen?*

Would theoretically substituting the "Dioxolane" portion of MDMA with a nitrogen species "Imidazole" or "Imidazolidine" (the saturated equivalent) make this compound more or less active than the parent compound?

Just curious... with seeing all these MDMA-like RC's on the market today (particularly the "furan" types) this idea has piqued my interest.

Is there a simple reason why this wouldn't be a viable substitute for MDMA?

I don't see any reason why it couldn't be synth'd, but I digress its been a few years since I've dabbled in O chem.






Pic related, 9000 hours in MSpaint


----------



## atrollappears

Cone said:


> Would theoretically substituting the "Dioxolane" portion of MDMA with a nitrogen species "Imidazole" or "Imidazolidine" (the saturated equivalent) make this compound more or less active than the parent compound?
> 
> Just curious... with seeing all these MDMA-like RC's on the market today (particularly the "furan" types) this idea has piqued my interest.
> 
> Is there a simple reason why this wouldn't be a viable substitute for MDMA?
> 
> I don't see any reason why it couldn't be synth'd, but I digress its been a few years since I've dabbled in O chem.
> 
> 
> 
> 
> 
> 
> Pic related, 9000 hours in MSpaint



I seem to recall these being horribly neurotoxic. Might have been a Nichols study.


----------



## sekio

Either that or the hydrogen bonding is not right to provide activity.


----------



## Vader

http://symyx-draw.en.softonic.com/download
Don't download the toolbars and shit, but yeah, no more struggling in Paint.


----------



## Ceres

symx draw is great


----------



## Cortexiphan

atrollappears said:


> I seem to recall these being horribly neurotoxic. Might have been a Nichols study.



I didn't find anything in reaxys or scifinder. The benzimidazole looks friendly enough but i don't think benzimidazolines are terribly stable, in vivo or otherwise.


----------



## ungelesene_bettlek

Cone said:


> Would theoretically substituting the "Dioxolane" portion of MDMA with a nitrogen species "Imidazole" or "Imidazolidine" (the saturated equivalent) make this compound more or less active than the parent compound?
> 
> Just curious... with seeing all these MDMA-like RC's on the market today (particularly the "furan" types) this idea has piqued my interest.
> 
> Is there a simple reason why this wouldn't be a viable substitute for MDMA?
> 
> I don't see any reason why it couldn't be synth'd, but I digress its been a few years since I've dabbled in O chem.
> 
> 
> 
> 
> 
> 
> Pic related, 9000 hours in MSpaint


is the single nitrogen in 5-IT not enough for your taste?


----------



## Vader

> symx draw is great


It's OK, no Chemdraw, but it's better than paint for sure.


----------



## Cone

I was just joking about the MSpaint 

I used BKchem to draw those.

Upon further review, it seems the two lone pairs on oxygen are necessary (at least the oxygen in the 4th position) to H-bond with the receptor.

Nitrogen, with its single lone pair + hydrogen would be vastly inferior in this regard. And probably toxic.

There was a thread on here a while back about using "Benzoxazole" (one O and one N) that proved promising...

I wonder if the resonance within the 5-membered ring helps or hurts its potency...


----------



## Limpet_Chicken

I sure wouldn't take a fluoroamine, but I think that the tendency towards explosive decomposition might not be nearly so pronounced with fluorine, compared to the other halides.

Compare nitrogen trifluoride with the other trihalides. Nitrogen trichloride/tribromide/triiodide will explode at pretty much no provocation whatsoever, but the trifluoride is actually used industrially, supplied in pressurized cylinders.


----------



## Ceres

Yes explosive drugs would be interesting, just be very careful when administering per rectum.


----------



## Limpet_Chicken

That could make for a nasty case of, quite literally speaking, explosive diarrhea


----------



## Munroe

Vader said:


> It's OK, no Chemdraw, but it's better than paint for sure.



How does eMolecules compare?


----------



## Vader

To be fair, that seems OK for most uses, I could happily use it to do pretty much anything I would want to for a BL post. Still, Symyx has a lot more features, and is just a more polished and professional product, and it's free, so I don't see why you wouldn't download it, but yeah, that applet (is it an applet?) isn't bad at all (better than some I've been forced to used in the past).


----------



## Ceres

is marvinsketch available free? I don't find symx wanting for anything really, it's pretty good at churning out IUPAC names for structures (although fails with some, like dxm for example). NMR prediciton would be nice perhaps.


----------



## King Kong

Why people doesn't download a cracked chemdraw version on "the pirate bay"?
Ok, it's illegal in most country, but using drugs too...


----------



## Vader

Internet piracy is not something we discuss on BL. Besides, IIRC it's hard to find a valid key.


----------



## nigl

A very good free drawing program is MarvinSketch

Also: Why haven't these been made? Or are they and I am just stupid?


----------



## pharmakos

^^ i would think that furan must have been made, but i cannot find anything about it either


----------



## Limpet_Chicken

I know 2-alkyl BENZOfurans are often/usually hepatotoxins, does this apply to furans also?


----------



## killermunchies

Cone said:


> I was just joking about the MSpaint
> 
> I used BKchem to draw those.
> 
> Upon further review, it seems the two lone pairs on oxygen are necessary (at least the oxygen in the 4th position) to H-bond with the receptor.
> 
> Nitrogen, with its single lone pair + hydrogen would be vastly inferior in this regard. And probably toxic.
> 
> There was a thread on here a while back about using "Benzoxazole" (one O and one N) that proved promising...
> 
> I wonder if the resonance within the 5-membered ring helps or hurts its potency...



6-APB only has the oxygen across from the 3 position and that seems to be active, and 5-IT has no oxygens at all.  5-IT seems to be pretty rough, but it is active.


----------



## Albion

I apologise to any chemists in the house:


----------



## sekio

WHY?

The Texas carbons/nitrogens (hypervalent- no carbon has 5 bonds!) are esp. distressing, and the strained double-bonds don't make this molecule look happy either. Nor the ketene moiteys.

This whole thing would just as soon blow up as exist


----------



## pharmakos

reminds me of froganamine =p


----------



## Vader

> WHY?
> 
> The Texas carbons/nitrogens (hypervalent- no carbon has 5 bonds!) are esp. distressing, and the strained double-bonds don't make this molecule look happy either. Nor the ketene moiteys.
> 
> This whole thing would just as soon blow up as exist


That nitrogen doesn't only have more bonds than electrons in its valence shell, it has more bonds than electrons in all its shells! But I have a feeling Albion knew that his structure might not be the easiest thing to knock up in the lab 


> I apologise to any chemists in the house


I'm sure it's fine, no chemists in ADD


----------



## Albion

Vader said:


> That nitrogen doesn't only have more bonds than electrons in its valence shell, it has more bonds than electrons in all its shells! But I have a feeling Albion knew that his structure might not be the easiest thing to knock up in the lab
> 
> I'm sure it's fine, no chemists in ADD



If nobody has conceived of that specific molecule before, do I get dibs on naming it?


----------



## amanitadine

No problems there  I am sure! I think most folk here would quickly distance themselves from conceiving such a beast!


----------



## Albion

You should have seen the statement of artistic intent I made to justify the molecule's scientific way.

Contains enough bullshit to drown 10 self-respecting adults.


----------



## amanitadine

Well come on with the name then! I think you may have dethroned the reigning batshit crazy chem-wanks in the house . . .( no names mentioned. . . .)


----------



## Albion

T,R-Ollytrol-L-amine


----------



## Pomzazed

This is my molecule:





Don't make a slaughter at me! that dot IS a technically correct structure!!
(it is *methane*, though!)


----------



## klfiend

If 2c-e had a baby with mescaline






2-FMA was pretty sweet, lets get some ring fluorinated phenmetrazine in this bitch






or is this one gonna be the winner?









Think I have heard this was made and disappointing






the phenmetrazine analog to 4-mmc and 4-mma






wonder what happens if we extend the alpha chain?






one more extension for good measure (or to get past bans)


----------



## Vader

If 2C-E had a baby with mescaline, that ethyl group would be in the para position and the methoxyls at both metas. And if we're going for structural isomers of 2C-E, psi-2C-E would be where I would look (although I imagine the duration might be on the high side).


----------



## Ceres




----------



## Vader




----------



## Ceres

Yeah it's obvious where this goes really, next step is a walk around the benzene ring.


----------



## Vader

Because everyone knows that 3,4-methylenedioxy is PURE WIN in any compound.


> Yeah it's obvious where this goes really, next step is a walk around the benzene ring.


The bases are pretty much covered, ketamine/tiletamine etc at the 2, methoxetamine and the 3-MeO-PCxs at the 3, 4-MeO-PCP apparently demonstrating that the para is not where the action is.




Thioether is a bit out there, but I would actually like to see a ketone and a piperidine ring on the same one, that should be nice.


----------



## pharmakos

the 2-Fluoro analogue of ketamine was made by a university in the middle east (University of Iran maybe?  i forget).  i feel like the 2-Fluoro is going to be the winner out of all the 2-Halos.  who knows tho.


----------



## Vader

I asked fnb about it once and he thought that the various halogens would lead to compounds of similar potency.


----------



## klfiend

thenightwatch said:


> the 2-Fluoro analogue of ketamine was made by a university in the middle east (University of Iran maybe?  i forget).  i feel like the 2-Fluoro is going to be the winner out of all the 2-Halos.  who knows tho.



Why haven't any of these alternate halo versions of ketamine hit the RC market, seems perfect to me.  If all your doing is changing the chlorine to another halo I would think it would be a very safe thing to sell from a legal standpoint, ketamine being schedule 3 and for instance 2-fluoroketamine being directly analogous to ketamine.  Not like methoxetamine where it could be easily argued that its an analog of PCE (eticyclidine) a schedule 1 substance.


----------



## pharmakos

unfortunately, things in the RC market are not often determined by logic =p


----------



## Vader

I don't think the case for methoxetamine being an analog of PCE is _much_ stronger that the case for iodinated/brominated ketathings being analogs of PCE.


----------



## doppelgänger1

Any guesses what this might be like? Allegedly it has been produced once by mistake instead of 4-meo-pcp


----------



## amanitadine

thenightwatch said:


> unfortunately, things in the RC market are not often determined by logic =p



  Good point! And nor are the machinations of the powers that be determined by logic! In fact quite the contrary. An analog is pretty much whatever they say it is. . .


----------



## klfiend

4-mmc prodrug if the metabolic route for dimethylcathinone holds true



 

http://en.wikipedia.org/wiki/Dimethylcathinone

How shitty would 4-methyl-N-methylpseudoephedrine be is the question? Since dimethylcathinone metabolizes into methcathinone and N-methylpseudoephedrine. My 4-mmc prodrug would prolly be absolute hell on blood pressure and heart rate...pity.


----------



## Vader

dimethylamphetamine is pretty shit compared to methamp, I imagine "dimephedrone" would be similarly crap. It would also be active in its own right and so not a prodrug.


----------



## pharmakos

too lazy to draw it out right now, but did nichols or whomever ever make any n-methyl-indole phenethylamines?  (i.e. 25x-NBOMe but with an indole instead of the methoxyphenyl)


----------



## sekio

http://en.wikipedia.org/wiki/5-MeO-NBpBrT

A few N-benzylated indoles have been tested but none of them look very promising. Also tested were ones sith a moiety similar to ketanserin.
Ralf Heim was the guy who came up with the NBOMes in his dissertation, by the way.


----------



## pharmakos

ah, i guess i should have actually drawn out the molecule i was thinking of

i didn't mean replace the phenethylamine part with a tryptamine.  i meant replace the other side of the molecule, the methoxyphenyl, with an indole instead.  i know they made the methylenedioxyphenyl version, but did they make an indole version?






25I-NIndMe?


----------



## Transform

sekio said:


> http://en.wikipedia.org/wiki/5-MeO-NBpBrT
> 
> A few N-benzylated indoles have been tested but none of them look very promising







Edit: didn't see the link in there seiko. Here's the picture anyway.


----------



## nigl

klfiend said:


> 4-mmc prodrug if the metabolic route for dimethylcathinone holds true
> 
> 
> 
> 
> 
> http://en.wikipedia.org/wiki/Dimethylcathinone
> 
> How shitty would 4-methyl-N-methylpseudoephedrine be is the question? Since dimethylcathinone metabolizes into methcathinone and N-methylpseudoephedrine. My 4-mmc prodrug would prolly be absolute hell on blood pressure and heart rate...pity.



Isnt 4-MMC itself metabolized to 4-methyl-N-pseudoephedrine? Keto groups get metabolized to hydroxy groups in general, at least I thought so.


----------



## pharmakos

thenightwatch said:


> ah, i guess i should have actually drawn out the molecule i was thinking of
> 
> i didn't mean replace the phenethylamine part with a tryptamine.  i meant replace the other side of the molecule, the methoxyphenyl, with an indole instead.  i know they made the methylenedioxyphenyl version, but did they make an indole version?
> 
> 
> 
> 
> 
> 
> 25I-NIndMe?



so this stuff hasn't been made before?


----------



## ungelesene_bettlek

can anyone recommend me a good and free program to draw organic molecule structures?


----------



## pharmakos

^^ there was a bit of discussion about such programs like two or three pages back in this thread


----------



## Vader

Accelrys Draw is what I use.


----------



## Lombergerh

*2-nitroamphetamine/4-nitroamphetamine*

Can anybody tell something about this?
Is it even possible? Active?


----------



## Jesusgreen




----------



## sekio

JG, that molecule has been "thought up" before but it does not have LSD-type central activity I'm afraid


----------



## Jesusgreen

Shame, it's pleasing to the eye though, like a molecular starship. 

Or a weird drunk alien..


----------



## sekio

This conspiratard blog wrote a whole bunch of speculative garbage about a related-looking compound.






The blog really lays it on thick. 90% of it is bull shit backed up by one guy's assertion he's an 3l173 ch3m1z7...


I worte some slag about it on Reddit -


> All known tryptamine/phenethylamine SAR models suggest that this compound is going to be much less active than the Mysterious Gentleman suggests. The racemic parent compound with no 5-methoxy or ethylthio substitutions is known in PubMed as RU-28306 but the article claims it is only equipotent to DMT at 5-HT2 (this was obviously before the eludication of the 5-HT2 subtypes). It is also totally synthetic, no such compound occurs in fish, and moreover no large-scale extraction of rare tropical fish occurs with any regularity.
> 
> 7-substitution on tryptamines enhances only toxicity as far as I can see - 5,7 dihydroxytryptamine is a neurotoxin. The 7-substitution motif was discussed in some depth at Bluelight and they concluded that 7-substitution is essentially useless (7-meo drugs are generally inactive). Fuunnily enough the 5-meO 7-etS motif was mentioned there.
> 
> This smells to me like the work of someone who knows just enough SAR to be dangerously incorrect. This compound is totally novel, likely not in production, and with 90% certainty I can say it will lack the claimed "potency", even as a drug cocktail.



The diethylamine analog you drew is probably more of a 5-ht1a agonist than anything else. I think it might be active but not very fun.


----------



## Cortexiphan

thenightwatch said:


> ah, i guess i should have actually drawn out the molecule i was thinking of
> 
> i didn't mean replace the phenethylamine part with a tryptamine.  i meant replace the other side of the molecule, the methoxyphenyl, with an indole instead.  i know they made the methylenedioxyphenyl version, but did they make an indole version?
> 
> 
> 
> 
> 
> 
> 25I-NIndMe?



The 4-bromo analogue has been made!


----------



## pharmakos

^^ awesome paper, thank you!


----------



## ungelesene_bettlek

I would like to draw random molecules as well; can someone recommend me a free software for windows to do so? I have just installed windrawchem, but it runs a little bit too unstable for my taste... 8(


----------



## Roger&Me

^marvinsketch is pretty good and IIRC it is free. 

So anyway, last month I was involved in a project developing some methodology for the direct esterification of phenols with organic acids... I won't get into synth discussion, but I know for sure cresols and catechols can be esterified under the right conditions. This got me thinking: what if one were to esterify the phenolic hydroxy group on THC with cypionic or propionic acid, with the goal of generating an ultra long-lasting derivative analogous to depo esters of steroids. 






My question is, since this is a phenolic ester, would it be readily metabolized back to the parent hydroxy compound in a way analogous to how regular esters are metabolized? In other words, would this phenolic ester be suitable as a prodrug for THC? Is it likely to have activity of its own?

I'm not planning on trying to make this, nor would I have the means to do so even if I wanted to... but its an interesting idea, at least upon first consideration, and I'd be interested to hear any input from people who know their pharmacology. Thanks


----------



## ungelesene_bettlek

Roger&Me said:


> ^marvinsketch is pretty good and IIRC it is free.


thank you a lot for the good hint! this is indeed bigger, more powerful and more stable than windrawchem; and much more so! 

I am particularly impressed by its ability to recognize loads of chemicals. but there are also some strange things I noticed: e.g. it recognizes hydrogen cyanide as "cyclon"; is this some kind of weird joke? also it refers to PCP as "selma" - what the hell is that supposed to mean?


----------



## Cortexiphan

ungelesene_bettlek said:


> thank you a lot for the good hint! this is indeed bigger, more powerful and more stable than windrawchem; and much more so!
> 
> I am particularly impressed by its ability to recognize loads of chemicals. but there are also some strange things I noticed: e.g. it recognizes hydrogen cyanide as "cyclon"; is this some kind of weird joke? also it refers to PCP as "selma" - what the hell is that supposed to mean?



Zyklon B was the "trade name" for HCN used by Nazi Germany to exterminate jews during WW2


----------



## ungelesene_bettlek

Cortexiphan said:


> Zyklon B was the "trade name" for HCN used by Nazi Germany to exterminate jews during WW2


yes, using nazi trade names is exactly what I meant with "weird"...


----------



## Gaius

Didn't feel like this warranted another thread, but guys, you should draw some silicon-containing analogues.


----------



## klfiend

I'd put this in me


----------



## MollyFein74

*Pyrole-ring substitued for methylenedioxy-ring on MDxx substances?*

Just an idea I came up when I was tweaked out and have always been curious about it - MDMA consists of meth with a methylenedioxy ring on it, what would the subtance be called and would it have any pharmacology if the MD ring was swapped for a pyrole ring instead, the ring on tryptamines?

Potential strogner serotonin receptor agonism? Is it even possible?






3,4-Benzopyrollemethamphetamine, potent non-neurotoxic, serotonin releasing agent/5ht2a agonist? Or is it not active or am I just wasting time.


----------



## TCMVegas

I assume that the methylenedioxy ring on MDMA has the pharmacological significance of being highly electronegative. A pyrole ring is much more weakly electronegative, I wouldn't expect it to do much. 

I'd expect it to be a not-so-great amphetamine. Perhaps similar effects-wise to 4-FA? Anyone care to weigh in on that? (4-FA releases 5-HT)

(note: "weaker" version of meth, not "tweaker" version of meth )

-TCM Vegas


----------



## sekio

This is an isomer of AMT. 



			
				A. Shulgin said:
			
		

> And there are five possible chain relocation, from the normal 3-position to the 2, the 4, the 5, the 6 or the 7-positions. All five "alpha-methyltryptamine" isomers are known, but only one is known to be active in man as a CNS active material. This is the 5-isomer, 5-(2-aminopropyl)indole or 5-IT, which, at 20 milligrams orally, is a long-lived stimulant producing increased heart-rate, anorexia, diuresis, and slight hyperthermia for about twelve hours.



this compound depicted is 6-IT. Ifyou flopped the nitrogen around to the "bottom", it's 5-IT.
5-IT is known to be neurotoxic and generally stressful as a recreational drug, it's probably not anything worthwhile... (I think there have been deaths from 5-IT in the Nordic countries)


----------



## Transform

Is it _known_ to be neurotoxic?

There have indeed been deaths from 5-IT where it has been sold as ecstasy (in scotland) or 6-APB (in sweden). The incredibly slow comeup leads to people taking more because they think it's weak when it's not at all.


----------



## sekio

I would put good money on it being a neurotoxin just because it's a potent monoamine releaser.
Put it this way, I don't think it's an excellent MDMA replacement.


----------



## cannibalsnail

Monoamine releaser =! neurotoxic. 

Take a look at Methylone, MDAI, 4-FA and arguably Amphetamine.


----------



## Incunabula

I just got interested in jimscaline, but I'm not completely clear on understanding it's structure compared to mescaline.

I see that it's an indane, with the 2 rings. but does jimscaline also have 3 methoxy groups like mescaline? Or are they something different.






edit:
I guess I just found my own answer in the IUPAC.
1-(4,5,6-Trimethoxy-2,3-dihydro-1H-inden-1-yl)methanamine


----------



## Transform

Right, so it's not _known_ to be neurotoxic then. I am sure it could be neurotoxic but you can probably see why I was confused.


----------



## sekio

Given how close the structure of 6-IT is to other known monoamine toxins (IAP, 5-IT, MDMA) I would put money on it causing 5HT depletion.


----------



## cannibalsnail

sekio said:


> Given how close the structure of 6-IT is to other known monoamine toxins (IAP, 5-IT, MDMA) I would put money on it causing 5HT depletion.



Citation on the toxicity of IAP and 5-IT please Sekio?


----------



## sekio

Honestly, you got me, I pulled that out of my ass.
There's been discussion on 5-IT before. 

I don't think that MDMA, MDA, and methamphetamine are the *only* stimulants that are neurotoxic if abused.

But honestly the evidence, to me, seems to suggest MDMA's toxicity is something that can be easily migitated by not acting like a 14 year old when it comes to dosing. In single bolus doses of 100-180mg, or even with a single half-size "boster" a few hours in, there's basically no reason to worry about monoaminergic toxicity in a well-fed and watered individual who isn't overheating in a club. With this in mind drugs like IAP et cetera that are reported as "rougher" than MDMA don't seem to me like less toxic substitutes...

There are papers that show methylone is not cytotoxic until combined with methamphetamine. Not sure what the implication of that is.

all I know is amphetamines are unlikely to be "potent non neurotoxic serotonin releasing agents". amphetamine type euphoriants are generally toxic at some level. and I would rather be telling people to be cautious rather than assuming it's non-toxic because there's been no reports of toxicity posted here.

some people use 4-bromo-methcathinone. would I touch it? not with a fucking barge pole.


----------



## cannibalsnail

I think its well established that the selective serotonergic toxicity of MDMA/MDA is due to metabolisation into an alpha-methyldopamine analogue: http://www.ncbi.nlm.nih.gov/pubmed/9128836

This explains why co-administration of MDAI with d-AMP showed toxicity and why users feel a worse hangover when combining MDMA and Amphetamine.


----------



## sekio

> [MDxx's metabolism to bis-glutathionyl-alpha-methyl-dopamine] explains how [...] MDAI with d-AMP showed toxicity



I don't follow. Neither amphetamine nor MDAI have a metabolic pathway to a-methyldopamine. (I can see the methylenedioxy ring busting open, but ring-hydroxylation of amphetamine is 10 to 50 times harder to do metabolically.)

I was under the impression that a wide variety of factors contributed to the so-called toxicity of MDMA. Namely, strong multi-monoamine release activity causing oxidative stress and elevation of body temperature. The massive monoamine release seems to be the biggest player in causing shitty after effects. 

How do you account for the toxicity of amphetamine (at high doses) and methamphetamine, on their own, then? I don't think the human liver will hydroxylate amphetamine in the 3' position. It will do the 4'position and make alpha methyl tyramine/4-hydroxyamphetamine but I don't think it will take it all the way to a-methyl-dopamine. And dopamine sure as shit won't get alpha-methylated.

I do know the *really* toxic amphetamines like 4-chloroamphetamine, 4-methylthioamphetamine, etc. are very powerful monoamine releasers. Some of them are MAOI's too. Maybe the real mark of toxicity is just a low EC50 for monoamine release. (But also, mephedrone is apparently not toxic to brain cells, and that's a powerful releaser.)

TL;DR: I don't know left from right. Please punch me in the face in front of my church friends.


----------



## amanitadine

Ditto. The "alpha methyl dopamine" metabolite is  just a piece of the puzzle, as the literature currently agrees. Not the sole factor!


----------



## MollyFein74

Even if, however it got there in the first place, alpha methyl dopamine was present, HOW would it be neurotoxic... taking into account dopamine itself is a catelcholamine and it functions at the dopamine receptors wouldnt its a-methly counterpart just provide a stronger attachment to the receptor or am i way off. I cant see how alpha methly dopamine is any more toxic than dopamine taking into account dopamine can oxidise into hydrogen peroxide from the hydroxyl bonds? How dose alpha methylation affect that?

Is it proven that alpha methly dopamine is even a HUMAN metabolite of MDMA? IIRC, it is in rat studies a metabolite? Im a firm believer that breakdown of dopamine into hydrogen peroxide occuring in serotonin neurons is the primary cause of serotonergic neurotixicty thus throwing amphetamine or any dopamine-releaser into the mix with MDMA or any other serotonin releasing drug causes drastically increases neurotoxicity.


----------



## cannibalsnail

EDIT: then why do other triple releasers not cause toxicity. Why does dopamine not cause serotonergic toxicity on its own?

Well if you read the study the dual hydroxylation isn't important, just a Hydroxy group for glutathione to bond to. So anything with an amphetamine backbone without ring substitutions is sufficient. This is coupled with the action of a serotonin releaser to induce transporter phosphorylation allows this new chemical to flow down the concentration gradient and into serotonin neurones where presumably MAO-B is involved in some way, then an unknown leap to oxygen radicals. My speculation is that it inactivates endogenous antioxidants through some mechanism allowing dopamine to be oxidised.

The clincher is the fact that injecting said metabolite directly into neural tissue still yields selective serotonergic toxicity, while injecting pure mdma does not (liver enzymes demethylate MDMA).


----------



## sekio

> EDIT: then why do other triple releasers not cause toxicity



Methamphetamine? The p-haloamphetamines?


----------



## cannibalsnail

Methamphetamine is toxic to Dopaninergic neurones mostly:www.aapsj.org/view.asp?art=aapsj080248

P-CA haven't been studied well enough to truley be claimed as neurotoxins in humans. 4-FA appears to be harmless and in the shulgin index shulgin references 2 studies claiming 4-CA was used in human trials for a year without ill effects.

I remember reading somewhere (but I can't remember where so take this as hearsay) that rather than being neurotoxic 4-CA merely induced SERT downregulation for 24 hours but levels returned to normal after. During this time however it would appear to havecaused serious neurotoxicity.


----------



## MrPorter

Several ideas that have probably been brought up in this thread, can't draw them though so I will explain in best of detail. on phone, tired but with ideas need to write down

Firstly, NBOMes. With a halogen substituent on the nbome. I don't know about positions in terms of activity so come up with the best. Will this work or just silly? 

1b. Other varying substituents on the Benzyl, essentially to the point of symmetry 

2. NPOMes - Phenyl instead of benzyl

3. 6-ethylamine tryptamine. PEA one way, TRYP the other.
4. As above but without tryps ethylamine so a PEA with NHCH2 on the ring. Indole and done before?

5. alpha aminating a PEA. I'd guess inactive/metabolised quickly

6. 2/3/4/3,4 hydroxy AMPs. Neurotoxic I guess?

I like peas, theyre easy to draw.

E: Yes 4 is pretty much 5-API/5-IT


----------



## pharmakos

^^check out the paper in this link



Cortexiphan said:


> The 4-bromo analogue has been made!


----------



## bloodshed344

*Thiophene Based Phenethylamine Psychedelics*

Okay, so looking at MPA, thinking about drugs like MDMA and 5/6-APB made think, why couldn't there be phenethylamine psychedelics with a thiophene ring?  The sulfur at the top could act as an oxygen and you would only need the proper substituents at the 4 and 5 position.  Probably won't work for a variety of reasons, but I figured I'd ask anyway.

Methiopropamine for an example: http://en.wikipedia.org/wiki/Methiopropamine


----------



## crazycatman

Maybe it's possible, there are still a lot of chemicals that haven't been tested for their effects or even synthesized.


----------



## sekio

> The sulfur at the top could act as an oxygen



that's not how it really works; thiophene is aromatic and the sulfur is not as reactive as a "normal" one. the thophenyl group is a bioisostere for phenyl.

you could still have substituted thiophenylethylamines though.


----------



## bloodshed344

sekio said:


> that's not how it really works; thiophene is aromatic and the sulfur is not as reactive as a "normal" one. the thophenyl group is a bioisostere for phenyl.
> 
> you could still have substituted thiophenylethylamines though.


So the sulfur would in no way replace the methoxy that is normally at the 2 position on psychedelic phenethylamines?

I don't think any drugs with this substitution would be that great but who knows.


----------



## sekio

No, not as such.

Refs to chase
http://www.ncbi.nlm.nih.gov/pubmed/2613523 (fulltext)
Wiki - isostere
Wiki - thiophene


----------



## bloodshed344

Thank you for the knowledge.  From what I got from all of that, my idea would be plausible but not the way I said it.  Thiophenethylamine psychedelics seem like a real possibility however.


----------



## pharmakos

here's an under-explored family of sulfur containing phenethylamine psychedelics that imo actually looks pretty promising:

http://en.wikipedia.org/wiki/TOM_(psychedelic)
http://en.wikipedia.org/wiki/TOET_(psychedelic)


----------



## bloodshed344

5-TOM and 5-TOET sound awesome, just like I expected for some reason... I've actually looked at these molecules before in Pihkal and would be interested in getting some of them synthesized for science!  5-TOET sounds amazing.


----------



## pharmakos

and imagine the possibilities when you start toying around with whats at the 4-position


----------



## bloodshed344

thenightwatch said:


> and imagine the possibilities when you start toying around with whats at the 4-position



Exactly!  You know what's up.  TOT-2...  with ethylthio at the 4 position.  too much sulfur in the molecule haha.


----------



## dingophone

Very cool, TOT and TOET look pretty rad.

Has anyone looked into 5-isopropoxy tryptamines by the way? The substituent might be too bulky, but the resemblance to 5-EtO-DMT (which IRC is active) is too tempting...


----------



## sekio

There are drugs like 5-nonyloxy-tryptamine that have been synthesized, they are selective for the 5ht1d receptor, may or may not be worthwhile in humans; I haven't read of any bioassays.


----------



## dingophone

sekio said:


> There are drugs like 5-nonyloxy-tryptamine that have been synthesized, they are selective for the 5ht1d receptor, may or may not be worthwhile in humans; I haven't read of any bioassays.


Right, the long alkyloxy chains certainly improve affinity for 5-HT1d, but unless I'm mistake the shorter alkyloxy chains (methoxy, ethoxy, ?isopropoxy?) have greater affinity for 5-HT2a. I guess the big question is here is whether or not isopropoxy is too big to fit the receptor or not.


----------



## dingophone

Also, here's something a bit silly for you guys:


----------



## toastmann

I think something like this was already done with Fluor

Also, was thinking about replacing the oxygen in MDMA with fluor, like 3,4-difluoromethanemethamphetamine. But I don't think that's a valid thing.





Bit of a random question, what are the requirements for an analogue to produce effects ? I have been drawing a lot just for fun the last few hours and the things I took in mind where shape and positive and negative fields.


----------



## sekio

Halogens don't really work like that.


----------



## Black

^^
fluorine does not do that.
and i'm pretty sure the first compound is quite impossible too. even if it were possible, it would be highly mutagenic.



i've been playing with the 5-ht2b receptor model and this thing should fit in nicely:





it could be a psychedelic and serotonin releaser (probably more of a releaser; even more so and less of a psychedelic when you attach another methyl to the N on the left).

another thing that could be interesting is dmt with the nitrogen fixed in lsd's configuration:


----------



## sekio

compounds like that chopped down LSD are known and active as 5ht1a agonists I think.


----------



## Black

sekio said:


> compounds like that chopped down LSD are known and active as 5ht1a agonists I think.



yes, apparently a similar compound (like the molecule above, but lacking the double bond in the upper ring and of course with the fully aromatic indole, which i forgot) has already been tested and called RU 28306, but it's selective for 5-HT2 over 5-HT1. but it's quite an old paper, they're only talking about _the_ 5-HT2 receptor...

edit: there's also a patent of the N,N-dipropyl analogue of RU 28306 as a prolactine inhibitor.


----------



## pharmakos

Black said:


> i've been playing with the 5-ht2b receptor model and this thing should fit in nicely



why 5HT2B?  just for novelty's sake?  i always thought 5HT2B activity contributed more to side effects.


----------



## Black

thenightwatch said:


> why 5HT2B?  just for novelty's sake?  i always thought 5HT2B activity contributed more to side effects.



because they recently made a model of the 2B receptor and someone posted it here in ADD. 

and i don't think that 5-HT2B is that bad at all. activation of 5-HT2B is apparently necessary for mdma-like serotonin release and most nice psychedelics have some affinity for it (lsd has a higher affinity to 2B than any other receptor).


----------



## Incunabula

in the wiki entry for 5-APDB, there's mentioned this:

"Methoxy-substituted analogues of 5-APDB and 6-APDB have also been made and substituted for DOM in animal tests, although they were around 10x less potent than DOM!"

What are these? I really can't get my head around were these methoxy groups are supposed to go? 2,5 on the phenyl ring? 

Also, I'm wondering if the Isobenzofuran analogs of MDA/MDMA could be possible? or maybe they have already been looked into?


----------



## toastmann

What a coincidence ! I was also thinking about isobenzofuran this week!

I think the compounds are called IBF5AP and IBF5MAP (They might have different names though, because I couldn't find much about them.)


----------



## Transform

I would be shocked if the isobenzofuran analogues were stable enough to be affordable to produce or practical to store.



> "Methoxy-substituted analogues of 5-APDB and 6-APDB have also been made and substituted for DOM in animal tests, although they were around 10x less potent than DOM!"



Most likely the analogues of MMDA?


----------



## pharmakos




----------



## sekio

ITT: Texas atoms of all sorts. Learn your valences kids.


----------



## pharmakos

sekio said:


> ITT: Texas atoms of all sorts. Learn your valences kids.



i knew i probably messed it up heh

thats what i get for trying to learn O-Chem from the top down =p


----------



## Incunabula

toastmann said:


> What a coincidence ! I was also thinking about isobenzofuran this week!
> 
> I think the compounds are called IBF5AP and IBF5MAP (They might have different names though, because I couldn't find much about them.)


Nice, there they are  Seems they are in the Shulgin index. Who came up with the APB/APDB names? by the way, and what do they mean? 3-desoxy-MDA and 4-desoxy-MDA makes alot more sense imo. 



Transform said:


> Most likely the analogues of MMDA?


Yeah, I guess that must be it...


----------



## Transform

The AP(D)B names are just abbreviations of the IUPAC naming schemes: 6-(2-*a*mino*p*ropyl)*b*enzofuran


----------



## gladiolus

*PB22 weirdness*






OK so many of you might not be familiar with this compound, it's the latest cannabinoid synth attempt to get around recent US and UK bans.
I have a real issue with this compound, I feel that it activates 5HT2A receptors and also acts as a partial NMDA antagonist.
I think people will be getting themselves into lot's o' mess with this one.
Bizarre, isn't it, to think that the major players in construction of the advance of psypharm is not in fact global science but bureaucracy.


----------



## sekio

Any evidence for those claims other than "it feels wierd"? Most of these cmpds seem very selective for CB1/2 over other targets, and overstimulation of CB1 can lead to very strange psychotic effects...


This cmpd is also known as QUPIC


----------



## blowjay

I got a bit bored and decided to post a few of my ideas, let me know what your thoughts are:


----------



## blowjay

That should be enough to get someones mind working.


----------



## Incunabula

last one: methylenedioxy-methylphenidate  ha ha


----------



## Doses

why hasn't this come about yet? Or any other azetine derivatives of pyrridines?


----------



## sekio

azetine rings are rather hard to construct.

also, blowjay, many of those compounds are hemiaminals, ketals, or lactones, so they wouldn't be very stable.


----------



## spephspeph

What happens if you add an acetyl group to the beta position on phenethylamines?


----------



## Black

spephspeph said:


> What happens if you add an acetyl group to the beta position on phenethylamines?



you mean like this:




?

then you'd get ephedrine and acetic acid because it's quickly cleaved by esterases.


----------



## spephspeph

Black said:


> then you'd get ephedrine and acetic acid because it's quickly cleaved by esterases.



Ooh ok. 

What about somewhere on the ring? (Still learning here )


----------



## Hammilton

What would be the point?

For moronic ideas: how about the nitrate ester of ephedrine?

It'll counter the increased blood pressure 

or explode


----------



## Black

Hammilton said:


> What would be the point?
> 
> For moronic ideas: how about the nitrate ester of ephedrine?
> 
> It'll counter the increased blood pressure
> 
> or explode



haha 

but why stop at one nitro group? trinitro-ephedrine would be fun, who doesn't like drugs with explosive effects


----------



## pharmakos

speed that you can really bang


----------



## blowjay

sekio said:


> azetine rings are rather hard to construct.
> 
> also, blowjay, many of those compounds are hemiaminals, ketals, or lactones, so they wouldn't be very stable.



How about the last one, any thoughts on it?


----------



## blowjay

Was wanting to throw this one out there last time since 3 and 4 meo exist, why not bridge them?


----------



## ebola?

hammilton said:
			
		

> For moronic ideas: how about the nitrate ester of ephedrine?
> 
> It'll counter the increased blood pressure
> 
> or explode



Let the future of terrorism be explosives concealed as research chemicals. 

ebola


----------



## dingophone

blowjay said:


> Was wanting to throw this one out there last time since 3 and 4 meo exist, why not bridge them?


That's super cool, 3,4-MDPCP?  I'd like to see the pharmacology of that one haha.

Here's some things I've come up with recently.
DMAA-based tryptamine analogue:





Non-hepatotoxic analogue of amineptine:





Methylenedioxybenzofuranylpropylaminopentane  or, MDBPAP!


----------



## blowjay

dingophone said:


> That's super cool, 3,4-MDPCP?  I'd like to see the pharmacology of that one haha.
> 
> Here's some things I've come up with recently.
> DMAA-based tryptamine analogue:



I liked this one, have always been interested in DMAA having activity, makes me wonder how much of a ring system is really needed for some recreational activity, propylhexedrine always intrigued me, what would a cyclohexene ring do instead and what about placement of double bond?

I am wondering about analogs of Phenmetrazine as well, why not move the oxygen over one closer to the nitrogen and see what that does of why not just replace said oxygen with a carbon instead? 

http://www.chemspider.com/Chemical-Structure.14447455.html 

Hell, why not methylate the nitrogen while we are at it? 

Someone entertain my ideas, always wanting to 'learn' (or at least ask questions).


----------



## dingophone

blowjay said:


> I liked this one, have always been interested in DMAA having activity, makes me wonder how much of a ring system is really needed for some recreational activity, propylhexedrine always intrigued me, what would a cyclohexene ring do instead and what about placement of double bond?
> 
> I am wondering about analogs of Phenmetrazine as well, why not move the oxygen over one closer to the nitrogen and see what that does of why not just replace said oxygen with a carbon instead?
> 
> http://www.chemspider.com/Chemical-Structure.14447455.html
> 
> Hell, why not methylate the nitrogen while we are at it?
> 
> Someone entertain my ideas, always wanting to 'learn' (or at least ask questions).



For some types of activity it certainly seems necessary. For this one, I would wonder if the absence of the pyrole ring would make a huge difference. It might prevent 5ht2a binding, but I'm not 100% sure. I think it might still have SERT affinity though, and might act as a releasing agent. Some cyclohexene ideas have been thrown around before actually, and I think it's a ripe field for discover 

I'm not honestly sure how removing the nitrogen would affect it. I would assume it would keep some sort of dopaminergic activity based on the structure of amineptine, but it could be a reuptake inhibitor rather than a releasing agent. Changing the position of the oxygen probably wouldn't change much.

Haha they actually have done that: http://en.wikipedia.org/wiki/Phendimetrazine 
Makes it into a prodrug!

Also, here's something else I made hoping to find a dopamine agonist/reuptake inhibitor and GABA transanimase/reuptake inhibitor (based on dopamine and bamaluzole/muscimol):


----------



## blowjay

dingophone said:


> Also, here's something else I made hoping to find a dopamine agonist/reuptake inhibitor and GABA transanimase/reuptake inhibitor (based on dopamine and bamaluzole/muscimol):



http://en.wikipedia.org/wiki/A-68,930

Check out this interesting fellow, not quite what you were wanting but very interesting IMO.

I am a bit interested in this guy below

http://en.wikipedia.org/wiki/A-77636

I find bromantane is useful and have stumbled on (distantly) related stimulants, the anxiolytic + stimulant combo is very ideal.

As an added bonus I will throw in another interesting dude below:

http://en.wikipedia.org/wiki/SKF-82958

I hope you find these at least mildly interesting, dopamine agonists seem to be extremely variable and have always intrigued me. 


Would love to find 'functional' dissociative with mild dopamine release, IMO this would be the perfect everyday boredom buster. Tune out everyone else but your self and your ambitions/duties and have motivation whilst doing so. Maybe throw in some neuroprotective properties for good measure but ehh sometimes we think a bit too much.


----------



## sekio

dingophone, that compound would sooner fall apart than be absorbed by a human cell. Typically the N-CH2-OH motif is pretty... uncommon warranting to its ability to decompose to formaldehyde and an amine.

Aromatic rings are needed for activity at most transporter sites and things like serotonin receptors - the exception tends to be the adrenoreceptors which seem to be pretty promiscuous for alkylamines especially (see, for instance, tuaminoheptane... possibly one of the simplest drugs?). I think NET has a little tolerance for bulky alkyl groups in general, but remember that propylhexidrine (hexahydro-dextro-methamphetamine) is about 1/100 - 1/1000 as potent as the drug it is 'derived' from !

Nobody gets arrested for extracting nasal inhalers to sell on the street, either...

Also, to my knowledge, nobody but rats and monkeys have been trialed on wierd ass D1 full agonists. I can only imagine using such a drug would have an effect somewhat similar to that of a rampaging bull in a china shop on the psychology of most people. A drug with no primary effects - not a stimulant nor a depressant nor a hallucinogen, that just induces reward? Seems like something out of a bad remake of Limitless...


----------



## dingophone

^ That makes sense. I am not sure what I was thinking lol.

Would these be a bit better?









I suspect the 2nd one would have the same issue (formaldehyde and amine), but I admit metabolism is not a strong suit of mine.


----------



## sekio

Those still look too polar and small-molecule-y to me... the second has a Texas carbon, you can't have a lactone with an unsaturated c=c bond.

lactones (lactams) will generally open up to the alcohol+the acid, (like gbl -> ghb) in vivo, the reason for salvinorin A's rapid metabolism etc


----------



## ebola?

sekio said:
			
		

> remember that propylhexidrine (hexahydro-dextro-methamphetamine) is about 1/100 - 1/1000 as potent as the drug it is 'derived' from !



Given anecdotes of recreational use, I think you're off by at least an order of magnitude (125-250 mg is a typical dose)...but it's not like anyone's run the relevant binding affinity or ec50 screenings.

ebola


----------



## dingophone

^ Well fuck. I need to not make chemicals when I'm tired and high lol.


----------



## blowjay

sekio said:


> Also, to my knowledge, nobody but rats and monkeys have been trialed on wierd ass D1 full agonists. I can only imagine using such a drug would have an effect somewhat similar to that of a rampaging bull in a china shop on the psychology of most people. A drug with no primary effects - not a stimulant nor a depressant nor a hallucinogen, that just induces reward? Seems like something out of a bad remake of Limitless...



The first molecule was being used to showcase its own uniqueness, antidepressant with anorectic properties producing wakefullness.... but also producing sedation? Just seems a bit crazy to me and I was giving that to dingophone to chew on, these things can be a little crazy.

The last 2 I listed did have primary effects, to quote the wiki article(s):

A-77636 is a synthetic drug which acts as a selective D1 receptor full agonist.[2] It has nootropic, anorectic, rewarding and antiparkinsonian effects in animal studies,[3][4][5][6][7] but its high potency and long duration of action causes D1 receptor downregulation and tachyphylaxis,[8][9][10] and unlike other D1 full agonists such as SKF-82,958, it does not produce place preference in animals.[11] A-77636 partially substituted for cocaine in animal studies, and has been suggested for use as a possible substitute drug in treating addiction,[12] but it is better known for its use in studying the role of D1 receptors in the brainstimulant effects

SKF-82,958 is a synthetic compound of the benzazepine class that acts as a D1/D5 receptor full agonist.[1][2] SKF-82,958 and similar D1-like-selective full agonists like SKF-81,297 and 6-Br-APB produce characteristic anorectic effects, hyperactivity and self-administration in animals, with a similar but not identical profile to that of dopaminergic stimulants such as amphetamine.[3][4][5][6][7][8][9][10][11]

Not to say they shouldn't stay with the monkeys and rats but they do seem to be interesting compounds.


----------



## MrPorter

In LSD, there's the phenethylamine structure mixed with tryptamine, so we basically get AMT with a methyl on the 4-position joined to the alpha methyl, creating a cyclohexane. Would this have any activity on it's own, do you think? 
How about the same thing again, but with an Oxygen bridging from the alpha to the 4-position?
Or with N,N-DiMethyl?

I just tried turning AMT into a fraction of LSD, so I imagine they've been attempted before but couldn't find anything.
I'll try and upload images in a tic.


----------



## sekio

Compounds like this?

http://en.wikipedia.org/wiki/RU-28306
http://en.wikipedia.org/wiki/Bay_R_1531

They are known and as far as I can tell non-psychedelic. But they are certainly centrally active *somehow*. I don't think they have been trialed in human usage.

The "let's staple the chain of a tryptamine onto itself to make a pseudo-ergoloid" idea has been kicked around for quite a long time. Never seen it pan out.


----------



## pharmakos

*RU-28306*

that looks pretty promising to me actually... possibly active itself, and ripe for substiution


----------



## pharmakos

because i'm bored and wanted a chemgiggle:






MDLSD-NBOMe


----------



## Black

^^ i've posted that one (with an added double bond to make it planar like lsd) two pages back. based on the old and not very specific receptor binding data for the one you have drawn, it could very well be active. i'm damn sure it is, but it has apparently never been tried in man.


^ haha, almost certainly inactive. i haven't looked closely at a 5-HT2A receptor model lately, but i've looked at the 2B model recently and have come to the highly speculative conclusion that the nitrogen in tryptamines and the nitrogen in phenethylamines bind at totally different places (that they require different substitution patterns also hints at this. most phens are most active as primary amines, but most tryptamines are inactive if not substituted [best activity usual with one methyl]). the pyrolle part of the indole rather seems (to me) to take the place of the 3 and 4 positions on the phenethylamine. my own stupid attempt to bring them all together in the same molecule is again two pages back


----------



## perfectphase

First timer compounds, just for fun.


*NSFW*:


----------



## pharmakos

^^ i see what you're doing with the first one, but whats that second one supposed to do/be?


----------



## perfectphase

The second one is a twist on AMT, something like "AMT-FLY"... I Don't know if it would do much, but it's visually interesting.


----------



## pharmakos

oh duh yeah i see the AMT skeleton now.

definitely visually interesting, but not likely to do anything too psychedelic =p


----------



## perfectphase

Another wild leap...


----------



## babylonboy

Playing around with some aminorexy/phenmetraziney things. Obviously the lactone won't be stable, and the last one is only there because it's a time-honoured ADD tradition that no chemwank reaches climax before you reach the methylendioxy motif, but I still think it's an interesting area, you could play around with regioisomers and saturation and whatnot until the cows come home, and these things wouldn't be covered by UK catch-all clauses.

EDIT: Looking at one of these things makes me wonder, has a-fluoroPEA ever been made?


----------



## Xaerne

Been thinking about this fella.


----------



## sekio

analog of http://en.wikipedia.org/wiki/Prolintane

generally long-chain stims w/o a beta-keto are less... abusable ... than their beta-keto counterparts. c.f. why mdpv is a drug of abuse, and not prolintane.


----------



## Xaerne

Also a non-beta-keto analog of Pentedrone -- my understanding is that the chain length was responsible for its relatively high potency.


----------



## Transform

My speculation is that with the polar B-keto group the long, lipophilic chain increases BBB penetration but with the amphetamines which already pass the BBB well it just hurts receptor affinity.


----------



## Jesusgreen




----------



## Transform

The primary effect of the close amphetamine analogue is as a psychedelic and cathinones need the N-methyl group for stability, which destroys psychedelic activity.

That would probably leave a pretty second rate stimulant. Why the a-ethyl chain?


----------



## Jesusgreen

My mistake, I'm a tad hungover, this was meant to be what I was drawing:






I don't really know my SAR at all other than making basic comparisons between similar drugs and what effect the change in structure has on their overall effects, so my thinking may be completely along the wrong lines here but I was looking at Buphedrone's structure and thought it might be more interesting if one could shift the balance towards more serotonin release and maybe some 5-HT2A activity.


----------



## ebola?

transformer said:
			
		

> The primary effect of the close amphetamine analogue is as a psychedelic and cathinones need the N-methyl group for stability, which destroys psychedelic activity.



I would argue that the primary activity of the amphetamine analogue is entactogenic instead (as it substitutes fully for other serotonin releasers in animal experiments, but only partially for LSD).  The very few human trials that have occurred (I've read of 2...RIP, coolio :/) suggest effects similar to MBDB.

However, the extended alpha chain and beta-ketone group of the compound shown suggest primary activity as a reuptake inhibitor, not a releaser, and reduced affinity for SERT.  The SAR here is completely different from amphetamine skeleton compounds, and you can't really coax anything except for different selectivities for NE vs. DA and overall potency (that's at least what we've seen with the plethora of crap built from the pentadrone and buphedrone skeletons).

ebola


----------



## sekio

methadone analogues


----------



## bloodshed344

sekio said:


> methadone analogues


Wonder if any of these would be dissociatives.


----------



## Gaius

Does someone know of an example of a drug that is an NMDA antagonist and mu agonist with similar degrees of efficacy, i.e. both effects are felt at about the same concentration?


----------



## pharmakos

bloodshed344 said:


> Wonder if any of these would be dissociatives.



with a bit of squinting the top two look like they could be.  who knows though.


----------



## sipete

Dicyclopropyltryptamine. Not particularly original but as there is a report of McPT being active, this sort of made sense. Anyone know if this has been synthesized (and tested)?

I have been reading BL for years, but this is my first post so please let me know if this breaks any rules/conventions and I will update it appropriately.


----------



## toastmann




----------



## Xaerne

toastmann said:


>



Maybe you've already seen, but there were a few posts back in 2011 talking about 4-trifluoromethylamphetamine:
http://www.bluelight.ru/vb/threads/...amphetamines?p=9448408&viewfull=1#post9448408


----------



## Xaerne

Also there's http://en.wikipedia.org/wiki/Norfenfluramine, with the substitution on the 3 position instead, as well as an N-methyl group.


----------



## pharmakos

sipete said:


> Dicyclopropyltryptamine. Not particularly original but as there is a report of McPT being active, this sort of made sense. Anyone know if this has been synthesized (and tested)?
> 
> I have been reading BL for years, but this is my first post so please let me know if this breaks any rules/conventions and I will update it appropriately.



the cyclopropyl groups sort of look like trumpets or speakers, and therefore i hope this molecule produces action similar to the diisopropyl


----------



## sekio

I heard y'all like cyclopropyl groups.




http://en.wikipedia.org/wiki/Syntin


----------



## sipete

_Now_ we have trumpets (and severe abuse of chemistry).

Also, regarding DCPT activity, I would speculate that it would be closer to DPT than DIPT as the level of auditory specificity of DIPT seems to be extremely rare. I suppose this makes it statistically less likely that DCPT will be close in action to DiPT, but I am just guessing really. Does anybody that knows tryptamine SAR have any ideas?

Also also, that is some pretty interesting looking rocket fuel! Unfortunately, I have now lost an hour reading about different types and the history of rocket fuel.


----------



## pharmakos

chemwank


----------



## bloodshed344

thenightwatch said:


> chemwank



Considering the flourinated and thio analogues are hard to synth, wouldn't this be most likely prohibitively expensive?  I'd love to have it on my receptors though!  I'd be fried!


----------



## Transform

If you wanted fried, why didn't you say so!


----------



## King Kong

thenightwatch said:


>



I would like to see the pharmacokinetic of this one.


Otherwise, I would be very interested to know more on the properties of this cyclic version of mescaline:






It doesn't fit in the classical SAR of psychedelics or stimulants, but it's quite close to pellotine, which is the main alkaloid of lophophora diffusa (old source: http://www.ncbi.nlm.nih.gov/pubmed/647075 ).
So, could be active!


----------



## bloodshed344

Transform said:


> If you wanted fried, why didn't you say so!



Is such a thing possible?  and why would it have such a frying effect?  I'd love to try it however!  I feel like it might lack in potency.


----------



## sekio

https://en.wikipedia.org/wiki/Sulfur_mustard

you would almost certainly not want to try it.


----------



## Transform

Yeah, that was a rather unconventional interpretation of fried. If it managed not to polymerise or autocyclise then it'd probably be all kinds of toxic!





King Kong said:


> Otherwise, I would be very interested to know more on the properties of this cyclic version of mescaline:
> 
> 
> 
> 
> 
> 
> It doesn't fit in the classical SAR of psychedelics or stimulants, but it's quite close to pellotine, which is the main alkaloid of lophophora diffusa (old source: http://www.ncbi.nlm.nih.gov/pubmed/647075 ).
> So, could be active!



Reminds me rather of Lorcaserin, the diet drug which just got approved despite being a significant 5HT agonist.


----------



## dingophone

Been thinking about beta-substituted tryptamines lately...


----------



## MrPorter

^Why the 6-methyl?

I imagine 6-(2-aminoethyl)benzofuran (6-apb without the 'a-methyl'?) would be inactive since MDPEA is, but would 6-(2-aminobutyl)benzofuran be? I'd guess MBDB vs MDMA / Butylone vs Methylone kind of 'downgrading', probably not a winner but active.

Also, cathinone analogue of 6-apb [ 6-(2-amino-propan-1-one)benzofuran ] might be active, but then it would be unstable due to dimerising so we'd need a N-Methyl on that and with the difficulty of synthing 6-MAPB, I can't imagine we'll see this in the forseeable future.

I wonder how trading out Tryptamine's Nitrogen for an Oxygen to produce 3-(2-aminoethyl)benzofuran would work for tryptamine derivatives - we could get N,N-DM... EB? BF? Numbering system is same so we could get the 4-HO/5-MeOs.
Saying that, doing the reverse (tryptamine->phenethylamine structure) didn't exactly work for 5-IT (5-API). I was going to suggest 6-API but Shuglin got there first on that one.


----------



## dingophone

MrPorter said:


> ^Why the 6-methyl?
> 
> I wonder how trading out Tryptamine's Nitrogen for an Oxygen to produce 3-(2-aminoethyl)benzofuran would work for tryptamine derivatives - we could get N,N-DM... EB? BF? Numbering system is same so we could get the 4-HO/5-MeOs.



My idea was to reduce polarity. I actually meant to put it at the 5 position but I fucked up  If I recall correctly, there is a paper that Dave Nichols published a few years back investigating various tryptamine analogues. If my memory is indeed right, it was either the indene or benzothiophene analogues that had the highest affinities for 5ht2a.


----------



## Incunabula

Shulgin mentions these 2 under the BOD entry in PIHKAL  lol

D.E.A (3,5-dimethoxy-4-ethylamphetamine)






I'm assuming this one would be active and a psychedelic. The next one I'm guessing would be a stimulant? if active at all? Did I even draw it the right way? I'm not sure.

C.I.A (4-cyclopropylmethyl-N-isopropylamphetamine)








sekio said:


> I heard y'all like cyclopropyl groups.
> 
> 
> 
> 
> http://en.wikipedia.org/wiki/Syntin


LOL :D It looks like a joke, ha, awesome.



sekio said:


> https://en.wikipedia.org/wiki/Sulfur_mustard
> 
> you would almost certainly not want to try it.



Would the Chloro-thio-methyl  functional group come off in the body and be poisonous like mustard gas? I guess that what your saying, right?


----------



## pharmakos

Fagott said:


> Shulgin mentions these 2 under the BOD entry in PIHKAL  lol
> 
> D.E.A (3,5-dimethoxy-4-ethylamphetamine)



the one you drew would actually be DPA =p


----------



## Transform

Fagott said:


> Would the Chloro-thio-methyl  functional group come off in the body and be poisonous like mustard gas? I guess that what your saying, right?



Kind of - the chlorine comes off to give a sulfonium ion, which is really good at binding to DNA and lots of other things.

Loving those other two you've drawn


----------



## bloodshed344

Transform said:


> Kind of - the chlorine comes off to give a sulfonium ion, which is really good at binding to DNA and lots of other things.
> 
> Loving those other two you've drawn



Hmm, so it's a mutagen?  No big deal, I come into contact with mutagens everyday!  Bring on the 2C-Mustard-gas.

To Fagott:  I like those 3,5,dimethoxy 4-substituted phenethylamines without that oxygen.  cool stuff.  I wonder what a methylthio or a trifluoromethyl or a diflouroethylthio group would do here.  I wonder if it's possible.


----------



## cannibalsnail

I've done it guys. I've created the ultimate molecule. It literally has everything you need. The hydroxylamine looked unstable so I figured a cobalt complex will stabilize it. Then water displaces the cobalt in vitro and the molecule unfolds in all its glory. With the spiritual awakening this will grant its users, surely world peace is imminent.


----------



## pharmakos

maybe today's vitamins were yesterday's recreational drugs =p


----------



## Jktm

*Possibility of New Opioid (spit-balling ideas)*

Would it be possible to engineer a µ/δ agonist with comparable strength to morphine that also acts as a selective, H1/2 antagonist? The idea came to me tonight thinking about how itchy this OP 80 has made me. A powerful opioid that keeps one from getting itchy and nauseated would just be so bad ass.


----------



## bloodshed344

You should go to the draw random molecules thread.  I think maybe a mix of diphenhydramine and tramadol's structure would work.  lol


----------



## endotropic

Jktm said:


> Would it be possible to engineer a µ/δ agonist with comparable strength to morphine that also acts as a selective, H1/2 antagonist? The idea came to me tonight thinking about how itchy this OP 80 has made me. A powerful opioid that keeps one from getting itchy and nauseated would just be so bad ass.



Delta agonists tend to produce convulsions. Why do you want delta agonist activity tacked on there in the first place?


----------



## SkyblueMolly

I enjoy random molecules! How do I post images from paint? It's like BDB-NBOMe.
BDB-NBOMe. Fake molecule!
http://www.flickr.com/photos/62423157@N04/8963345909/


----------



## SkyblueMolly

2m2bOH (2-methyl-2-butanol). Real molecule!
http://www.flickr.com/photos/62423157@N04/8964591874/


----------



## Gaius

endotropic said:


> Delta agonists tend to produce convulsions. Why do you want delta agonist activity tacked on there in the first place?



It'll help to wake him up if he nods off, obviously. :D


----------



## Jktm

The reason for the delta agonism would be for the additional analgesia.


----------



## sekio

Benzonatate aka 2-[2-[2-[2-[2-[2-[2-[2- (2-methoxyethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethyl4-butylaminobenzoate




needs more ethoxy groups


----------



## babylonboy

Is there not some animal toxin (a cardiotoxin perhaps?) that has many many ether groups in sequence?


----------



## spephspeph

Have there ever been ultra long lasting versions of opioid receptor antagonists, or buprenorphine?

Similar to the decanoate ester versions of antipsychotics like haloperidol?

Could this help people detox without having to have a daily dose of something?


----------



## DrPonzi

Sorry guys I'm tweaking and found a free super easy chemdraw! Why haven't one of you synthmeisters produced these yet? Just shut up and take my money!





I happen to be one of the few people who actually thought DMAA was kind of great recreationally. It seems to have affected me quite differently from other people; I actually got an opiate-like very pleasurable long lasting high with some hints of some MDMAish effects at 100mg oral. My uptake is very efficient / I have a very low tolerance / my kidneys might be fucked.

Put me on my ass, just lay around on the couch all day sighing from pleasure because everything felt so great that I couldn't concentrate. Alas, didn't feel too healthy.

No I'm not tweaking on DMAA right now it's not tweaky.


----------



## DrPonzi

Ok so that should have been 5,6-methylenedioxy-4-methyl-hexane-2-amine? And it would be an "analogue" of 2,3-MDA instead of the good one. What if you lengthen the hexanamine to a heptanamine so you can have a 6,7-methylenedioxy?


----------



## DrPonzi

Here are some novel compounds that will blow your mind:


----------



## sekio

The MDO-DMAA would probably fall apart to the diol + formaldehyde. Typically acetals like that are... less than stable.


----------



## bloodshed344

DrPonzi said:


> Here are some novel compounds that will blow your mind:



I like Nitroglyscaline, but shouldnt it be something like Trinitroglyscaline?  Nitroglyscaline should have methoxy groups at 3 and 5.  Also, is it even possible?  and when will then 2C and NBOME versions be out?  Price per gram?  Just joking about those last two sentences...

Also anyone wanna talk about possible activity / possibility of even being created of the 2C with an amine at the 4 position he posted?


----------



## pharmakos

DrPonzi said:


>


^^ idk, but its symmetry pleases me


----------



## cannibalsnail

Diamines are toxic AFAIK although I might be confusing that with aromatic amines.


----------



## babylonboy

That 4-ethylamino 2C is one of the cornerstones of elementary chemwank, been posted time and time again. I don't see why anyone would want a cathinone/dmaa hybrid, and I don't fancy the stability of the MD ring without an aromatic cycle next door. Also, not entirely sure, but that nitroglyscaline might have the potential to really blow you away.


----------



## pharmakos

^ that was the point =p



DrPonzi said:


> Here are some novel compounds *that will blow your mind*:



emphasis mine


----------



## babylonboy

Duh, teach me to only look at the pretty pictures.


----------



## Jesusgreen

First two are just random structures I drew because I liked the look of them, third is self explanatory though dunno if it'd be active.


----------



## babylonboy

Holy hypervalent chlorine, Batman! The last one, I imagine would be active, but not very good, and probably rather long-lived. Without that extra carbon in the middle, that second one could be a kind of arylalkylamine, sort of a PCP-looking thing:




though AFAIK pyrollodine leads to drastically reduced potency over the piperidine, and without a chyclohexane ring it probably wouldn't work at all (take this with a pinch of salt, SAR/chem in general is not my strong suit).


----------



## Gaius

Yeah, that third one seems pretty similar to MDPPP which, let me tell you_, sucks._ I have never seen a drug with a pyrrolidine ring that I liked.


----------



## toastmann

Semi-Serious doodling


----------



## pharmakos

what's the fourth one supposed to be?


----------



## SkyblueMolly

Another photo of a fake random molecule. Leela! http://www.flickr.com/photos/62423157@N04/9096483778/
I don't know why the image code doesn't accept flikr pictures.


----------



## babylonboy

[IMG]http://farm8.staticflickr.com/7326/9096483778_f22d7c958e_o.png[/IMG]


----------



## SeenSoFar

Hi everyone,

Long time lurker, first time poster here. As much as I love all of Bluelight, this thread has always been one of my favourites, because among all of the random chemwanks that are posted, I have noticed more than a few that have some real promise, at least in my opinion. I do have a fair bit of o-chem experience, and while I have often thought up some funny and almost certainly useless compounds over the years, occasionally I do come up with something that I would like to taste, or at least see explored in more detail. I'd like to make my first post here one that provokes some discussion, even if the SAR behind it is perhaps flawed. So I bring you my first public monstrosity: the DMT-with-the-n-pharmacophore-of-ketanserin-thing!






The logic behind it is as follows: Ketanserin is a 5-HT2a antagonist (among other things), but when the (1-ethylpiperidin-4-yl)(4-fluorophenyl)methanone pharmacophore is replaced with the 2-methoxybenzyl one from the NBOMe series, the activity at 5-HT2a is switched from an antagonist to an agonist. When the n-benzyl pharmacophore is applied to a tryptamine, such as with 5-MeO-NBpBrT, the result is a highly selective 5-HT2a antagonist. Could it be possible that the (1-ethylpiperidin-4-yl)(4-fluorophenyl)methanone pharmacophore, when attached to a tryptamine, could possibly have an interesting effect while retaining a reasonable level of selectivity for 5-HT2a and agonist activity? Probably not. From my understanding, there is not very much tolerance for bulk at that position with tryptamines, at least if you want agonist activity at 5-HT2a. Still, it's an interesting idea. I would appreciate any insights or ideas that anyone may have.


----------



## Jesusgreen




----------



## SeenSoFar

Jesusgreen said:


>



I would be very interested in seeing the first one explored in more detail. I'd also like to see the alpha-methylated analogue.

The second one I think would not have the effect you are aiming for. Alpha-methylated n-benzyl phenethylamine compounds are inactive from my understanding. The alpha-desmethyl might have some activity, but I believe it would probably be too bulky for the SERT. Still, it would be interesting to see what effect it did have...


----------



## sekio

N-benzyl-MDA is known and inactive.


----------



## crazycatman

*3,4-dichloro-ethylphenidate*

Hi, I already posted a  few questions on this hypothetical compound in a few other places, but apparently there isn't any info about the compound in question. So I thought ADD would be my best bet.

Anyway for quite some time I've been wondering would such a combination of 3,4-CTMP and EPH be possible to make and what kind of effect it would have. But apparently there is zero info about it online (like nobody ever even bothered synthesizing it). Since this is the most advanced part of the board regarding these things I thought I'd ask my questions here.

-has this ever been synthesised/tested?
-if not is there a particular difficulty in the synthesis that makes it problematic (not looking for instructions so hope this is fine by the rules) or has just nobody tried it yet?
-can anyone make an educated  guess what the effect would be like? similar to 3,4-CTMP? to EPH? to MPH? to a long acting EPH that works at mg doses? something completely different? inactive?
-can anyone make an educated guess about it's toxicity? similar to other MPH modifications? worse? less toxic?
-could did be made by the body in the presence of alcohol the same way MPH can be turned to EPH? Or is it's structure different enough to prevent the enzyme from working? 

Anything else you think about this compound and it's possible properties?

Thanks!


----------



## SeenSoFar

sekio said:


> N-benzyl-MDA is known and inactive.



I don't believe there are any active α-alkylated n-benzyl phenethylamines, are there? I haven't heard of them if there are. If anyone knows of such a compound, I would be very interested in hearing about it. 

I would also be curious to hear how β-substitution worked on N-benzylated phenethylamines. I have not heard of such compounds, but considering that the N-benzyl moiety has been said to shift the binding position relative to the N-desbenzyl parent compounds, I think it would be safe to say that the effect would be different from β-substituted N-desbenzyl phenethylamines.

Has anyone heard of such a compound? If so, has it(have they) been assayed, either _in vitro_ or _in vivo_? What was the result?


----------



## sekio

move to random molecules thread



> I don't believe there are any active α-alkylated n-benzyl phenethylamines, are there?



benzphetamine? or is that a meth prodrug?

technically, the N-benzyl-DOx compounds are active, just 1/10 the potency or less of the "parent" NBOMes.



> But apparently there is zero info about it online (like nobody ever even bothered synthesizing it). Since this is the most advanced part of the board regarding these things I thought I'd ask my questions here.



you could also try a literature search. although if the paper describing 3,4-diCl-TMP doesn't mention the EPH analogue, there's a good chance nobody's made it, because the people doing research have a finite supply of time and money, and making all possible analogues of a compound can be a devlish task.

regarding actual kinetics/toxicity we can't say anything, only guess, until it gets tested. but given the differences between the dichloro-mph and plain mph, one would reasonably expect it to be more selective for DAT & have a longer duration of effects, due to increased lipophilicity.

i seem to recall that the "wrong" enantiomer of ethylphenidate is made in the liver, preferentially, so ethanol+methylphenidate coingestion isn't really as big of a concern as most people make it out to be.


----------



## crazycatman

Sekio, thanks for your indepth reply. I tried another more thorough search and found a few papers describing the various mph modifications including 3,4-diCl-TMP, but nothing about a 3,4-dichloro ethylphenidate (in fact most of the articles than mentioned ethylphenidate were the ones talking about your body making it in your liver if alcohol is present). I also found a thread on another board where some members speculated if 3,4-CTMP could also get transesterified in your body like mph to eph if alcohol is present. No proof of course.

As for your guess about the effects, that be nice if it were true. A longer lasting EPH. If it were also active in mg doses.... well it would make a fine RC as far as I'm concerned.


----------



## babylonboy

Dichloroethylphenidate is just not something that's going to excite the market, if you want to see it it's going to be a labour of love.


----------



## sekio

> A longer lasting EPH. If it were also active in mg doses.... well it would make a fine RC as far as I'm concerned.



This is where Mother Nature throws a big ol' curve ball to us chemists... dichloro-mehylphenidate had a much higher potency, but I recall it lacked the reinforcing effects of rapid administration MPH, because it took so long to reach peak plasma concentrations (higher potency = more fat soluble = poorer absorbtion) Hoisted by its own petard as it were...


----------



## SeenSoFar

So, I was perusing some literature on methaqualone and it's analogues tonight, and it occurred to me that I had never heard of ring-closed analogues. I figured that they were an obvious and possibly interesting avenue of exploration, considering the popularity the all-mighty Quaalude enjoyed at one time. 

Going from the top down, left to right, the first one is methaqualone (duh) (EDIT:The topmost nitrogen in the methaqualone structure should have a double bond connecting it to the carbon on it's right. I don't know how that slipped through...), the second and third are two possible ring closures depending on which ortho- position the methyl group belongs on (I have seen it drawn both ways), the fourth is a combination of the second and third, the fifth is the third with an added double bond to make it planar, the sixth is the fifth with an added amino group (I have seen mention of an amino group at this position increasing potency in literature), and the seventh is something that no chemwank should be without! 

I have a feeling that the second would not be very potent, if active at all, since the modification of the ketone into part of a pyran ring has altered the geometry significantly. The fifth and sixth are perfectly planar, and I would be interested to know what effect this would have on things. Any and all comments would be appreciated!


----------



## bloodshed344

2(I think it's 2)-methoxy MDPEA


Analog of MDA and mescaline.  What do you guys think?  I know the amphetamine version is known but I couldn't find any good description of the effects.






4-methylmescaline

and just because I'm lazy, I'll copy one... cheating I know but I thought of the chemical in my head




A,N,N-TMT aka alpha-methyl DMT.

I would be happy to be the test subject for all of these chemicals, and close derivatives, and the obvious variations (amphetamine versions of the phenethylamines, 4-HO and 5-MeO versions of A,N,N-TMT)


----------



## pharmakos

first one has a mention in the PiHKAL entry for 2-methoxy-3,4-MDA, from http://www.erowid.org/library/books_online/pihkal/pihkal134.shtml



> The product, 2-methoxy-3,4-methylenedioxyphenethylamine hydrochloride (2C-3a) melted at 143-145 °C. A series of subjective evaluations were made, and there are reports of marginal effects in the 40 to 120 milligram range. At 40 milligrams, perhaps the hint of a psychic energizer; at 65 milligrams, there was a pleasant mood elevation; at 80 milligrams, there was a brief paresthetic twinge noted at about the hour and a half point, and at 120 milligrams, about the same at one hour, and then nothing. The fact that there can be such a modest change of effect over a three-fold range of dosage suggests that this compound might have some merit as an anti-depressant. It would be interesting to know if it blocks serotonin reuptake!



second one has a full PiHKAL entry of its own: http://www.erowid.org/library/books_online/pihkal/pihkal052.shtml

the third one surprisingly doesn't seem to have been discussed in TiHKAL, and barely has any google hits

edit -- my google skills suck apparently.  there's a metnion of a,N,N-TMT here http://www.erowid.org/library/books_online/tihkal/tihkal08.shtml

as well as a wikipedia article here: http://en.wikipedia.org/wiki/Alpha-N,N-Trimethyltryptamine

and it even has a very short bluelight thread here: http://www.bluelight.ru/vb/threads/...pha-N-N-Trimethyltryptamine-(-N-N-TMT)-Thread


----------



## bloodshed344

thenightwatch said:


> first one has a mention in the PiHKAL entry for 2-methoxy-3,4-MDA, from http://www.erowid.org/library/books_online/pihkal/pihkal134.shtml
> 
> 
> 
> second one has a full PiHKAL entry of its own: http://www.erowid.org/library/books_online/pihkal/pihkal052.shtml
> 
> the third one surprisingly doesn't seem to have been discussed in TiHKAL, and barely has any google hits
> 
> edit -- my google skills suck apparently.  there's a metnion of a,N,N-TMT here http://www.erowid.org/library/books_online/tihkal/tihkal08.shtml
> 
> as well as a wikipedia article here: http://en.wikipedia.org/wiki/Alpha-N,N-Trimethyltryptamine
> 
> and it even has a very short bluelight thread here: http://www.bluelight.ru/vb/threads/...pha-N-N-Trimethyltryptamine-(-N-N-TMT)-Thread



Thanks, but I've already seen the BL thread on A,N,N-TMT but I wasn't sure if those people had even had the real thing because it's unheard of nowadays.  Also the TIHKAL entry on A,N-DMT had very little info of A,N,N-TMT (it just mentioned it and that was it)

Also, DESOXY (or as I say 4-methylmescaline) seems pretty interesting, but not as good as I hope.  The 4-bromo variant mentioned in the page is interesting too, I'd love to see a TFM there.  Would be a magical molecule most probably.

and the last one, MMDA-3a is not what I was referring to.  The one I posted was the phenethylamine version, not amphetamine.  However MMDA-3a sounds amazing!
_edit:_ Okay thanks for the clarification thenightwatch.

Thank you for the information... I hope to come up with more cool mescaline-MDA mixes.  The idea fascinates me for some reason.  Also I'm dying to try A,N,N-TMT!

But I should have figured most of my ideas were already thought of, haha.


----------



## pharmakos

bloodshed344 said:


> and the last one, MMDA-3a is not what I was referring to.  The one I posted was the phenethylamine version, not amphetamine.  However MMDA-3a sounds amazing!



i know what you meant.  the PiHKAL entry on MMDA-3a has a paragraph on the phenethylamine version (i quoted the paragraph above, note the first line "The product, 2-methoxy-3,4-methylenedioxy*phenethylamine* hydrochloride (2C-3a) )


----------



## SeenSoFar

Just a quick one tonight. I was messing around and figured out a compound that overlays almost 100% perfectly with Ketamine as far as 3D geometry is concerned. I made the cyclohexane ring a piperidine ring to bypass the arylcyclohexylamine analogue laws that have recently been passed in a few locations. I have not found any references regarding this substitution one way or another, so I would be very interested in knowing what effects this would have on activity. Any opinions?

Here is the model, and comparative 3D structures so people can see how it overlays!


----------



## pharmakos

very interesting.  hopefully the nitrogen on the piperidine wouldn't alter activity too much... that's the only glaring difference between the 3d structures.


----------



## SeenSoFar

I almost wonder if the conversion of the cyclohexane to piperidine is even necessary... I don't know that it would even be considered an arylcyclohexylamine even with the cyclohexane intact, considering it is an indoline. Can someone with knowledge of the way the arylcyclohexylamine catch-all is written confirm if this would be considered controlled?


----------



## MrPorter

4-HO-MMT + some other effects like heroin/morphine & 4-AcO-DMT/4-HO-DMT. Was thinking of doing it with the DMT but not sure how that would work. 4 covalents (one coordinate) so N+ ion, plus a negative ion, chlorine or something? Or have a trimethyl on the Nitrogen, keep the diester as an o- and have electrostatic attraction? But yeah, just something fun I made up. Or maybe just a carbonate ion joining both?


----------



## Incunabula

SeenSoFar said:


> Just a quick one tonight. I was messing around and figured out a compound that overlays almost 100% perfectly with Ketamine as far as 3D geometry is concerned. I made the cyclohexane ring a piperidine ring to bypass the arylcyclohexylamine analogue laws that have recently been passed in a few locations. I have not found any references regarding this substitution one way or another, so I would be very interested in knowing what effects this would have on activity. Any opinions?
> 
> Here is the model, and comparative 3D structures so people can see how it overlays!
> 
> 
> *NSFW*:



I don't understand......You made a structural isomer of ketamine? and you expect it to be active?

I guess I just don't get the 3D thing...


----------



## SeenSoFar

Its not a structural isomer, the cyclohexane ring is replaced with a piperidine ring and there is an extra bond as well, with the carbon at the end of the amine chain bound to the piperidine ring to form the 5 membered ring of an indoline. There are also three less hydrogen atoms in the novel compound. 

Ketamine chemical formula: C13H16ClNO
Novel Compound chemical formula: C12H13ClN2O

It is a different molecule with a unique structure, but shares a similarity with ketamine in an important way. Imagine you could take a molecule of ketamine and a molecule of this new compound, and enlarge them to the point that they were visible with the naked eye. You would see two unique compounds with two unique structures. Imagine as well that you could superimpose one on top of the other in 3D space and see how they would overlap. You would see that these two compounds occupy almost exactly the same position in 3D space. The 3D geometry of a ligand is a very important part of its ability to bind to a particular target. The only glaring difference is the nitrogen in the cyclohexane ring, which is why I had asked if anyone had heard of this being tried before and if so, what the results were.

Sorry if I didn't explain myself clearly in my first post.


----------



## ebola?

> Can someone with knowledge of the way the arylcyclohexylamine catch-all is written confirm if this would be considered controlled?



The problem is that it will ultimately be a judge who decides this, not a biochemist (or anyone working in a related field).  So who knows...

VERY intriguing observation, btw... 

ebola


----------



## SeenSoFar

MrPorter said:


> 4-HO-MMT + some other effects like heroin/morphine & 4-AcO-DMT/4-HO-DMT. Was thinking of doing it with the DMT but not sure how that would work. 4 covalents (one coordinate) so N+ ion, plus a negative ion, chlorine or something? Or have a trimethyl on the Nitrogen, keep the diester as an o- and have electrostatic attraction? But yeah, just something fun I made up. Or maybe just a carbonate ion joining both?



***THE FOLLOWING IS HUMOR ONLY AND NOTHING BUT COMEDY HAS BEEN TAKEN INTO ACCOUNT IN MY DESIGN***

Imagine if you will that your compound was to have a tryst with LSD and produce a bastard child... A bastard child that was afflicted with the "LSD-induced genetic damage" that we were told to fear once upon a time... It might look a little bit like this...






*Don't forget, it has a methylenedioxy ring, that means it MUST be chock full of AWESOME!*

EDIT: Just for the record Mr. Porter, I'm just using your compound as a jumping-off point for some silly comedy. I'm not trying to make fun of you or your design. In fact, I find it somewhat intriguing, and while I have absolutely no idea if it would be active, I do enjoy looking at it.

EDIT 2: Is it just me or does the MDO ring stacked on the pyrrole ring look like a man with a sharp jaw wearing a pope hat and cocking his head?


----------



## SeenSoFar

ebola? said:


> The problem is that it will ultimately be a judge who decides this, not a biochemist (or anyone working in a related field).  So who knows...
> 
> VERY intriguing observation, btw...
> 
> ebola



That's always the problem isn't it... The laws are written (necessarily) with language that the person with the gavel in their hand does not comprehend. This leaves them open to having the facts misinterpreted to them for malicious reasons by people who do not have fairness and justice as their goal...

Thanks for noticing and taking the time to reply!:D


----------



## Gaius

Is there any location on the structure of MDA-likes eg MDMA, 6-APB, 5-APB that adding steric bulk doesn't significantly affect their monoamergic activity?

Said another way, when they bind to the transporters are they 'enveloped' or do they have an 'exposed' face that can be structurally elaborated on?


----------



## SeenSoFar

Don't hold me to this, because its late and I can't be bothered to find sources at the moment, but I seem to recall that there is very little tolerance for structural modification in such compounds. Take for example EDMA, it is essentially inactive. MDEA is active but considered to be less enjoyable than MDA/MDMA. It seems those compounds are the sweet spot, and just about any addition takes away from the experience... I will look for concrete references in the morning to back up my wild allegations. :D


----------



## Xerolad

Hey, let me know what you think of this randomness...









They are the same molecule in different configurations, btw.

http://www.bluelight.ru/vb/threads/681398-Activity-of-indole-4-ethanamines


----------



## Transform

SeenSoFar said:


> Just a quick one tonight. I was messing around and figured out a compound that overlays almost 100% perfectly with Ketamine as far as 3D geometry is concerned. I made the cyclohexane ring a piperidine ring to bypass the arylcyclohexylamine analogue laws that have recently been passed in a few locations. I have not found any references regarding this substitution one way or another, so I would be very interested in knowing what effects this would have on activity. Any opinions?
> 
> Here is the model, and comparative 3D structures so people can see how it overlays!
> 
> 
> Spoiler: pics




This of course assumes that the conformer of ketamine you have shown is the active conformer - lots of those bonds can rotate!


----------



## bloodshed344

Xerolad said:


> Hey, let me know what you think of this randomness...
> 
> 
> 
> 
> 
> 
> 
> 
> 
> They are the same molecule in different configurations, btw.
> 
> http://www.bluelight.ru/vb/threads/681398-Activity-of-indole-4-ethanamines


I'm not sure how possible these are, but they could be only stimulants like some analogs of this nature or completely different like cannabinoids with the indole skeleton.



Transform said:


> This of course assumes that the conformer of ketamine you have shown is the active conformer - lots of those bonds can rotate!



and with a molecule as weak as ketamine that's not a good sign.  The molecule posted could be very different.


----------



## Incunabula

SeenSoFar said:


> Its not a structural isomer, the cyclohexane ring is replaced with a piperidine ring and there is an extra bond as well, with the carbon at the end of the amine chain bound to the piperidine ring to form the 5 membered ring of an indoline. There are also three less hydrogen atoms in the novel compound.
> 
> Ketamine chemical formula: C13H16ClNO
> Novel Compound chemical formula: C12H13ClN2O
> 
> It is a different molecule with a unique structure, but shares a similarity with ketamine in an important way. Imagine you could take a molecule of ketamine and a molecule of this new compound, and enlarge them to the point that they were visible with the naked eye. You would see two unique compounds with two unique structures. Imagine as well that you could superimpose one on top of the other in 3D space and see how they would overlap. You would see that these two compounds occupy *almost* exactly the same position in 3D space. The 3D geometry of a ligand is a very important part of its ability to bind to a particular target. The only glaring difference is the nitrogen in the cyclohexane ring, which is why I had asked if anyone had heard of this being tried before and if so, what the results were.
> 
> Sorry if I didn't explain myself clearly in my first post.


I think you did make your self clear, but I still don't understand it  But never mind that.

As your saying, it "almost occupy exactly the same position in 3D space". I don't think "almost" is good enough. If it was to occupy the same space as ketamine, then it would be ketamine (obviously :D) So yeah, to know if your compound has any chance of being active one would have to look at SAR for arylcyclohexylamines. And I don't know too much about that (yet, I intend to learn more, currently I'm digging the phenethylamines) 

I'm grasping this out of nowhere, but it looks so different from ketamine, that if it were active at all, I'm guessing it would be very different in effects.



Xerolad said:


> Hey, let me know what you think of this randomness...
> 
> 
> 
> 
> 
> 
> 
> 
> 
> They are the same molecule in different configurations, btw.
> 
> http://www.bluelight.ru/vb/threads/681398-Activity-of-indole-4-ethanamines


I think you have to make up you mind if you are making a tryptamine or a phenethylamine.

The 2 methyl groups on the nitrogen at the end of the ethylamine is going to make it inactive as a psychedelic phenethylamine. Remove them and you actualy have 2CB-5-hemifly, with the oxygen in the cyclopentane ring exchanged for a nitrogen and with double bonds. Not sure what that kind of ring is called (aromatic? some one enlighten me )

I'd say _that _would actually have a chance of being active (I would guess)


----------



## SeenSoFar

Transform said:


> This of course assumes that the conformer of ketamine you have shown is the active conformer - lots of those bonds can rotate!



Naturally! That's why it's more of a fun little what-if fuck-around than anything serious. After a long day I like to unwind by playing around like this, so I figured I would post when something interesting came out the other end. Speaking of which, here's a few more following the same formula as the ketamine monstrosity.


----------



## SeenSoFar

Fagott said:


> I think you did make your self clear, but I still don't understand it  But never mind that.
> 
> As your saying, it "almost occupy exactly the same position in 3D space". I don't think "almost" is good enough. If it was to occupy the same space as ketamine, then it would be ketamine (obviously :D) So yeah, to know if your compound has any chance of being active one would have to look at SAR for arylcyclohexylamines. And I don't know too much about that (yet, I intend to learn more, currently I'm digging the phenethylamines)
> 
> I'm grasping this out of nowhere, but it looks so different from ketamine, that if it were active at all, I'm guessing it would be very different in effects.
> 
> 
> I think you have to make up you mind if you are making a tryptamine or a phenethylamine.
> 
> The 2 methyl groups on the nitrogen at the end of the ethylamine is going to make it inactive as a psychedelic phenethylamine. Remove them and you actualy have 2CB-5-hemifly, with the oxygen in the cyclopentane ring exchanged for a nitrogen and with double bonds. Not sure what that kind of ring is called (aromatic? some one enlighten me )
> 
> I'd say _that _would actually have a chance of being active (I would guess)



You would be correct and not correct in reference to what you had to say to me. Sometimes almost is good enough, sometimes it isn't. It depends on a lot of things, such as how "tight" the compound you are comparing to binds in the first place, and whether any of the differences that make it "almost" instead of "exactly" create any problems, such as blocking or misaligning with important residues on the receptor. This is my understanding of things anyway, even the best know far from everything on this topic, and I'm by no means anywhere close to that level. Still, you are absolutely correct that there are about 1,000,000 possible things that can go wrong when executing such a procedure, and I've not even made the smallest amount of effort to check for them all. Like I said, it's more of a happy fun what-if exercise than anything else.

By the way, you are correct in your terminology, that particular ring is in fact aromatic, and is called an indole ring (when referring to both the 6- and 5-membered rings as one unit) or a pyrrole ring (when referring to just the 5-membered ring on it's own)


----------



## Incunabula

SeenSoFar said:


> You would be correct and not correct in reference to what you had to say to me. Sometimes almost is good enough, sometimes it isn't. It depends on a lot of things, such as how "tight" the compound you are comparing to binds in the first place, and whether any of the differences that make it "almost" instead of "exactly" create any problems, such as blocking or misaligning with important residues on the receptor. This is my understanding of things anyway, even the best know far from everything on this topic, and I'm by no means anywhere close to that level. Still, you are absolutely correct that there are about 1,000,000 possible things that can go wrong when executing such a procedure, and I've not even made the smallest amount of effort to check for them all. Like I said, it's more of a happy fun what-if exercise than anything else.


I get it :D That twist on PCP looks pretty interesting. 



SeenSoFar said:


> By the way, you are correct in your terminology, that particular ring is in fact aromatic, and is called an indole ring (when referring to both the 6- and 5-membered rings as one unit) or a pyrrole ring (when referring to just the 5-membered ring on it's own)


Thanks, I learn something new everyday 

Besides from LSD, do we know of any active psychedelics that are both phenethylamine and tryptamine?


----------



## babylonboy

All the other lysergamides, for a start. Identifying drugs as containing a phenthylamine or tryptamine "backbone" in their structure is a useful way of classifying simpler chemicals, but with something that has a more complex structure, saying "it is both a tryptamine and a phenethylamine" isn't a very useful way of understanding the nature of the drug. Fentanyl is a phenethylamine in a sense, but no pharmacologist or chemist would categorise it as such, because to do so gets you nowhere.


----------



## pharmakos

Fagott said:


> I'm grasping this out of nowhere, but it looks so different from ketamine



don't look at the line drawing, look at this one:



SeenSoFar said:


>


----------



## electrodevo

SeenSoFar said:


> *Don't forget, it has a methylenedioxy ring, that means it MUST be chock full of AWESOME!*



I had to chuckle when I encountered the kavalactone methysticin for that reason.

(I'm actually surprised how little information there is out there on kavalactones, although my guess is that structurally the isolated compounds would be rather weak in whatever action they have.)


----------



## Jesusgreen

Just playing around, my lack of any decent sort of SAR knowledge leaves me clueless as to whether or not this would be in any way active:


----------



## sekio

active where? i think given its similarity to flavourants like e.g. menthyl benzoate, cyclohexyl benzoate etc it would not be psychoactive, although it might have an interesting smell.


----------



## SeenSoFar

Shady Dealer: "*PSST* Hey kid, over here! I got what you need!"
Kid: "Oh yeah? What's it do?"
Shady Dealer: "Fuckin' nothing! It smells AWESOME though!"
Kid: "...I'll take an ounce."


----------



## sekio

You joke, but some flavourants can be ghastly expensive...


----------



## SeenSoFar

sekio said:


> You joke, but some flavourants can be ghastly expensive...



Of course, it would not make sense if they weren't. The cosmetics industry is all over them, and we all know what kind of prices such products command. I'm not making fun of Jesusgreen's attempt either, the setup was just too good to pass up for that one.


----------



## babylonboy

Aside from smelling righteous, it's going to be chopped by esterases quicksharp, JG.


----------



## SeenSoFar

electrodevo said:


> I had to chuckle when I encountered the kavalactone methysticin for that reason.
> 
> (I'm actually surprised how little information there is out there on kavalactones, although my guess is that structurally the isolated compounds would be rather weak in whatever action they have.)


 
I have heard discussion on using the MDKavalactones as precursors for MDXX production. I seem to recall that the kavalactones are very hard to isolate and pretty unstable too which is why they seem to be relatively unexplored.


----------



## ebola?

>



Is this dimethocaine inspired?  Dimethocaine inspired things are a dead end.

ebola


----------



## SeenSoFar

Here's a long one tonight. The phenethylamine-based compounds are actually based on hard science and theories, while the tryptamines were just a funny way to fill up the rest of the page.

The phenethylamine-derived compounds are based on two methodologies. The first, as tested and theorized by Shulgin in PiHKAL, is that the heavier elements in column 16 of the periodic table can and do substitute for oxygen in phenethylamine SAR, albeit adding their own flavour along the way. The second is the observation that with PEAs, especially releasing agents, the less planar the molecule, the lower the activity. Hence why MD(M)A is beloved, while ED(M)A is for all intents and purposes inactive. After having studied the 3D structures of these and other related compounds, the conclusion that I come to is that the more planar the ring systems are, the more likely it is that the compound will be a winner. Perhaps the transporters do not have much tolerance for non-planar rings... Anyway, armed with these ideas, I have sketched up several compounds that may show promise.

The tryptamines on the other hand are just a hilarious hypothetical into heavy atom benzenes. The phosphorine is the only one that I think might theoretically be active... I also think ingesting it might have unforseen consequences on your health...

Anyway, enjoy!


----------



## babylonboy

The first two are actually the same compound (look at the names)- single bonds allow free rotation, so the two structures are equivalent. The sulfur/selenium/tellurium compounds would stink (literally). As for the tryptamines, your valences are all over the shop, and in general, with all these things, I find myself asking- why? Although I do understand the pleasures of noodling away some time with Chemdraw.


----------



## sekio

i thought the mescaline analogues with sulfurs at the 2/3/5 positions were less active than e.g. 4-thiomescaline

and yeah, the precursors would smell like satan's ass.

also, aromatic rings with phosphorous, boron and *tin*?! i don't think so


----------



## SeenSoFar

Actually, those aromatic rings are real compounds (siline, borabenzene, stannabenzene, phosphorine) they're just hideously unstable! Most of them fall to pieces under anything other than very specific conditions. Hence why I said the tryptamine-esque compounds were nowhere near serious.

As for the phenethylamine-esque compounds, I am aware of the fact that the first two compounds are identical, the original plan was to draw another compound there, so I copy/pasted the first one, made a few changes, and then got sidetracked with something else and never came back to it! By the time I noticed it was already posted and I figured I would just leave it and not say anything .

I do believe that potency is lost with thioether analogues of mescaline as sekio pointed out, but I was more looking for an interesting active compound, not necessarily the next NBOMe . Anyway, its all just a fun diversion. If I thought I was on to something serious I would be calling for custom synthesis. I just love this thread too much!

PS: Could you imagine a powerful psychedelic with a horrendous smell? Imagine the street names it could get! "God's Asshole," "Shit On My Mind," or the ever-so-obvious "Holy Shit!"


----------



## sekio

another nit to pick: the dehydro-ethylenedioxy groups don't look like a stable thing to me... I think it would sooner fall apart to hydroxyacetaldehyde.


----------



## SeenSoFar

I'm not sure in that regard, sekio. I would not be surprised if you're right though. I trust your judgement over mine for sure!


----------



## babylonboy

> PS: Could you imagine a powerful psychedelic with a horrendous smell? Imagine the street names it could get! "God's Asshole," "Shit On My Mind," or the ever-so-obvious "Holy Shit!"


Many (most even) batches of AMT smell like shit.


----------



## SeenSoFar

babylonboy said:


> Many (most even) batches of AMT smell like shit.



This actually worked to my advantage recently. A batch of aMT came in and by smell alone I knew that it was not aMT. Turns out someone made a (possibly intentional) fuck-up and left me the proud owner of far more 5-MeO-DALT than I think I will ever know what to do with... Why couldn't it have been something more interesting that it got mixed up with?!


----------



## Jesusgreen

ebola? said:


> Is this dimethocaine inspired?  Dimethocaine inspired things are a dead end.
> 
> ebola



Indeed it was. 

This next one's probably shown up in the thread at some point already, or at least the non ketone version:


----------



## bloodshed344

Jesusgreen said:


> Indeed it was.
> 
> This next one's probably shown up in the thread at some point already, or at least the non ketone version:


I love replacing oxygens with a sulfur and I love MDMA analogs.  Hard on achieved.

Some ideas I don't feel like drawing...
5-methylthioDMT
alpha-methylpsilocin
4,5-dihydroxyDMT
4-acetyl-5-methoxy-DMT
2,3,4,5,6-pentamethoxyphenethylamine
3,5-dimethoxy,4-trifluoromethylphenethylamine

and finally... 
3,4 Methylenedioxy phenyl bicyclobutanamine (tcb-2 version of mdma because I dont know if the name is right)


----------



## sekio

bloodshed344 said:


> I love replacing oxygens with a sulfur and I love MDMA analogs.  Hard on achieved.
> 
> Some ideas I don't feel like drawing...



*5-methylthio-DMT*
http://www.erowid.org/library/books_online/tihkal/tihkal46.shtml
http://en.wikipedia.org/wiki/5-MeS-DMT
http://www.bluelight.ru/vb/archive/index.php/t-588378.html?


*alpha-methylpsilocin
*
https://en.wikipedia.org/wiki/4-HO-αMT

*4,5-dihydroxyDMT*
unlikely to be very good
http://www.bluelight.ru/vb/archive/index.php/t-319891.html

*4-acetyl-5-methoxy-DMT*
known in masturbatory biosynthetic musings
may actually be a prodrug for 4,5-diHO-Ts.. which may be toxic, see above.
*
2,3,4,5,6-pentamethoxyphenethylamine*
given the low activity of.e.g. tetramethoxyamphetamine, i dunno.

*3,5-dimethoxy,4-trifluoromethylphenethylamine*
probably a winner... 2ctfm is probably also nice


----------



## bloodshed344

sekio said:


> *5-methylthio-DMT*
> http://www.erowid.org/library/books_online/tihkal/tihkal46.shtml
> http://en.wikipedia.org/wiki/5-MeS-DMT
> http://www.bluelight.ru/vb/archive/index.php/t-588378.html?
> 
> 
> *alpha-methylpsilocin
> *
> https://en.wikipedia.org/wiki/4-HO-αMT
> 
> *4,5-dihydroxyDMT*
> unlikely to be very good
> http://www.bluelight.ru/vb/archive/index.php/t-319891.html
> 
> *4-acetyl-5-methoxy-DMT*
> known in masturbatory biosynthetic musings
> may actually be a prodrug for 4,5-diHO-Ts.. which may be toxic, see above.
> *
> 2,3,4,5,6-pentamethoxyphenethylamine*
> given the low activity of.e.g. tetramethoxyamphetamine, i dunno.
> 
> *3,5-dimethoxy,4-trifluoromethylphenethylamine*
> probably a winner... 2ctfm is probably also nice


Thank you very much for all of that especially the info about 4,5-dihydroxy-DMT and the other.  2,3,4,5,6-tetramethoxyphenethylamine is supposed to be more potent than mescaline according to what I read but i'm not sure if I gleaned that information right. Just one thing 4-ho-amt isn't alpha-methylpsilocin.  Alpha-methylpsilocin would be 4-hydroxy-a,n,n-TMT.  Probably less potent than psilocin.


----------



## Hammilton

I'm not suggesting this as a psychoactive.  Obviously it's not (it's diclofenac).

However, what I am wondering is if anyone has ever made a phenethylamine derivative with a substitution pattern like this.  I don't predict any, much less strong activity, but I don't know that it doesn't either.  No one would have suspected the O-methoxybenzyl substitution would have been as potency enhancing as it is for PEA's either.  It wouldn't be hard to take diclofenac and produce a phenethylamine, but I'm not well situated for that (I can throw nitro's on anything though ).  Given that aromatic amines aren't exactly hepato-friendly, perhaps replacing the aniline NH with a simple methylene.


----------



## Hammilton

bloodshed344 said:


> Thank you very much for all of that especially the info about 4,5-dihydroxy-DMT and the other.  2,3,4,5,6-tetramethoxyphenethylamine is supposed to be more potent than mescaline according to what I read but i'm not sure if I gleaned that information right. Just one thing 4-ho-amt isn't alpha-methylpsilocin.  Alpha-methylpsilocin would be 4-hydroxy-a,n,n-TMT.  Probably less potent than psilocin.



I would be careful with 4,5-DiOH-DMT.  Looks like a potential dopaminergic neurotoxin.


----------



## Hammilton

bloodshed344 said:


> I love replacing oxygens with a sulfur and I love MDMA analogs.  Hard on achieved.




Doesn't often work out well.  MPA loses to MA, 4-MTA loses to PMA (hard to believe!) 4-MTMA loses to PMMA too.

Does anyone know of a phenethylamine/tryptamine/amphetamine type drug which a sulfur-for-oxygen substitution produces a favorable result?

I'd probably have to go to depressants to find a good one.


----------



## pharmakos

4-desoxythio-mescaline is 10x as potent as mescaline

http://www.erowid.org/library/books_online/pihkal/pihkal156.shtml


----------



## babylonboy

2CT series is win, 2,4,5-tmpea is inactive.


----------



## MrPorter

What makes the amines so important, why don't we get phenethanols or tryptanols(?) ? Somehing to do with it being basic I presume.

Loved the MrMDPorLSDter molecule as well, I think the MD ring is essentially required to complete any chemwank session


----------



## King Kong

MrPorter said:


> What makes the amines so important, why don't we get phenethanols or tryptanols(?) ? Somehing to do with it being basic I presume.



Yep! If I remember correctly, the amine have to be protonated to bind to the different serotonin receptors. So it's related to the basicity of the amine...


----------



## RtHonLordBob




----------



## endotropic

RtHonLordBob said:


>



Why not give the first one a 5' hydroxy a la serotonin?


----------



## babylonboy

Well, then it would be really unstable and probably too polar too penetrate the BBB well.


----------



## SeenSoFar

I believe the first one was in Ralf Heim's thesis, the same one containing RH-34 and 25I-NBOMe. If memory serves me right it is either untested or an antagonist at 5-HT2a, but I will have to double check to be sure. I am close to 100% positive that he did in fact synthesize it though.


----------



## Pression

*GPCR ligand                 0.23*
*Ion channel modulator       0.30*
Kinase inhibitor           -0.51
Nuclear receptor ligand    -0.18
Protease inhibitor         -0.20
*Enzyme inhibitor            0.22*

miLogP         -1.703

or





*GPCR ligand                 0.28*
*Enzyme inhibitor            0.27*


----------



## QUARE

So how do I link a picture to this? I have a brand new phenethylamine.


----------



## babylonboy

Upload the image to a hosting site then use the


----------



## Cruel Intentions

LOL. This thread is fucking hilarious. I love it.


----------



## QUARE

I let you guys find the name for this


----------



## Cruel Intentions

QUARE said:


>


Impossamine. Did you butcher an idea from Buckminster Fuller?


----------



## QUARE

I only tried to put as much methylenedioxy and phenylethylamine as possible in the same molecule lol


----------



## QUARE

How about this one 
Carfentanil-APB ???

Would it be opioid, serotoninergic, both or none ?


----------



## Cruel Intentions

None. LOL.


----------



## sekio

what's going on with the Texas peroxy oxygen with a methyne off of it?

if you fix that up chances are it wil follow the fentanyl SAR. the presence or absence of methylenedioxyphenyl grous is by no means a metric for "is this an empathogen or not".


----------



## QUARE

Im just playing lol, I have no idea how this work.


----------



## Pomzazed

QUARE said:


> {big picture}
> I let you guys find the name for this



Nay, the molecule will spontaneously decompose to dodecahydroxydodecadehydrocoronene (the core) and 3,4-(2,2-dihydroxymethylenedioxy)phenethylamine.
The latter might then break down to glyoxal too...


----------



## QUARE

Pomzazed said:


> Nay, the molecule will spontaneously decompose to dodecahydroxydodecadehydrocoronene (the core) and 3,4-(2,2-dihydroxymethylenedioxy)phenethylamine.
> The latter might then break down to glyoxal too...



Intresting, would 3,4-(2,2-dihydroxymethylenedioxy)phenethylamine be active ?


----------



## sekio

unlikely. the methylenedioxy group doesn't tolerate much bulk, and chemically a geminal dihydroxy compound like that would decompose to water and 2-keto-MDPEA.


----------



## Incunabula

Ketamine without the ketone? I can't find anything about it, any one knows anything? it must have been made.


----------



## QUARE

(RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexane


----------



## babylonboy

You'll know all about it as soon as AiHKAL is published.


----------



## QUARE

babylonboy said:


> You'll know all about it as soon as AiHKAL is published.



is that a work in progress ?


----------



## ebola?

Everyone wishes it were. . .

ebola


----------



## Incunabula

Shulgin didn't consider arylcyclohexylamines to be true psychedelic entheogens, and didn't care to do any reseach on them.

I think the ketamine analog I proposed without the keto must have been made? it's so obvious. And it must have increased duration than ketamine (?) Since the ketone is making it easier for the body to excrete it.

Funny thing is, as an analog you couldn't call it something with ketamine (like 2-meo-ketamine,n-ethyl-ketamine etc) because the "keta" in ketamine comes from ketone, and it would be pretty stupid to just call it "amine" 8)

Quare, you have some lazy software that writes the right IUPAC?


----------



## pharmakos

desketamine?


----------



## babylonboy

> Quare, you have some lazy software that writes the right IUPAC?


Any software for drawing formulas will do this, I use Symyx Draw.


----------



## QUARE

Fagott said:


> Quare, you have some lazy software that writes the right IUPAC?



Nah, I simply replace the cyclohexanone for a cyclohexane on the ketamine IUPAC name and the molecule is draw from emolecules.com


----------



## Jesusgreen

(Remember I know fuck all about SAR :D if you're wondering why the second one - I based it on the fact that Mephtetramine appears to be active, even if people are reporting poor results. Wanted to make something that looks like it really wouldn't be active but that might be.)

Edit:

I was bored so here's a few more:









I'm guessing the second from last was already made and probably mentioned in PiHKAL somewhere but I was a bit too lazy to check.


----------



## pharmakos

Jesusgreen said:


> I'm guessing the second from last was already made and probably mentioned in PiHKAL somewhere but I was a bit too lazy to check.



http://www.erowid.org/library/books_online/pihkal/pihkal008.shtml


----------



## bloodshed344

Jesusgreen said:


>



This one, along with another DMT analog where the indole ring is replaced with the thiophene ring has been made.  Both are reportedly active.  Read this on BL in a thread from like 2007 or 2009 or something.


----------



## Anon0631

If MDAI is active, what about the DOx analogues?


----------



## pharmakos

^ my completely amateur guess is that those would be active but substantially less potent


----------



## Anon0631

I wonder how the experience would be.


----------



## bloodshed344

Anon0631 said:


> If MDAI is active, what about the DOx analogues?



2C-B-Ind is what this is called.  It's on wikipedia.


----------



## pharmakos

2C-B-Ind isn't quite the same thing.  this is from the 2C-B-Ind Wikipedia article:






the aminoindane version that anon posted looks more promising to me.  2C-B-Ind tries to squeeze an extra carbon atom in there.


----------



## Anon0631

Why hasn't someone invented a machine where you can upload a picture and receive a couple of hundred milligrams of sample to experiment with. It would be much more efficient than all this speculation 

Edit: Should the molecule be called DMAI-B?


----------



## sekio

> Why hasn't someone invented a machine where you can upload a picture and receive a couple of hundred milligrams of sample to experiment with.



it's called a computer 

The rigid aminoindane analogue of DOM was made by Nichols in 1972, as well as the slightly more potent tetralin analogue. It's something close to 1/5 to 1/10 the potency of DOM and has a different character... more of a stimulant, apparently.

see Journal of Medicinal Chemistry 1974, vol. 17,  p. 161


----------



## pharmakos

sekio said:


> see Journal of Medicinal Chemistry 1974, vol. 17,  p. 161



cool

http://www.scribd.com/doc/35944448/Journal-of-Medicinal-Chemistry-Volume-17-Issue-2-1974


----------



## Toz

Anon0631 said:


> Why hasn't someone invented a machine where you can upload a picture and receive a couple of hundred milligrams of sample to experiment with. It would be much more efficient than all this speculation
> 
> Edit: Should the molecule be called DMAI-B?



it's on the way (or well at least someone has the right idea) :D

http://theweek.com/article/index/246091/can-you-3d-print-drugs


----------



## sekio

That's page 151, not 161

here is the article


----------



## Anon0631

Here's another one. If the n,n-diethyl substitution of LSD can be cyclicised to form LSZ - a substance with very similar properties, then can the same logic be applied to DET?






Or DMT?


----------



## sekio

The latter compound is N-methylenetryptimine. Would decompose to tryptamine and formaldehyde.

I think cyclic analogues of DET have been made (pyr-T, pip-T) but they are generally regarded as fucked up poisons.


----------



## Anon0631

It's fun playing this game - well, until someone gets poisoned.


----------



## QUARE




----------



## ebola?

IIRC, pyr-T involved multi-hour blackouts, one of which had the subject walking out onto the street...

ebola


----------



## sekio

QUARE, I don't think you can form S-methoxy thiophenes easily.


----------



## QUARE

I really need to finish that book. lol

Anyway what makes it so hard to form ?


----------



## sekio

they are never observed in chemistry
thiophene-1-oxides have a double bonded oxygen afaik


----------



## QUARE




----------



## pharmakos

tasty


----------



## atara

Surprised this rather promising tree hasn't been barked up a bit more:






			
				ebola? said:
			
		

> Everyone wishes it were. . .



Sadly, the authors keep dying of kidney failure.


----------



## bloodshed344

atara said:


> Surprised this rather promising tree hasn't been barked up a bit more:
> 
> 
> 
> 
> 
> 
> Sadly, the authors keep dying of kidney failure.


What's with the allyloxy?  and can you think of a ghetto hypothetical name for this, it looks very strange.  why not try the amine on the left position instead of where it's at (it's currently at the same spot it'd be on 2C-B-IND but the guys on the last page said the amine would be better to the side)


Obviously I know nothing at all about this.


----------



## atara

Structural rationale: First, allylescaline was the most potent of the mescaline analogs, though cyclobutyl may be somewhat better (and more stable). 

Secondly, jimscaline had improved potency relative to mescaline, while 2CB-Ind had _reduced_ potency relative to 2C-B. But TCB-2 had improved potency relative to 2C-B! What can we make of this?

The key, I suggest, lies in the distance between the nitrogen and the upper-methoxy group, if the molecule is oriented so the amine is at the "top". In 2CB-Ind, the indane actually pushes the nitrogen closer to the methoxy, which is unfavorable, but in TCB-2, the cyclobutane pushes it away, which is favorable. But in mescaline, the ortho methoxy has migrated over to the meta position, increasing the nitrogen-oxygen distance more and making the indane restriction favorable! We can capitalize on this by using the optimal 4-substituent. 

http://pubs.acs.org/doi/abs/10.1021/jm060272y

Also, thiophene S-oxides are hepatotoxic and should be avoided. BTCP is a prime example.


----------



## sekio

> thiophene S-oxides are hepatotoxic and should be avoided



Is it all S-oxides?  There are many thiophene drugs; tiagabine, duloxetine, thiambutenes, sulfentanil, etc. and I don't think they're hepatotoxic.

I would not claim that because benzene is carcinogenic that phenylalanine would be too.


----------



## atara

sekio said:


> Is it all S-oxides?  There are many thiophene drugs; tiagabine, duloxetine, thiambutenes, sulfentanil, etc. and I don't think they're hepatotoxic.
> 
> I would not claim that because benzene is carcinogenic that phenylalanine would be too.



Much like epoxides, S-oxides are reactive intermediates, but, in the same way that not all naphthalenes are metabolised to epoxides (cf naproxen), not all benzothiophenes are metabolized to their S-oxides. The 2-substituted benzothiophenes (BTCP) seem to be particularly susceptible to this transformation. The S-oxides react readily with thiols, i.e. glutathione:

http://pubs.acs.org/doi/abs/10.1021/ja00020a089?journalCode=jacsat

Tiagabine is apparently discouraged in patients with poor liver function; its metabolism proceeds to the 5-oxo, a conjugated thioester (???). Tiagabine is used to treat seizures, which in any case are worse than hepatotoxicity. http://onlinelibrary.wiley.com/doi/10.1111/j.1528-1157.1997.tb01734.x/pdf

Duloxetine is oxidised in the naphthyl ring, oxidation of thiophene was not mentioned: http://dmd.aspetjournals.org/content/31/9/1142.full

Some hindered S-oxides may be less reactive, but in general the Michael-type reaction seems like it could deplete bodily glutathione in all but the most potent S-oxide-producing drugs. 

I feel like I know where this is going: MPA is metabolised _primarily_ at the amine function, though S-oxides are produced and GSH depletion may be a concern, especially in conjunction with e.g. Valium.


----------



## sekio

Here's where I was kind of going: why isn't etizolam (dosed around 1-10mg) toxic like BTCP (1-10mg) ?


----------



## blueberries

http://imgur.com/YiTR475

I drew this up just to see how vastly you could change an ACH without losing too much activity. I made it in a similar format to Bromadol for potency, ideally that middle benzyl ring would be twisted but com ce com ca. The broken benzyl ring on the amine should also increase potency, or make it somewhat more psychoactive but the methylenedioxy ring on the propyl was just for giggles, I would hope it would decrease potency, so it's not such a dangerous chem as Bromadol. Am I right in thinking the Methoxy bond next to the propylpyrole would change it into a potent DRI/NMDA antag instead of an opiate? The 3 positioned hydroxy however should add a bit of opiate flavour I think. That 2-fluoro would also decrease potency slightly, similar to how the oxy on K/MXE does the same, but with those they're double bonded so I'm not sure. Also I got the impression that it would also add a bit of opiateyness to the compound but I'm not so sure.

Anyway, I am by no means a chemist but the ACH's seem a bit like lego so I would hope this works out. Let me know what you think.


----------



## pharmakos

blueberries said:


> I drew this up just to see how vastly you could change an ACH without losing too much activity. I made it in a similar format to Bromadol for potency, ideally that middle benzyl ring would be twisted but com ce com ca. The broken benzyl ring on the amine should also increase potency, or make it somewhat more psychoactive but the methylenedioxy ring on the propyl was just for giggles, I would hope it would decrease potency, so it's not such a dangerous chem as Bromadol. Am I right in thinking the Methoxy bond next to the propylpyrole would change it into a potent DRI/NMDA antag instead of an opiate? The 3 positioned hydroxy however should add a bit of opiate flavour I think. That 2-fluoro would also decrease potency slightly, similar to how the oxy on K/MXE does the same, but with those they're double bonded so I'm not sure. Also I got the impression that it would also add a bit of opiateyness to the compound but I'm not so sure.
> 
> Anyway, I am by no means a chemist but the ACH's seem a bit like lego so I would hope this works out. Let me know what you think.



i think NMDA activity is greatly reduced with that much bulk on the phenyl ring

bit of a frankenstein molecule you have going on there


----------



## atara

blueberries said:
			
		

> http://imgur.com/YiTR475



You appear to have switched the cyclohexyl and phenyl rings.



sekio said:


> Here's where I was kind of going: why isn't etizolam (dosed around 1-10mg) toxic like BTCP (1-10mg) ?



Etizolam is metabolized on the alkyl chain; the thiophene S is highly hindered. Upon searching the only reference to a metabolite of etizolam I found was alpha-hydroxyetizolam. The tricycle in etizolam (triazolo-[1,2-a]azepino-[7,6-b]thiazole?) is so weird it's hard to number, but oxidation happens on the ethyl chain attached to the thiophene ring. Wiki calls this the 4-ethyl. I assume the alcohol is then maybe glucuronidated?

Benzene is toxic for metabolism to the epoxide (oxepin), toluene is less toxic because metabolism is 95% to benzyl alcohol and 5% epoxide, and benzyl alcohol is used in IV preparations because the alcohol is metabolized much more readily than the ring to ultimately hippuric acid.



> can you think of a ghetto hypothetical name for this, it looks very strange.



In keeping with jimscaline and tomscaline, the only appropriate name for 4-desmethylallyljimscaline is atarascaline, clearly. 8)


----------



## Deinonychus

bloodshed344 said:


> atara said:
> 
> 
> 
> Surprised this rather promising tree hasn't been barked up a bit more:
> 
> 
> 
> 
> 
> 
> 
> What's with the allyloxy?  and can you think of a ghetto hypothetical name for this, it looks very strange.  why not try the amine on the left position instead of where it's at (it's currently at the same spot it'd be on 2C-B-IND but the guys on the last page said the amine would be better to the side)
> 
> Obviously I know nothing at all about this.
Click to expand...


I'm not too sure here, but possibly 2-(5-allyloxy-2,3-dihydro-4,6-dimethoxy-1H-inden-1-yl)ethanamine?

2-(X-1-yl)ethanamine would mean you have a complicated structure connected to ethylamine. The 1-yl is indicating that the bond between the complicated thing and the ethylamine falls at the 1-position on the complicated thing, and the 2-(...) means that the bond between the complicated thing and the ethylamine is off of the 2-carbon of the ethylamine. 

Then for the 'complicated thing' you'd have indane, which is 2,3-dihydro-1H-indene, and the substituents are two dimethoxies and an allyloxy, so alphabetically you'd have 5-allyloxy-2,3-dihydro-4,6-dimethoxy-1H-indene, chop off the final 'e' and replace with 1-yl, and yeah, 2-(5-allyloxy-2,3-dihydro-4,6-dimethoxy-1H-inden-1-yl)ethanamine. 

Is this as wrong as I expect it to be? There's *always* a gotcha when it comes to IUPAC...

EDIT: Oops, shit that's a methylamine not an ethylamine! So (5-allyloxy-2,3-dihydro-4,6-dimethoxy-1H-inden-1-yl)methanamine, not what I wrote earlier. I guess we could be picky and put it as (2,3-dihydro-4,6-dimethoxy-1H-5-[prop-2-en-1-yloxy]-inden-1-yl)methanamine but come on, just call it allyloxy! Or for that matter instead of this 2,3-dihydro-1H-indene nonsense just call it indane and get (5-allyloxy-4,6-dimethoxyindan-1-yl)methanamine. Blah.. or not.


----------



## bloodshed344

atara said:


> Structural rationale: First, allylescaline was the most potent of the mescaline analogs, though cyclobutyl may be somewhat better (and more stable).
> 
> Secondly, jimscaline had improved potency relative to mescaline, while 2CB-Ind had _reduced_ potency relative to 2C-B. But TCB-2 had improved potency relative to 2C-B! What can we make of this?
> 
> The key, I suggest, lies in the distance between the nitrogen and the upper-methoxy group, if the molecule is oriented so the amine is at the "top". In 2CB-Ind, the indane actually pushes the nitrogen closer to the methoxy, which is unfavorable, but in TCB-2, the cyclobutane pushes it away, which is favorable. But in mescaline, the ortho methoxy has migrated over to the meta position, increasing the nitrogen-oxygen distance more and making the indane restriction favorable! We can capitalize on this by using the optimal 4-substituent.
> 
> http://pubs.acs.org/doi/abs/10.1021/jm060272y
> 
> Also, thiophene S-oxides are hepatotoxic and should be avoided. BTCP is a prime example.



Thank you, I appreciate this.  So you're saying the mescaline positioning of methoxys is better than 2C's for the positioning of the amine the way you have it.  So has the actual 4 methoxy version of what you're talking about been thought of or made?  I don't recall seeing anything like that besides 2CB-Ind.  I always love the SAR lessons, keep it up!

To Deinonychus: You, my friend, have also increased my knowledge of how this works.  Thanks.  One question though, why is it 4,5,6 for the -oxys and not 3,4,5 like in mescaline or allylescaline?  EDIT:  Nevermind, I reread it and kind of get it.  Confusing though.  I understand what you're saying but I couldn't quite number it myself

A bit of SAR input of my own, the TFM-version would probably be much more potent than the allyloxy-version of this, based on what I know of mescaline/phenethylamine SAR.  You're probably tired of hearing about the trifluoromethyl substituent on the 4 position of phenethylamines but I think there will be few substitutions as effective as that one based on what I've seen.  Maybe pentafluoroethyl or trifluoroethyl if penta is too bulky?  I only bring this up because you're basing it off of allylescaline because of it's potency.  I think trifluoromethylscaline would be a great deal more potent.


----------



## Jesusgreen

Once again a combination of looking at existing structures, a ton of fucking around, and a lack of any decent SAR knowledge:






Or how about these fellas:


----------



## sekio

I think it depends a lot on stereochemistry. The top one looks like oripavine, the bottom 2 smell inactive (too wierd of a substitution)


----------



## Jesusgreen

Been bored and felt like making a few more quick ones, these ones I'd be more hopeful about, at least the first two:





Reasoning for the first two being the aminoindanes seem to be quite serotonergic, with little DA/NA activity, and that adding a b-keto group often tends to shift the focus of the activity more in the direction of DA/NA. The 4-MMC analogue was chosen since it's fairly dopaminergic already, the 5-MAPDB analogue was chosen as an alternative if the 4-MMC based one was too dopaminergic.

The last one is just me playing around since seeing the aminoindanes with a b-keto group reminded me a little of phenmetrazine and aminorex derivatives.


----------



## QUARE

I dont know if any of those are possibly active but it was fun to draw.


----------



## dingophone

indolylpropylaminopentane, or IPAP. Possibly a serotonin activity enhancer and MAOI?





MetachloroBcarboline (aka mCPP's even more unpleasant brother):


----------



## Jesusgreen

Since my lack of SAR knowledge makes speculating on interesting structures a little hard, but I love making them, I figured I'd just make a whole load of structures without putting much thought into them, and maybe if I hit anything somewhat interesting in the process someone'll notice and point it out. 

So here's a bunch, some of which I'm fairly certain would be inactive:





Of those the ones that seem like they might have some potential to me are a couple of the Methylphenidate analogues and the 2-Benzylpiperidine and 4-Benzylpiperidine analogues. Dunno though.

Decided to pop another one in before I head off for the night:





Not sure if I'm right but I just went under the assumption that while taking something like Mephedrone and switching out N or 4-Methyl groups for Ethyl ones results in less enjoyable effects, with something like Buphedrone that seems to be almost purely dopaminergic maybe these sorts of additions would be worthwhile. I imagine 4-Ethylbuphedrone might be interesting too, more so than 4-Methylbuphedrone (4-MeMABP) would be anyway. All just newbie speculation here though.

Drawing structures is pretty addictive, especially when there's at least some thought behind them, even if it's usually quite flawed in my case. Did a couple more, finally getting off to bed now because I'm exhausted:


----------



## clubcard

*SNDRI activity in animal models*


----------



## atara

jesusgreen: Arecoline analogues like the one you've shown are, IIRC, actually somewhat interesting DRIs... though personally I think arecoline's pro-muscarinic activity is far more interesting in and of itself, too bad it's carcinogenic as all hell. I see you've chosen the cocaine-pattern which is of course a good one.

I can't of course say something about all of those, a few are very likely inactive -- in particular tertiary amines from the phenethylamine class tend to be active only by dealkylation cf MDDM and phendimetrazine, excepting the use of pyrrolidin-1-yl since it is compact and conformationally advantageous. The beta-methoxy alpha-methyl phenethylpyrrolidine may be good.

Antimuscarinics (tricyclics and deliriants) induce mania so I've long wondered if perhaps muscarinic agonists like arecoline could be useful mood stabilizers, if the efficacy is low enough to prevent convulsions that is. It would sure beat the hell out of the atypicals and anticonvulsants (valproate, ugh) typically used for this purpose.


----------



## Repulse

Someone told me about this piperazine-based molecule from IUPAC, and with the limited knowledge IUPAC-reading & structure building from that, that I have, I attempted drawing it in ChemDraw.
Is it a completely impossible molecule? (Hint: its base-structure is para-methylpiperazine)

The naphthalen-functional group is perhaps to cause some analgesia? They were pretty common in some of the JWH-series cannabinoids, but this is a different beast.


----------



## QUARE

I was looking at Tapentadol molecule and I immediately thought; How about a methylenedioxy on that phenyl ring. lol !


----------



## Soulfake

Fencamfamine looks quite similar to Tilidine and has some opioid effects. What would happen if you put an ethyl-carboxylate chain on Fencamfamine at the same place where Tilidine has it? Would an additional 3´OH-hydroxilation on the phenyl ring of FCF or Tilidine make sense? (like o-desmethyltramadol). 
(I drew the tilidine without the dimethyl ´couse it´s only active with none or just one methyl-unit.)

ethyl 3-(ethylamino)-2-phenylbicyclo[2.2.1]heptane-2-carboxylate
ethyl 3-(ethylamino)-2-(3-hydroxyphenyl)bicyclo[2.2.1]heptane-2-carboxylate
ethyl 2-(methylamino)-1-phenylcyclohex-3-ene-1-carboxylate
ethyl 1-(3-hydroxyphenyl)-2-(methylamino)cyclohex-3-ene-1-carboxylate


----------



## toastmann

Bottom two look a bit like an NMDA-antagonist.


----------



## toastmann

Look at this wacky molecule :
https://en.wikipedia.org/wiki/Hyperforin

"Hyperforin"
Serotonine, Dopamine, Norepinephrine and GABA reuptake inhibitor :O





Anyways :


----------



## Transform

toastmann said:


> Anyways :



Thiols are usually covalent receptor substrates which makes them very dangerous. That second one would condense to give an aromatic aldehyde which would then polymerise.

The third I doubt would be active as a stimulant and it's a bit far from anything to hint other activity.

I don't fancy that thioketone either, they stink and the a-dimethyl isn't much good either.

Soulfake's definitely appear to have potential. Close comparison to NMDA antagonists will likely show pretty quickly they won't have much activity there - the amine is in the wrong place.


----------



## pharmakos

would that thioketone dimerize since it has an open nitrogen?


----------



## toastmann

I really don't know why I used the alpha dimethyl, I was drinking haha. That would make the substance somewhat more selective for norepinephrine right ?

Thioketone looks cool, because if I remember correctly there is a synthesis where you can replace normal oxygen ketone with sulphur. Would make synth easy, if it doesnt destroy the compund. Yes it would stink and probably you to from all that stinky sulphur containing sweat :D


----------



## toastmann

prothionamide seems more stable.


What about alpha-thioketone phenethylamine ?


----------



## sekio

Thioamides are different than thioketones.


----------



## atara

Thioamides exhibit significant delocalization rendering the amine function no longer very basic, which would likely make the molecule inactive. 

toastmann's oxazolidine would isomerize to the 4H rather than 2H, as the imidate is a more stable isomer owing to amide-like delocalization around the OC=N bonds. It seems to make more sense as an oxazole, though, as diarylmethyl- is a rather common DRI motif.


----------



## klfiend

was just pondering how I would make a "legal" mephedrone replacement

fuck me right? loved and hated that drug...


----------



## Dresden

klfiend said:


> was just pondering how I would make a "legal" mephedrone replacement
> 
> fuck me right? loved and hated that drug...



What's wrong with 3-MMC (3-methylmethcathinone)?  I thought it was good overall.


----------



## ebola?

Yet it lacks the massive serotonergic release conferred by mephedrone.

ebola


----------



## SeenSoFar

*Phosphindole tryptamine analogues: Possible avenue for drug discovery?*

So, I was thinking tonight, a logical (at least to me) step that one could take in discovering some new active tryptamine analogues would be to examine the phosphindole analogues of conventional psychedelic compounds such as DMT. I have checked around, and I cannot find any mention of such compounds being explored, or even synthesized for that matter. Does anyone see anything immediately wrong with this idea? If not, what are your thoughts on it? I have included an image of one such possible compound, just to illustrate it for the casual reader.


----------



## sekio

I don't think "phospindole" is a known compound, but it's possible, I guess. Wierd heteroaromatics (e.g. borabenzene) tend to behave less... nicely than the CNOS analogs.


----------



## pharmakos

"phosphindole" does return about 15,000 hits on google, but none of the results seem like they'd be too relevant here.

also, silabenzene would be a better analogy here than borabenzene, no?  neither one seems too hopeful as far as SAR is concerned, though.


----------



## SeenSoFar

Well, phosphindoles are a known family of compounds, and they are stable without the ridiculous stabilizing structures required for things like silabenzenes and borabenzenes. Phosphorus does indeed share some characteristics with nitrogen, and is in the same column on the periodic table. I think you would have much more luck with a phosphindole DMT analogue than a silabenzene DMT analogue (yes, I know I drew some of the homobenzenes a few pages back, but that was more for fun than anything), especially since from my understanding, you would require something like this to stabilize it[1]:






Now, I'm not going to say that I know 100% that something that looks like that will not be active, but I can say that my level of surety vis-a-vis the inactivity of the aforementioned compound is about as close to certain as anyone could be without actually tasting it. I doubt it would cross the BBB, and if it did, it would almost certainly be too sterically hindered to bind to 5-HT2A.

The phosphindole, on the other hand, I believe to have much more promise. Considering a similar compound, known as dimemebfe[2], using oxygen instead of phosphorus in place of the pyrrole nitrogen, has been synthesized, and sampled to positive result[3]. Similarly, the benzothiophene analogue of various tryptamines has also been synthesized and tasted, to some positive reviews, although I cannot seem to find references to this at the moment, but I will post them once I remember where they are.

All that being said, it seems that the tryptamines are somewhat tolerant to substitution of the nitrogen while retaining affinity for and efficacy at the 5-HT2A receptor. Therefor, it would seem logical to me that the phosphindole analogues of at least a few well-known tryptamines should at least be considered as candidates for novel psychedelic compounds.


----------



## Hammilton

The fencamfamine analogues of tilidine are a neat idea.  Smart one too


----------



## atara

> The phosphindole, on the other hand, I believe to have much more promise.


Big problem with phosphindole is that it is almost indubitably toxic as hell, and susceptible to hydrolysis if that weren't enough. Reduced phosphorus (i.e. not phosphate/esters) basically never appears in biological systems.


----------



## SeenSoFar

atara said:


> Big problem with phosphindole is that it is almost indubitably toxic as hell, and susceptible to hydrolysis if that weren't enough. Reduced phosphorus (i.e. not phosphate/esters) basically never appears in biological systems.



You are absolutely correct, and there is a good chance that it may be quite toxic. This is why I said it might be useful to take a look at it as a possible avenue of exploration. To me, this would involve animal testing of the compound to ensure that it wasn't a horrible poison. I really do appreciate your contribution though, I'm glad you commented about the possible toxicity, the last thing we need is some irresponsible person to read this thread, synthesize it, do 0 testing, slap some brand name like "SyntheTRIP TRIPLESTACKED B34NZ" on it, and start selling it as the next LSD or something.


----------



## Usirius1

*So, I was messing around in ChemDraw today and....*

I was wondering if anyone thought this compound would seem interesting?


----------



## sekio

Somehow I doubt it. The 2 and 5 positions on the 2C- series don't handle a lot of steric bulkiness - certainly not whole tryptamine molecules glued on.


----------



## pharmakos

should have had the oxygens attach to the DMT molecules another position or two over


----------



## Usirius1

Gotcha.


----------



## Str

I like cyclobutanes. Sorry if any is a repost.


----------



## SeenSoFar

I like the second one, the DMT-esque one with the cyclobutane ring in place of the pyrrole ring, but you are missing one carbon in your sidechain, at least if your goal was tryptamine-style SAR as I imagine it was.


----------



## Str

SeenSoFar said:


> I like the second one, the DMT-esque one with the cyclobutane ring in place of the pyrrole ring, but you are missing one carbon in your sidechain, at least if your goal was tryptamine-style SAR as I imagine it was.



Ah yes sorry about that.

Just looked it up and apparently the scaffold is called benzazetidine. Couldn't find a DMT derivative on SciFinder though. Not one with a dihydro quinoline scaffold either.


----------



## atara

That tricyclic thing looks interesting, it's got so many weird moieties but it looks stable to me, and why not? Good luck synthesizing it though!


----------



## Usirius1

I'm thinking of 25i-NDMT


----------



## sekio

Please don't post 2000x1000 images. Scale them down to a reasonable size..


----------



## pharmakos

Usirius1 said:


> I'm thinking of 25i-NDMT



dig back in this thread a ways and there's a link to a paper detailing a bunch of 25x analogues with groups other than NBOMe.  a few of them have an Indole there, so they're close to what you drew... just without the dimethylethyl bit.


----------



## Usirius1

I can't remember where I read it, but I read somewhere that the reason why 25i-NBOMe is not active orally is because it is cleaved during first pass metabolism, essentially leaving you with extremely small amounts of 2C-I. My thought is that if the 25i-NDMT was consumed orally, if it would be broken down in metabolism to 2C-I and DMT


----------



## pharmakos

DMT isn't active orally either, though, so if thats your goal.... may as well just make 2C-I

the molecule you pictured would make 4-Methyl-DMT tho


----------



## Usirius1

Except 2C-I is a controlled substance. That's the whole reason I drew this up.I agree though. Since that would break down to 2Ci and 4-Me-DMT (which I read wasn't very pychoactive) could that be redrawn to breat down into 4-Aco-DMT or 5-MeO-DMT? Because that would be beautiful. The combination of 2CI and 4-Aco-DMT is beautiful.


----------



## Usirius1

Perhaps this maybe?


----------



## pharmakos

^^ your acetyl group is missing a carbon

now you've got to do some molar conversions to see what the relative ratio of 2C-I to 4-AcO-DMT is


----------



## Str

atara said:


> That tricyclic thing looks interesting, it's got so many weird moieties but it looks stable to me, and why not? Good luck synthesizing it though!



I see now that I put one of the oxygens in the wrong place. I tried to make a cross-over from MDMA and MMDMA but wanted to keep the hydrogen acceptor.

Without going into synthesis I was thinking of CH2I2 and a base, but I don't know. I think the only nitrogen substituent I've seen is 2C-N.


----------



## Usirius1

Mol ratio is 1.2469 of 2C-I to 4AcODMT.  I guess I should put that missing carbon in there and send it off to the lab for synthesis. Anyone wanna try it first?


----------



## Anon0631

I'm sure someone must have already thought of 2c-AL but I can't find anything about it:






Interestingly if you cyclicise the two methoxys to make a FLY compound, it's totally UK legal:


----------



## SeenSoFar

I would be interested in seeing 2C-AL be studied a little more. Considering the activity of 2C-P, Allylescaline, and Methallylescaline, something tells me that this one could be a real winner. 2C-AL-FLY and/or 2C-AL-DragonFLY might also be real interesting compounds. Someone get synthing, immediately!

Correct me if I'm wrong, but wasn't Shulgin working on a book of allyl-subbed Ts and PEAs?


----------



## Anon0631

He was working on n, allyl tryptamines (DALT, NALT, MALT, EALT, PALT, IALT, etc)

Talking of which, why allyls and no vinyls?

4-HO-DVT






5-MEO-MVT






n,n-EVT






And finally returning to my 4-sub phenethylamine question, why has nobody made 2c-v?






Edit: looking at the 3D structure, 2c-v is pretty similar in shape to 2c-t. I don't know much about SAR but this would seem to suggest that 2c-v-2 would be worth exploring. No?

2c-v-2


----------



## SeenSoFar

You can't have a vinyl tryptamine, it isn't stable. If such a compound were attempted, tautomerization will result in a resonance between the amine & the imine, and the imine is unstable and tends to hydrolize, breaking down to a lower order amine and acetaldehyde. In the case of your compounds, you would end up with:

4-HO-DVT	-> 4-HO-T		+ 2x 	Acetaldehyde
5-MeO-MVT	-> 5-MeO-NMT	+ 	Acetaldehyde
EVT		-> NET		+ 	Acetaldehyde


----------



## Incunabula

Str said:


> I like cyclobutanes. Sorry if any is a repost.



I don't think the top one would be active, because you can't put a alpha-methyl on a cyclobutane, it locks the alpha methyl in place. According to Solipsis anyway.
Acually I don't know what you are trying to make, psychedelic or stimulant? putting a methyl on the nitrogen (making them secondary or tertiary  amines) will leave them inactive as psychedelics. But I don't think they will be stimulants instead.

Take the third one from the top, it`s basically N-methyl-bk-2C-G-2. The N-methyl will make it inactive as a psychedelic, and the beta ketone will cause it to dimerize if the the N-methyl wasn't there. Remove it and you have 2C-G-2 

I like the look of the bottom one. Looks a bit like something I was drawing a while ago. Might post some of them later.


----------



## Str

Fagott said:


> I don't think the top one would be active, because you can't put a alpha-methyl on a cyclobutane, it locks the alpha methyl in place. According to Solipsis anyway.
> Acually I don't know what you are trying to make, psychedelic or stimulant? putting a methyl on the nitrogen (making them secondary or tertiary  amines) will leave them inactive as psychedelics. But I don't think they will be stimulants instead.
> 
> Take the third one from the top, it`s basically N-methyl-bk-2C-G-2. The N-methyl will make it inactive as a psychedelic, and the beta ketone will cause it to dimerize if the the N-methyl wasn't there. Remove it and you have 2C-G-2
> 
> I like the look of the bottom one. Looks a bit like something I was drawing a while ago. Might post some of them later.



Thanks!

I was going for stimulants except the cyclobutane-DMT one. 

The third one was like a cyclized 3,4-DMMC. While on the subject, let's talk about the dimerization. I can see how this happens in solution, especially in acidic solutions like in your stomach. But storing this, as a salt, should not cause b-keto amines to dimerize right? So any parenteral ROA should work. Also, the formation of the ketimine in the condensation is reversible. The problem is it's bidentate so it's pretty favorable entropically but since you have alot of water in your stomach maybe this evens up? 
I haven't looked in to it very much but are there any trials with oral cathinones? I know khat, which contain cathinone, produces stimulation but since it's supposed to be chewed maybe it's absorbed sublingually.


----------



## Str

ktp said:


> maybe because its metabolic epoxide causes cancer ?
> 
> en.wikipedia.org/wiki/Styrene_oxide



P-450 would turn it into the epoxide which, being a benzylic and a good electrophile, is not something you want in your body. The option would be to use allyloxy like in allylescaline. This one ("2C-OAl") is prone to Claisen rearrangement though and I found an old article from '58 showing a hammett plot with EDGs increasing the reaction rate. And since you have two methoxys maybe this could happen at 37 C? The product would be 3-allyl-2,5-dimethoxy-4-hydroxyphenethylamine.


----------



## Usirius1

Ive fixed it by adding the missing carbon atom. Now the question I have is, without getting into the details of synthesis since I'm pretty sure that's against the rules, would it even be possible to synthesize this?


----------



## QUARE

Would it work to replace the indole by a benzofuran, just a random thought.


----------



## atara

QUARE said:


> Would it work to replace the indole by a benzofuran, just a random thought.


http://en.wikipedia.org/wiki/dimemebfe


----------



## QUARE

Woah, im suprised that I finally got something that might be active lol


----------



## tweex

Methortetamine (aka 2-Methylmethamphetamine or 2-MMA)

Found a couple papers talking about it from an analytic chem perspective, nothing on pharmacology. A more powerful version of ortetamine?





2-Methyldimethylamphetamine (sup dawg, we herd u liek meth, so we put two more meths on your meth so you can methmeth while you meth)

No info on it anywhere, but I'd think this is a workable structure? I designed it as a hybrid of ortetamine and dimethylamphetamine, keeping in mind both of their relative properties to regular methamphetamine. Possible properties as a fairly nontoxic (albeit likely low potency by weight) functional stim?

Edit: I also wonder about perhaps 2-Fluorodimethylamphetamine (2-FDMA)
Following in the series of 2-FA and 2-FMA... actually this is 2503 in PiHKAL


----------



## ebola?

2-Methyldimethylamphetamine (sup dawg, we herd u liek meth, so we put two more meths on your meth so you can methmeth while you meth)



> No info on it anywhere, but I'd think this is a workable structure?



The potency drop from n-dimethylation is too great.



> Methortetamine (aka 2-Methylmethamphetamine or 2-MMA)



Maybe more serotonergic?  2-methylation of amps is relatively under-explored.  It could be neurotoxically serotonergic.

ebola


----------



## tweex

ebola? said:


> The potency drop from n-dimethylation is too great.



Do you think the issue with potency would be so great as to be non-bioactive, or simply require much higher dosing for decent effects?

Struck me as an interesting idea for more "clean"/safer meth analogs, even if you'd have to take a lot...



> By contrast, equivalent doses of methamphetamine depleted serotonin in the rat brain by 82%. These results indicate that N,N-DMA, the N-methylated analog of methamphetamine, is considerably less potent than its parent compound both as a dopaminergic and serotonergic neurotoxin, and raise the question of whether or not it may be possible to dissociate the neurotoxic effects of methamphetamine from its reinforcing actions by means of N-methylation. Safety of N,N-DMA in humans remains to be investigated.


http://www.sciencedirect.com/science/article/pii/0006899389902473

Methylation in the ortho position of amphetamine on the other hand apparently results in about a 90% potency drop, but similar effects: 
https://www.ncbi.nlm.nih.gov/pubmed/2093186

Edit: Whoa, this is a cool read: http://bitnest.ca/Silo42/Books/AmphetamineAndItsAnalogs3.pdf
In relation to these couple compounds, Nichol's claims n-dimethyl is 80% less potent, and that ortho-methylation is 90% less potent but the only ring position that retains classical stim properties. Really cool stuff


----------



## sekio

> .
> Do you think the issue with potency would be so great as to be non-bioactive, or simply require much higher dosing for decent effects?



I think when you turn to N,N-dialkylamphetamines or their cathinone counterparts, they are more like prodrugs for the N-monoalkyl and dealkylated product. Diethylproprion (N,N-diethylcathinone) is that way; people consider it to be more of a prodrug for ethcathinone. I think the exception are small cyclic N-alkyl groups like pyrrolidine though, which actually work to increase potency somewhat. (c.f. MDPPP versus methylone)


----------



## klfiend

a potency bump from a-pvp?


----------



## ebola?

probably works, maybe a bit more potent, probably feels horrid.

ebola


----------



## mad_scientist

^^^

This is a known compound with code number O-2390, CAS# 850352-61-3


----------



## bloodshed344

*5-meo-lsd and 6-fluoro-lsd*

So just a quick idea I had when thinking about LSD's relation to tryptamines:

"5-Meo"-LSD








"6-Fluoro"-LSD







Fluorotenin (5-trifluoromethyl-DMT or 5-methylfluoro-DMT)








Psulfurcin (4-Methylthio-DMT (I know this is much different than 4-hydroxy) could anyone answer the question if a sulfonyl would be possible here and if it would be similar to acetyl or phosphoryloxy)


----------



## SeenSoFar

You have mixed up the 4- and 5- positions in your final 2 drawings. The compound you have titled 'Fluorotenin' you have actually drawn as 4-Trifluoromethyl-DMT, and the compound you called Psulfercin you have actually drawn as 5-Methylthio-DMT.  As an interesting note, while I have never heard of 4-MeS-DMT (what you meant to draw), 5-MeS-DMT (what you actually drew) was made and assayed by Shulgin, its #46 in the index of TiHKAL. The dose is given as 15-30mg and the duration as less than 1 hour.


----------



## bloodshed344

SeenSoFar said:


> You have mixed up the 4- and 5- positions in your final 2 drawings. The compound you have titled 'Fluorotenin' you have actually drawn as 4-Trifluoromethyl-DMT, and the compound you called Psulfercin you have actually drawn as 5-Methylthio-DMT.  As an interesting note, while I have never heard of 4-MeS-DMT (what you meant to draw), 5-MeS-DMT (what you actually drew) was made and assayed by Shulgin, its #46 in the index of TiHKAL. The dose is given as 15-30mg and the duration as less than 1 hour.



Thank you!  I'm too lazy to redraw but I meant them the way they were said, not drawn.  I knew about 5-MeS-DMT and it seemed kind of a dud.  Judging by 4-MeO-DMT I don't think psulfurcin would be any good but who knows...


----------



## SeenSoFar

bloodshed344 said:


> Thank you!  I'm too lazy to redraw but I meant them the way they were said, not drawn.  I knew about 5-MeS-DMT and it seemed kind of a dud.  Judging by 4-MeO-DMT I don't think psulfurcin would be any good but who knows...



Its not as clear-cut as you might think. Consider 2,4,5-TrimethoxyPEA vs 2,5-Dimethoxy-4-Methylthio-PEA, also known as 2C-T. TMPEA is not known to be active at any dose, whereas we all know how active 2C-T is. It might not be a perfect example, seeing as it involves PEAs as opposed to tryptamines, but it is a useful parallel. I would actually think that 4-HS-DMT is a better idea though.


----------



## atara

Ew, thiols. A stench that will make AMT seem like a flower garden.


----------



## bloodshed344

4-HS-DMT would have been the actual psulfurcin if I had realized that a hydrosulfur group was possible!  What's the real name of this group?

Also, what about a 4-Sulfonyl-DMT?


----------



## SeenSoFar

That group would be a thiol group, analogous to an alcohol group with a sulfur replacing the oxygen. The thio- prefix is used when an oxygen has been swapped out for a sulfur.

As for a sulfonyl group, it seems like an odd choice. It seems like a sulfate ester of psilocin or a sulfate thioester of 4-HS-DMT would be more logical. I am getting the idea that this is what you actually meant when you said 4-Sulfonyl-DMT. Was it? Or did you actually mean sulfonic esters?


----------



## bloodshed344

SeenSoFar said:


> That group would be a thiol group, analogous to an alcohol group with a sulfur replacing the oxygen. The thio- prefix is used when an oxygen has been swapped out for a sulfur.
> 
> As for a sulfonyl group, it seems like an odd choice. It seems like a sulfate ester of psilocin or a sulfate thioester of 4-HS-DMT would be more logical. I am getting the idea that this is what you actually meant when you said 4-Sulfonyl-DMT. Was it? Or did you actually mean sulfonic esters?



I'll have to look it up again, I could easily be getting sulfonyl confused with sulfate or sulfonic... confusing!  I looked all 3 of those up and while I know what they are I still don't know which one I intended.  What would a sulfate ester or sulfate thioester be, exactly, of 4-HS-DMT?  Would it be to 4-HS-DMT as 4-AcO-DMT is to Psilocin?  Interesting stuff.  Thanks for your help so far.


----------



## Transform

Is there any precedent for ring substitution of LSD, ala the 5-MeO suggested there.


----------



## SeenSoFar

bloodshed344 said:


> I'll have to look it up again, I could easily be getting sulfonyl confused with sulfate or sulfonic... confusing!  I looked all 3 of those up and while I know what they are I still don't know which one I intended.  What would a sulfate ester or sulfate thioester be, exactly, of 4-HS-DMT?  Would it be to 4-HS-DMT as 4-AcO-DMT is to Psilocin?  Interesting stuff.  Thanks for your help so far.



A sulfate ester of psilocin would be a logical choice considering the activity of the phosphate ester (4-PO-DMT a.k.a. psilocybin) and the acetate ester (4-AcO-DMT) and would be analogous to either of them, just another ester of psilocin that may be cleaved to form psilocin in vivo, functioning as a prodrug for psilocin as has been the commonly accepted theory regarding the activity of 4-PO-DMT and 4-AcO-DMT. Its also possible it may have activity of its own as is now being theorised about 4-AcO-DMT and 4-PO-DMT. It might be a combination of these as well, with a portion hydrolysing to form the parent phenol and a portion remaining intact, with the effect profile being a result of both substances simultaneously. The sulfate thioester of 4-HS-DMT would be exactly analogous to the sulfate ester of psilocin. A thioester just means an ester formed with an HS (thiol) group instead of an HO (alcohol) group. And a sulfonic ester just means an ester formed by an alcohol and a sulfonyl group. Sulfonic ester is just the correct way of saying sulfonyl ester.

I see no immediate reason why a sulfonic ester would be unwise, its just a slightly less obvious choice compared to a sulfate ester. That's why I asked.



Transform said:


> Is there any precedent for ring substitution of LSD, ala the 5-MeO suggested there.



The thought has definitely crossed my mind before, as I'm sure it has crossed many others, but I don't believe that such compounds have ever been synthesized. If they have, I've not heard of them. It seems like a logical step to take for sure, considering how fertile the ground seems to be in tryptamine chemistry. Then again, lysergamides do not behave exactly like tryptamines, so we will just have to see... Make 'em and taste 'em! Such a shame the 4- position is occupied, the thought of 4-HO-LSD makes me need to change my undergarments.


----------



## bloodshed344

SeenSoFar said:


> A sulfate ester of psilocin would be a logical choice considering the activity of the phosphate ester (4-PO-DMT a.k.a. psilocybin) and the acetate ester (4-AcO-DMT) and would be analogous to either of them, just another ester of psilocin that may be cleaved to form psilocin in vivo, functioning as a prodrug for psilocin as has been the commonly accepted theory regarding the activity of 4-PO-DMT and 4-AcO-DMT. Its also possible it may have activity of its own as is now being theorised about 4-AcO-DMT and 4-PO-DMT. It might be a combination of these as well, with a portion hydrolysing to form the parent phenol and a portion remaining intact, with the effect profile being a result of both substances simultaneously. The sulfate thioester of 4-HS-DMT would be exactly analogous to the sulfate ester of psilocin. A thioester just means an ester formed with an HS (thiol) group instead of an HO (alcohol) group. And a sulfonic ester just means an ester formed by an alcohol and a sulfonyl group. Sulfonic ester is just the correct way of saying sulfonyl ester.
> 
> I see no immediate reason why a sulfonic ester would be unwise, its just a slightly less obvious choice compared to a sulfate ester. That's why I asked.
> 
> 
> 
> The thought has definitely crossed my mind before, as I'm sure it has crossed many others, but I don't believe that such compounds have ever been synthesized. If they have, I've not heard of them. It seems like a logical step to take for sure, considering how fertile the ground seems to be in tryptamine chemistry. Then again, lysergamides do not behave exactly like tryptamines, so we will just have to see... Make 'em and taste 'em! Such a shame the 4- position is occupied, the thought of 4-HO-LSD makes me need to change my undergarments.



I think replacing LSD's phenyl or indol rings with a thiophene or benzofuran ring would be a next logical step, considering I've seen a version of DMT with the indol replaced with thiophene and a version of DMT with the phenyl replaced with thiophene.  Crazy chemistry but I guess it'd be about 100x harder to do with LSD.  I think light substituents on the phenyl ring could lead to good analogs, that was my point with 6-Fluoro-LSD, to create something that would maybe be similar to LSD... but there's a low chance of that being true.


----------



## SeenSoFar

bloodshed344 said:


> I think replacing LSD's phenyl or Indol rings with a thiophene or benzofuran ring would be a next logical step, considering I've seen a version of DMT with the indol replaced with thiophene and a version of DMT with the phenyl replaced with thiophene.  Crazy chemistry but I guess it'd be about 100x harder to do with LSD.  I think light substituents on the phenyl ring could lead to good analogs, that was my point with 6-Fluoro-LSD, to create something that would maybe be similar to LSD... but there's a low chance of that being true.



So you know, indole describes the combination of the 5- and 6- membered rings, if you want to refer to just the 5- membered ring, its called a pyrrole ring. Anyway, the thienopyrrole analogue of DMT (with the thiophene ring replacing the benzene ring) does bind to 5-HT2A, however it is inactive as a hallucinogen[1]. On the other hand, the benzothiophene analogue (with the thiophene ring replacing the pyrrole ring) is around (CAS#:10275-64-6) and has been reported to be a hallucinogen (at about half the potency of DMT) on Bluelight[2] and other anecdotal sources but I don't believe its binding efficacy has ever been formally assayed. If anyone knows otherwise, please chime in! The benzofuran analogue of 5-MeO-DMT[3] has been discussed on Bluelight[4], check out the discussion there for some interesting facts and back-and-forth.

While this is interesting information and might make a very interesting avenue of exploration in the future as far as analogues of known tryptamines (I know I would be interested in assaying benzothiophene aMT analogues), ergoloid chemistry is a whole 'nother ball-game. Ring substitutions are one thing, and I can think of a few ways they could be accomplished without TOO much trouble, but replacing either of the rings in the base indole of LSD is a HUGE proposition. Whereas with the former you can still start with the same precursors as you would with LSD, for the latter you are looking at a total synthesis, and that is not a small job. You're looking at huge costs, lots of work, and a small yield. While it would definitely be an interesting avenue to explore, especially the benzothiophene analogues, I just don't see it happening unfortunately... The simple ring substitutions are something I definitely would like to see happen though.

[1] - http://www.ncbi.nlm.nih.gov/m/pubmed/10090793/

[2] - http://www.bluelight.ru/vb/threads/344768-Other-aromatic-analogues-of-PHE-and-T

[3] - http://en.m.wikipedia.org/wiki/Dimemebfe

[4] - http://www.bluelight.ru/vb/threads/592648-Benzofuran-analogues-of-Tryptamines-(e-g-5-MeO-BFE)


----------



## toastmann

Im interested what 6-trifluoro-aMT would feel like. 
But let's first see reports of 5/6-fluoro-aMT. I wonder why it hasn't been synthesized on a large scale. I mean they are strong MAO-A inhibitors but I have seen more dangerous chemicals pop up so that shouldn't be a problem.


----------



## SeenSoFar

toastmann said:


> Im interested what 6-trifluoro-aMT would feel like.
> But let's first see reports of 5/6-fluoro-aMT. I wonder why it hasn't been synthesized on a large scale. I mean they are strong MAO-A inhibitors but I have seen more dangerous chemicals pop up so that shouldn't be a problem.



I guess 6-TFM-aMT might be interesting. I'm actually also very interested in 5- and 6-Fluoro-aMT. I've also wondered why they are so scarce, I wonder if it has anything to do with the bad reputation of 5-MeO-aMT. I've actually wondered what alpha-TFM-Tryptamine or 5-MeS-aMT would be like.


----------



## atara

Transform said:


> Is there any precedent for ring substitution of LSD, ala the 5-MeO suggested there.



The only known derivative is inactive:

http://en.wikipedia.org/wiki/2-Bromo-LSD

The LSD pharmacophore is... touchy. A slight modification to the ergoline core throws the binding profile totally out of whack, but LSD itself has really high affinity for five receptors and relatively high affinity for another six. Dihydro-LSD is about 25 times less potent.


----------



## bloodshed344

atara said:


> The only known derivative is inactive:
> 
> http://en.wikipedia.org/wiki/2-Bromo-LSD
> 
> The LSD pharmacophore is... touchy. A slight modification to the ergoline core throws the binding profile totally out of whack, but LSD itself has really high affinity for five receptors and relatively high affinity for another six. Dihydro-LSD is about 25 times less potent.



Well, I don't know much about all this but that doesn't seem like a spot that's too good for modification compared to where I had the MeO at.

SeenSoFar:  Amazing post.  I will be reading into the information you have provided me for a little while.


----------



## SeenSoFar

atara said:


> The only known derivative is inactive:
> 
> http://en.wikipedia.org/wiki/2-Bromo-LSD
> 
> The LSD pharmacophore is... touchy. A slight modification to the ergoline core throws the binding profile totally out of whack, but LSD itself has really high affinity for five receptors and relatively high affinity for another six. Dihydro-LSD is about 25 times less potent.



Honestly, its really not at all surprising to me that 2-Br-LSD is inactive as a hallucinogen. From everything I've read, 2-substituted tryptamines lose all affinity for 5-HT2A and instead are moderately selective for 5-HT1B, 5-HT1D, and/or 5-HT6, as either an agonist or antagonist, depending on the 2- substituent[1][2][3]. If anything, the fact that 2-Br-LSD is an antagonist without 2A affinity seems to confirm that at least some tryptamine SAR carries over to the LSD pharmacophore. More than ever, I'm interested in seeing some of these explored. 



bloodshed344 said:


> Well, I don't know much about all this but that doesn't seem like a spot that's too good for modification compared to where I had the MeO at.
> 
> SeenSoFar:  Amazing post.  I will be reading into the information you have provided me for a little while.



I absolutely agree with you, its not a good place for substitution in regards to retaining psychedelic activity, for the reasons I already stated.

Also, I'm glad I could help! Feel free to ask anything anytime!

[1] - http://pubs.acs.org/doi/abs/10.1021/jm990550b?journalCode=jmcmar

[2] - http://www.ncbi.nlm.nih.gov/m/pubmed/9240350/

[3] - http://www.ncbi.nlm.nih.gov/m/pubmed/10411472/?i=2&from=/9240350/related


----------



## Wandering Girl

*Someone please humor me, all opinions welcome with reasoning given.*

Let me just start off saying that I have no formal knowledge of chemistry, just stuff that I've researched on my own. I am genuinely interested in it, but I'm not sure if I'll ever really end up taking any serious classes on it. I do like messing around with things though, and I just spent a little time putting this together mostly because I'm bored and thought it would be fun.



Spoiler: a bunch of different molecules











As I'm sure is quite clear to anyone here, *A* is tryptamine and *G* is DMT. The rest of the changes I made here may or may not seem a little random, but I was following a set pattern for them.

*M* is of course a piperidine analogue of tryptamine, which I thought to add because of experiments on another forum I read where people were trying to alter the metabolism of tryptophan first to form DMT, and then on a separate experiment to form that piperidine analogue by inhibiting aldehyde dehydrogenase and having the resulting compound formed from tryptamine being metabolized by MAO mix with supplement-increased levels of dimethylamine or piperidine, respectively, in the body. Now, I have no real idea if what they were doing is correct or if it would work just how they wanted, but they definitely did report altered effects when they gave it a shot, so I figure something is going on at least. The reason I was most interested by this is because their results found that the effects lasted for much longer, and that was something they had expected from the start, citing PCP and its analogues as an example of how piperidines can take much longer to metabolize than their corresponding amines as a reason to predict increased half-lives. So that's the reason for that.

I decided next to think about other ways to keep a chemical around in your body for even longer. I thought that maybe a good example to follow in that regard would be starting at scopolamine (pic), which is really not all that different from phenethylamine and tryptamine in structure relatively speaking, and try to continue down the path they took in the Edgewood Aresenal experiments, given that one of the goals of that was to make longer-lasting compounds to be used as chemical warfare agents. That's where the beta-hydroxy came from in my picture. I realize that that's actually a shorter version than what's on scopolamine, but what I had in mind was the next step between that and QNB (pic), which as far as I could tell actually lasts even a little bit longer than scopolamine can, which is already pretty long. That's also where the beta-phenyl came from, and why some of them have both the hydroxy and phenyl there. I have to ask, knowing as little as I do, is that still valid here? (Like, can you have both there?) Either way, that's how I arrived at that point. Obviously, I also didn't change them to tropanes and just left either the amines or piperidine structures there, and instead of the main phenyl I kept it an indole. From there I took it a step further to EA-3167 (pic), the compound made with the longest duration of effect, reaching a ridiculous 120-240 hours in delirium from an injected dose. That's where that last change comes from... I know it shouldn't be called pyrrolidine without the nitrogen atom, but I don't know what exactly it would be called. Is that the "cyclopentyl" in EA-3167's full name? Please correct me if I'm wrong. Anyway, I thought that just based on this alone if anything was going to increase the half-life of these structures that could be it.

So really the first thing I'm interested in is all that: am I even close to being on the right track here in terms of things that would lengthen the lives of these chemicals in the body? I know that I'm going at this in a very basic way and it's not the best way to understand it, but this is generally how I tend to learn things... just trial and error with what seems right and then getting feedback on why it is or isn't correct... so I thought I'd take it here to ask. Whether I'm right or not, if you have something to say, please do explain!

The main other thing I was wondering is how anyone here thinks these changes to the original structures of tryptamine and DMT might effect their activity in the brain and body. All I really have to go on is how I can relate them to different chemicals I recognize. *H* feels somewhat reminiscent to an indole-y diphenhydramine (pic). *P* makes me think of synthetic cannabinoids like JWH-018 (pic) which doesn't exactly make me feel too confident about the duration, but it does make me wonder about its potential activity. I also can't help but think about compounds like desoxypipradrol (pic) when I look at *N*, which I'm interested in particularly because of the duration but also from the effects. Anyway, I think I've made my point here.

So the second thing I'm wondering is, am I way off base here too or am I on my way to understanding some things? Also, what do you guys think just from what you know about what any potential changes in activity these things would have? Do you see any resemblance between these and other significant molecules that I've missed that might give over clues to how they would behave? Again, if you have something to say, please give reasoning for it so I can learn from it!

This is obviously, like I said, a very basic way to look at this stuff and I know I probably seem like I know very little of what I'm talking about. But I really am just curious about this stuff and wondering if what I've picked up on from my casual research really means anything at all, and also just what anyone thinks about these. Whether you're think they're good, useless, toxic... like I said, any opinions are welcome. And if you actually do read all this and respond, I thank you in advance for taking the time!


----------



## sekio

Moved to the Random Molecules thread.

You forgot to draw the double bond between the 2 and 3 positions on the indoles.



> So really the first thing I'm interested in is all that: am I even close to being on the right track here in terms of things that would lengthen the lives of these chemicals in the body?



Strictly speaking, yes. Then more bulk a molecule has, the longer its half life. But not all of the compounds you drew will be active as psychedelics. The structure-activity relationships of scopolamine, atropine, BZ and the like is different from the tryptamine/phenethylamines. Atropine and BZ and friends exert activity by blocking muscarinic acetylcholine receptors, whereas DMT acts as a serotonin receptor agonist.



> given that one of the goals of that was to make longer-lasting compounds to be used as chemical warfare agents. That's where the beta-hydroxy came from in my picture.



The general theme with making long-duration compounds is avoiding hydroxyls as much as you can. Any groups that can give a liver enzyme a metabolic 'handle', to oxidise or stick sugar molecules on, is going to reduce duration. Also, adding OH groups increases polarity by encouraging hydrogen bonding, making the compounds less fat-souble. 



> I have to ask, knowing as little as I do, is that still valid here? (Like, can you have both there?)



Yes, carbon is tetravalent. It can have up to 4 things bonded to it. (Although, having 4 different things connected to a carbon makes the molecule chiral - for every 'chiral center' there are two molecules, like a left and a right hand, that cannot be overlaid in space and are mirror images of each other).



> but I don't know what exactly it would be called. Is that the "cyclopentyl" in EA-3167's full name? Please correct me if I'm wrong. Anyway, I thought that just based on this alone if anything was going to increase the half-life of these structures that could be it.



Yes, a 5-membered cyclic carbon ring is a cyclopentane, or cyclopentyl group. Typically, because alkanes and cycloalkanes are nonpolar and not very reactive, they can be 'glued on' to increase duration. The caveat, of course, is that too much blk might stop the compound from binding properly.

Shuklgin talks a bit about this in PiHKAL.


			
				AEM said:
			
		

> The extension of the two-carbon chain of mescaline by alpha-methylation to the three carbon chain of TMA approximately doubled the potency of the compound. And it was felt to be a completely logical possibility that, by extending it one more carbon atom, to the four carbon chain of α-ethylmescaline, it might double again. And following that logical progression, the doubling of potency with each additional carbon atom, the factor would be 2 to the 7th power by the alpha-octyl (or 256× that of mescaline, or a milligram as active dose) and with a side chain of a 70-carbon alkyl group (α-heptacontylmescaline) it would take just a single molecule to be intoxicating. This was rich fantasy stuff. As an active compound, just where would it go in the brain? With an 80-carbon side-chain, would one-thousandth of a single molecule be enough for a person? Or might a single molecule intoxicate a thousand people? And how long a chain on the alpha-position might be sufficient that, by merely writing down the structure on a piece of paper, you would get high? Maybe just conceiving the structure in your mind would do it. That is, after all, the way of homeopathy.
> 
> Maybe it was just as well that this added two-carbon side-chain with lowered activity was already enough to disprove the doubling pattern. But by the time this non-activity had been learned, the alpha series had already been pushed out quite aways. [...] But since the first of these, AEM, was not active, there was no enthusiasm for tasting anything higher. This family was never published; why publish presumably inactive and thus uninteresting material?



Compound M has been made, it is known as pip-T. The one with a 5-membered ring, pyr-t, is known and not particularly promising at all. 5-MeO-pyr-T caused some wierd fugue/blackout states.



			
				TiHKAL said:
			
		

> The piperidine material, pip-T, is made via the glyoxylamide (mp 182-183 °C) which is reduced with LAH to the target amine (mp 149-150 °C, HCl salt 220-221 °C). The morpholine analogue also came to be via the glyoxylamide (mp 187-188 °C) and the reduction to the amine which can be an oil, but which has been reported to have a mp 145-147 °C. The only trials I know of with either of these is with mor-T which, as the fumarate salt, had no effects at all upon the i.m. injection of a 30 milligram bolus.





> So the second thing I'm wondering is, am I way off base here too or am I on my way to understanding some things? Also, what do you guys think just from what you know about what any potential changes in activity these things would have? Do you see any resemblance between these and other significant molecules that I've missed that might give over clues to how they would behave? Again, if you have something to say, please give reasoning for it so I can learn from it!


Some of these compounds remind me of mazindol. But to be honest, I don't know if they're even known compounds, the beta-substituted tryptamines...


----------



## tweex

Had a totally crazy idea.

The "phenmetrazinated" analog of PRL-8-53 





SMILES: C1=CC(=CC(=C1)C(=O)OC)CCN2CCOC(C2C)C3=CC=CC=C3

Any idea what the hell, if anything, it might do? Similar to the compounds in this patent.


----------



## Dresden

2-methoxy-4,5-methylenedioxymethcathinone (methylone replacement)
3,4,5-trifluoroamphetamine


----------



## pharmakos

Dresden said:


> 3,4,5-trifluoroamphetamine



i have very little basis for this, but i feel like that would be a bad one


----------



## Dresden

4-chloropsilocin
N,N-dimethyl-5-methyltryptamine
3-methylmethamphetamine


----------



## pharmakos

Dresden said:


> 3-methylmethamphetamine



i always wondered about this one.  seems so obvious.... the amphetamine version of mephedrone.  i assume there must be a good reason that its not around, but i do not know what that reason might be.


----------



## Wandering Girl

sekio said:


> Moved to the Random Molecules thread.



Woah, I didn't see this here before lol. Good to know.



sekio said:


> You forgot to draw the double bond between the 2 and 3 positions on the indoles.



I actually didn't forget, I wasn't sure how to do it in that sketcher... but thanks for the heads up anyway. 



sekio said:


> Strictly speaking, yes. Then more bulk a molecule has, the longer its half life. But not all of the compounds you drew will be active as psychedelics. The structure-activity relationships of scopolamine, atropine, BZ and the like is different from the tryptamine/phenethylamines. Atropine and BZ and friends exert activity by blocking muscarinic acetylcholine receptors, whereas DMT acts as a serotonin receptor agonist.



Yeah, I figured most of them wouldn't be active as psychedelics, or at least would have a considerably lessened chance to as it went on.... I was really more concerned about the duration anyway so that's okay with me, I just thought it would be cool to draw them with the indole group instead of the phenyl like those anticholinergics have. I figured it couldn't hurt.

I actually keep coming across this frustratingly obscure reference that hyoscyamine is a serotonin antagonist too, which does make me wonder if a change like that would possibly still keep some serotonin receptor affinity (good or bad), but I really can't find any actual source of that information, just mentions.... Any idea about that?



sekio said:


> The general theme with making long-duration compounds is avoiding hydroxyls as much as you can. Any groups that can give a liver enzyme a metabolic 'handle', to oxidise or stick sugar molecules on, is going to reduce duration. Also, adding OH groups increases polarity by encouraging hydrogen bonding, making the compounds less fat-souble.



Ah, that's very interesting! Thanks much for this, I had no idea! :D



sekio said:


> Yes, carbon is tetravalent. It can have up to 4 things bonded to it. (Although, having 4 different things connected to a carbon makes the molecule chiral - for every 'chiral center' there are two molecules, like a left and a right hand, that cannot be overlaid in space and are mirror images of each other).



That's pretty cool, I've always found chirality interesting but never knew much about it.... Thanks again, that's good to know!



sekio said:


> Yes, a 5-membered cyclic carbon ring is a cyclopentane, or cyclopentyl group. Typically, because alkanes and cycloalkanes are nonpolar and not very reactive, they can be 'glued on' to increase duration. The caveat, of course, is that too much blk might stop the compound from binding properly.
> 
> Shuklgin talks a bit about this in PiHKAL.
> 
> Compound M has been made, it is known as pip-T. The one with a 5-membered ring, pyr-t, is known and not particularly promising at all. 5-MeO-pyr-T caused some wierd fugue/blackout states.



Ah, that indeed doesn't sound very promising.... Still pretty neat to think about though. I wonder what activity caused such the drastically different effects compared to related compounds? It definitely doesn't sound like the best path to take though. But thanks again!



sekio said:


> Some of these compounds remind me of mazindol. But to be honest, I don't know if they're even known compounds, the beta-substituted tryptamines...



Woah, that's a neat one... and pretty interesting that it's a stimulant. I can definitely see the similarities, and I would compare it to desoxypipradrol too just like I did with some of the ones I drew. That certainly gives me something more to think about, thanks for that!

And thanks one last time for a very helpful and informative response!


----------



## babylonboy

Psilocin is already substituted at the 4 position with a hydroxyl group. 3-methylmethamphetamine isn't the reduced form of mephedrone, 4-methylmethamphetamine is, and probably has neurotoxic and monoamine oxidase inhibiting and generally not very good effects.


----------



## ebola?

> 3-methylmethamphetamine



One could hope it safer than the 4-methylated homologue. . .  might actually fell pretty nice, but it's up in the air whether it'll be entactogenic at all.

ebola


----------



## babylonboy

hypericin with hydoxyls substituted for methyls because wow so symmetry such carbonyl


----------



## pharmakos

much chem wank


----------



## buildersoftime

This is the same relationship to DMT as Naratriptan is to Sumatriptan. I wonder what it would be like to smoke.


----------



## atara

^Looks like a serotonergic MPTP. If you replace the piperidine with a pyrrolidine it would be a little less scary. I like the idea though.


----------



## SeenSoFar

atara said:


> ^Looks like a serotonergic MPTP. If you replace the piperidine with a pyrrolidine it would be a little less scary. I like the idea though.



Not that I claim to understand the subtleties of MAO-A or anything, but if metabolism to an MPP+-like compound were indeed a danger, wouldn't that happen already with naratriptan? According to a paper on triptans and their metabolism and possible interactions[1], naratriptan undergoes metabolism by MAO-A, P450 (which specific P450 has not been elucidated), as well as renal metabolism. The creation of MPP+ from MPTP on the other hand, is via MAO-B[2]. Perhaps the creation of MPP+-esque compounds from MPTP analogues requires some specific mechanism of MAO-B. Either way, I've not heard of naratriptan being a serotonergic neurotoxin, so I'm guessing it probably wouldn't happen with buildersoftime's compound either, unless I'm missing something here. The only mechanism I could think of that would make naratriptan safe and the compound under discussion not safe would be that naratriptan has no SERT affinity while buildersoftime's compound does, since the DAT is also required for MPTP-induced neurotoxicity[2]. Of course, I could be missing a million other things here, if I am, please let me know!

[1] - https://notendur.hi.is/meb1/wikiverk/triptans.pdf

[2] - http://www.ncbi.nlm.nih.gov/books/NBK27974/


----------



## tweex

SeenSoFar said:


> Not that I claim to understand the subtleties of MAO-A or anything, but if metabolism to an MPP+-like compound were indeed a danger, wouldn't that happen already with naratriptan? According to a paper on triptans and their metabolism and possible interactions[1], naratriptan undergoes metabolism by MAO-A, P450 (which specific P450 has not been elucidated), as well as renal metabolism. The creation of MPP+ from MPTP on the other hand, is via MAO-B[2]. Perhaps the creation of MPP+-esque compounds from MPTP analogues requires some specific mechanism of MAO-B. Either way, I've not heard of naratriptan being a serotonergic neurotoxin, so I'm guessing it probably wouldn't happen with buildersoftime's compound either, unless I'm missing something here. The only mechanism I could think of that would make naratriptan safe and the compound under discussion not safe would be that naratriptan has no SERT affinity while buildersoftime's compound does, since the DAT is also required for MPTP-induced neurotoxicity[2]. Of course, I could be missing a million other things here, if I am, please let me know!
> 
> [1] - https://notendur.hi.is/meb1/wikiverk/triptans.pdf
> 
> [2] - http://www.ncbi.nlm.nih.gov/books/NBK27974/



Reminds me, I was reading a guide to working with MPTP for research a while ago and found out Selegiline is actually given prophylactically.


----------



## blueberries

I'm not sure if this has been tested before but:






Possibly a 5-Methyl/Methoxy in there?


----------



## pharmakos

would that be planar like MDMA?


----------



## babylonboy

That oxygen is an epoxide, the strain on the bonds makes it highly, highly reactive. The cyclobutyl group is also strained. It would be difficult and expensive to produce and likely to decompose easily. Yeah, it's planar.


----------



## toastmann

What would happen if you make an amine/amphetamine like compound based on ascorbic acid?


----------



## babylonboy

It gets chopped to shreds by metabolism and doesn't cross the BBB. For a start, it's a lactone, so that ring is going to open up in any acidic or basic environment.


----------



## blueberries

I expect this to be a fairly potent opioid, is there anything inhibiting this?






I threw the ketone group in last minute, just to stabilise/decrease potency/increase opioid activity. It can be removed.

_________________

Also I noticed this earlier in the thread but for some reason it didn't work, I altered it slightly though. This, however is a fairly obvious choice as a successor to TCB-2, so did Nichols make it and it was a dud or what?


----------



## MrPorter

@toastmann, you mean like a 2,5-dihydrofuran ring i guess substituted at 2 with an ethylamine?


----------



## Dresden

4-trifluoromethylmethcathinone


----------



## toastmann

MrPorter said:


> @toastmann, you mean like a 2,5-dihydrofuran ring i guess substituted at 2 with an ethylamine?



Yes you can faintly see the phenethylamine like structure. As in a circular form (benzo/dihydrofuran) shape with the dihydroxyethyl group switch with an ethylamine.


----------



## bloodshed344

babylonboy said:


> It gets chopped to shreds by metabolism and doesn't cross the BBB. For a start, it's a lactone, so that ring is going to open up in any acidic or basic environment.



But so are the kavalactones.  Care to explain the difference?




blueberries said:


> Also I noticed this earlier in the thread but for some reason it didn't work, I altered it slightly though. This, however is a fairly obvious choice as a successor to TCB-2, so did Nichols make it and it was a dud or what?


Ahh, yes!  I've thought of this molecule in my head many times!  My guess is that it will be more active a psychedelic than MDMA is, but while retaining some characteristics.  It may even be mescaline-like.



Dresden, TFM-MCat sounds like a pretty decent chem, but maybe a bit harder on after-effects than regular MCat (knowing how the halogens work there on phenethylamines)

and toastmann, I think you'd have to at least modify the structure a bit to stabilize it.  I definitely see the similarity though.


----------



## Soulfake

The 3d-alignments of a Fencamfamine-Tilidine and a Morpholine-Meperidine derivative look quite promising:

http://s7.directupload.net/images/user/131122/m6tfhvkt.jpg

http://s7.directupload.net/images/user/131122/kucrjz9i.jpg


----------



## buildersoftime

I'm assuming something like this has been discussed before?






Or this






Or (while I'm cyclicizing everything in sight) 4,5 cylicized analogues of:

2c-d






2c-e






2c-p






Then there are the respective hemi-fly analogues which would all be UK legal. 4,5 cyclicized analogues of:

2c-d-hemi-fly






2c-e-hemi-fly (this one should be called MickyMouse)






2c-p-hemi-fly






And finally (because it's beautiful) MickyMouse-AI


----------



## babylonboy

Would those saturated cyclic ethers not be considered alkoxy substitutions under the MODA? Is there any precedent? bromo-dragonfly would be considered class A, no? I like your DOM-indane, pretty thing.


----------



## Transform

The UK MoDA did not cover 6-APDB (they temp scheduled it specifically) so would not cover that. Good chance that at least a few of those would be pleasantly active, the problem would be the expensive synthesis - puts of the profiteers that run the industry if they aren't certain they'll be profitable.


----------



## babylonboy

They only temp scheduled it this year, and no UK vendors were selling it before that (early batches of 6-APB were raved about, then it transpired they were likely the reduced analogues and pulled from sale, no?). It's interesting, though, I'd agree with you, it seems they've actually implicitly stated that benzodihydrofurans aren't covered when the industry had assumed they were and policed itself.


----------



## piller97

This is actually the most wonderful thread I've ever seen because this is pretty much the relativity of quite a few stimulant users.

fabulous idea


----------



## Albion




----------



## sekio

What is that, a K-hole?


----------



## Transform

Reminds me of cancerdrone


----------



## babylonboy




----------



## buildersoftime




----------



## babylonboy

Protip: Ctrl+A, then you should have an option somewhere on the toolbar of your software called "Clean", it'll tidy up those bond angles for you.


----------



## MrPorter

builder, your cyclised 2c-e is essentially 5-methoxy 6-apdb (i think) and I remember reading either 5-methyl or 5-methoxy 6-apb was active, so i went to find where i read it and all i came across was this - http://en.wikipedia.org/wiki/F-2_(psychedelic) which is pretty damn close. While this F-2 is active but shit, it's known bulk on the heterocycle lowers activity so removal of that methyl might actually get somewhere. I'm not sure why shulgin wanted that bulk on the ring, he made f-22 as well (another methyl on the 2 position). As far as I can see he didn't just make 'F' which is what you suggested. He's an odd man.


----------



## MrPorter

bk-2c-b dimerisation problem solved by whacking 2,5-dimethoxy 4-Br on the Aminorex phenyl ring! (maybe). I'd guess the DOx (BOx?) derivitive could be done by whacking them on 4-MARs phenyl.

I was thinking about linking th 2 Os by a MD ring, but it would have 6 sides and wouldn't be aromatic at all, mind you it looks tryptamine-y with a bit of rotation and squinting


----------



## babylonboy

Erm, this thread is, like, for drawing random molecules, not, y'know, like, just describing them, hello, skeletal tits or gtfo


----------



## MrPorter

chrome os sucks  use your imagination :D











I'm bad at coming up with imaginative names, so my buddy came up with this. Great.


----------



## babylonboy

Don't let sekio see those Texas oxygens, he'll have a hissy fit 8(

Don't know if you could run this but it might be worth a try.


----------



## tweex

babylonboy said:


> Don't let sekio see those Texas oxygens, he'll have a hissy fit 8(



Texas Oxygens? Is that a slang term for Oxonium?


----------



## babylonboy

"Texas" just refers to hypervalent atoms, like trivalent oxygens as in the pic above, or the classic favourite, pentavalent carbon. I don't know why it's called that, ask someone who learnt chemistry in a school.


----------



## MrPorter

oh balls here i am doing a chemistry degree, didnt even know. Actually meant to have isofuran but whatevs


----------



## Soulfake

Two Methylphenidate-analogues: (I think they aren´t new, wouldn´t the morpholine-analogue have potential as a Research Chemical?)

http://s7.directupload.net/images/131129/ya2736t6.png

And some Cannabinoids:

http://s7.directupload.net/images/131129/spezk9sk.png

(The Methoxy-units can be replaced by Methyl or various Halogen-substitutions, I just like the effects of JWH-250 so I used Methoxy)


----------



## a tree

bloodshed344 said:


> But so are the kavalactones.  Care to explain the difference?



Propably because the ring is aromatic (correct?), what stabilizes it/makes it hard to break up.


----------



## babylonboy

No, pyran isn't aromatic. My guess would be that those kavalactones do open up, and that they are prodrugs for the resulting acids.


----------



## a tree

Sorry, my bad.


----------



## babylonboy

Don't sweat it. Aromatic rings have delocalised electrons, and are resonance structures, yeah? I don't want to patronise you if you know already...


----------



## a tree

I really should think twice before posting shit. Quite embarassing for someone who already had OC1 at university 
Thank you for clarifying that.


----------



## nuke

babylonboy said:


> No, pyran isn't aromatic. My guess would be that those kavalactones do open up, and that they are prodrugs for the resulting acids.



Kavalactones have 2-pyrone rings, not pyrans, which have different properties.  The 2-pyrone ring is planar and is very difficult to hydrolyze, unlike a lactone ring.  I would guess the active product is not the ring-opened form.

Many of the metabolites of the drug have the ring intact or intact and reduced: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085297/#B30


----------



## Soulfake

Could this Substance hydrolyze into Niacin and Amphetamine? An Amphetamine-Prodrug with an added vasodilator could be useful against the vasoconstriction.


----------



## pharmakos

idk about it hydrolizing, but niacin's doses are so much higher than methamphetamine's that idk if there would be enough niacin per dose to actually cause any substantial vasodilation


----------



## SeenSoFar

Really straight-forward one that I've been bouncing around for a while. Lorcaserin shows that cyclizing the ethanamine side-chain of a PEA into an azepane ring does not eliminate affinity for and efficacy at 5-HT-related targets, at least in terms of the 5-HT2 subtypes anyway. Hopefully that applies to the SERT as well. Hopefully the cyclization of the sidechain is sufficient to stave off MAO without the need for a 6-methyl (equivalent to an α-methyl on a PEA). Thoughts?


----------



## LucidSDreamr

atara said:


> http://en.wikipedia.org/wiki/dimemebfe



nichols has a review commenting on some work such as this.    they made thiobenzofurans of dmt as well and they were agonists at 5ht receptors but not as good as dmt, serotonin, etc. so yea they still work.


----------



## LucidSDreamr

lol, i just clicked on your link after typing this post which is the wiki page which provides a link to the nichols review i mentioned....its a good review on topics being discussed in this thread.


----------



## black53

This just popped up in my head - 6-allyl-6-nor-lysergic acid 2,4-dimethylazetidide (al-lsz?). Anyone think it would be active?


----------



## ebola?

I'm just going to interrupt briefly to note that this thread has been cultivating surprisingly good, fruitful exchanges lately.  Keep it up, guys!

ebola


----------



## Incunabula

Black53, the thought occured to me aswell 

Or how about Acetyl-ETH-LSB


----------



## Incunabula

looks like I missed a double bond


----------



## black53

Is it just me or do most LSD analogues only change stuff at one of the nitrogen atoms?

Or how about bk-5-mapb and bk-6-mapb:


----------



## Incunabula

black53 said:


> Is it just me or do most LSD analogues only change stuff at one of the nitrogen atoms?


No, your right. If you change anything else, it won't be a Lysergamide anymore, and probably won't be active. (Well, both the tryptamine and phenethylamine skeleton is inside of there, so I guess it's not completely impossible, but it won't really be a LSD analog anymore)

That list of lysergamides on wikipedia isn't complete, by the way, there's more than that. After Hoffman invented/discovered LSD he wen't on making analogs with substitutions on R2 and R3. I think he made like 10 different ones there, non as active as LSD though, but most still active in the 500-2000 ug range. (MIPLA, LSM-775, LAE-32 etc) He made one with  a acetyl at R1 though, ALD-52.

Shulgin was next, in Tihkal he made a line of LSD analogs based on substitutions on R6. He made something like 6 or 7 there. (the xx-LADs)

It was Nichols who later made the next subs on R2 and R3. Namely LSZ, LSB, LSP.


----------



## black53

I meant more in the sense that most change either R2 and R3 or R6 or R1. Changes to both R6 and R2/R3 (like that AL-LSZ from my drawing for example) or R1, R2, R3 and R6 (the compound you posted) seem to be rarer. Is there a reason for this (problems with synthesis? inactivity?) or is it simply because nobody has gotten around to doing it?


----------



## Incunabula

I don't know 

I _think_ it's mostly a question of synthesis, but it's also because there has been so little research on lysergamide SAR compared to phenethylamines and tryptamines. The hybrid compounds we both drew might very well be inactive, so potentially not worth the trouble/money/time.


----------



## black53

Well, the LSZ modification is supposed to increase binding, so an additional modification on R6 or R1 that binds fine with LSDs  R2 an R3 should still work right? Of course since sar is more of an art... who knows. I guess nobody wants to risk investing in it without knowing it would be good... perhaps one day...


----------



## Str




----------



## pharmakos

^ all tasty looking simple modifications

i would be willing to personally guinea pig all of those other than #6 and #8

#6 might be incredibly stinky... #8 might have pretty different activity

the rest of them though should be pretty similar to ketamine if they have any activity at all


----------



## ebola?

black53 said:


> Is it just me or do most LSD analogues only change stuff at one of the nitrogen atoms?
> 
> Or how about bk-5-mapb and bk-6-mapb:



With the key exception of mephedrone, has the addition of a beta-ketone ever improved the effects-profile of a recreational drug?*  You might be on to something though, insofar as making the APB series less serotonergically selective might hold promise.  However, the serotonergic selectivity of these compounds is as of yet up in the air (the one study showing 6apb to lack significant affinity for SERT requires replication, as they got weird results for some of their 'control' compounds, and other studies have found 6apdb and 5apdb to be more serotonergically selective than MDMA).

*I have seen only scattered reports of 4-Me-MA, and 4-Me-A might well be pretty damn fun, but it also appears to be hideously neurotoxic, somewhere between a longer acting MDMA and PCA.

ebola


----------



## atara

ebola? said:


> With the key exception of mephedrone, has the addition of a beta-ketone ever improved the effects-profile of a recreational drug?*



Hamilton apparently prefers methcathinone to methamphetamine, and all of the N,N-dialkylated things (which are inevitably mere stimulants, consider eg a-PPP) seem to improve with this modification. It might be closer to say that beta-oxo is no good for serotonergics, and as the empathogenic effects of 6-APB seem to be primarily mediated by 5-ht2b we can probably extend the reasoning there.


----------



## babylonboy

I understand that s-PVP is preferred to prolintane, too.


----------



## black53

ebola? said:


> With the key exception of mephedrone, has the addition of a beta-ketone ever improved the effects-profile of a recreational drug?*  You might be on to something though, insofar as making the APB series less serotonergically selective might hold promise.  However, the serotonergic selectivity of these compounds is as of yet up in the air (the one study showing 6apb to lack significant affinity for SERT requires replication, as they got weird results for some of their 'control' compounds, and other studies have found 6apdb and 5apdb to be more serotonergically selective than MDMA).
> 
> *I have seen only scattered reports of 4-Me-MA, and 4-Me-A might well be pretty damn fun, but it also appears to be hideously neurotoxic, somewhere between a longer acting MDMA and PCA.
> 
> ebola


I don't know if improved is the right word, but adding the beta-ketone to 2c-b preserved most of the good effects while extending duration.


----------



## babylonboy

I don't think improved is the right word, a ten-fold drop in potency and mediocre effects. 2C-B is wildly popular and soughtafter, the ketone analogue is not making waves in the same way. Also, having mentioned para-halogenated cathinones, 4-bromomethcathinone seems to be better than the amphetamine, in that people have used it recreationally and not suffered horrendous neural damage.


----------



## black53

Hm, I agree about the drop in potency (tho it does last longer), but the effects were, as far as I'm concerned very nice for an entry level psy (to be fair, I didn't get any of the bad effects some have complained about like inconsistency in effects and a headache in the end), especially considering the price and legality. I definitely plan on buying more. Now of course I'd rather have al-lad (or a test batch of al-lsz to see if what looks good on paper actually is good in rl), but to be fair I don't thing they are competing for the same market, one is more of a light psy, while the other is a lsd analogue with all that can bring.

As to the bk-apb versions, I have no idea. I'd like to see them tested, but I have no idea if it would be an improvement or not. Luckily only 5 and 6 apb are illegal in my country, so I can still legally use the others. Speaking of that, I'd like to se 5 and 6 MAPDB tested, perhaps they'd be good like 6-apdb or perhaps nothing special like 5-apdb.


----------



## Jesusgreen

Some more silly ideas that probably are way off in terms of what I was going for:


----------



## babylonboy

What are you going for?


----------



## black53

5-MAPDB





6-MAPDB





Would anyone else like to see these two made and tested? I've always wondered about their effects....


----------



## black53

3,4 - CTEP





3,4 - FTEP





3,4 - FTMP


----------



## black53

5-EAPDB


----------



## babylonboy

I don't get it... ethylphenidate and 3,4-dichloroRitalin are both a bit shit, let's make them breed, maybe they'll produce something really shit? If those drugs are your cup of tea, fair play, but I can't see them being much fun. Likewise, are 5-APB and n-ethylMDA the kind of big winners we want to explore the derivatives of? Not to piss on your cornflakes, I just don't quite understand the appeal. By the way, it looks like you're using paint or something to add alkyl groups to preexisting skeletal formulas, Symyx draw is free and is what I use. It's not as good as ChemDraw, but it's a million percent more free.

JG, those things look a bit like naphyrone to me, which wasn't well recieved. There's other bicyclic amphetamines, too, but I unfoundedly feel like phenmetrazine/aminorex type things are the most promising designer stimulants of the future.


----------



## babylonboy

^The saturated analogues (5- and 6-aminopropylbenzodihydrofuran) are already available, it's only the N-alkylation that would be novel.


----------



## ebola?

> ethylphenidate and 3,4-dichloroRitalin are both a bit shit



Have there been sufficient human bioassays to establish the latter as shit?



> JG, those things look a bit like naphyrone to me, which wasn't well received.



Such a wide array of miscellaneous cathinones was sold as naphyrone that the compound hasn't really yet been received at all.

ebola


----------



## babylonboy

^It's been sold by UK vendors under the name 3,4-CTMP for over a year, quite a lot of EADDers have tasted it, the consensus is that it's even more rubbish than ethylphenidate. There's a thread here about it, there's probably others, but given the fondness of Brits for stimulant RCs, I think the fact that no-one's particularly bothered about it says a lot. My unscientific impression is that people would opt for methiopropamine or ethylphenidate over it, which makes me think it's not the best thing since sliced bread.


> Such a wide array of miscellaneous cathinones was sold as naphyrone that the compound hasn't really yet been received at all.


Very true.


----------



## black53

No offense taken babylonboy, it's a perfectly valid complaint, so let me explain.

The reason for the eph/3,4-ctmp variations is that I like eph a lot, so I bought some 3,4-ctmp hoping to get something similar with a longer duration and lower dose. What I got was rubbish that I barely feel (30mg ~ about a cup of tea, when 10mg should provide long lasting stimulation). Now it's possible that I was scammed by the vendor, but I bought it twice from two different vendors. Each time it looked/tasted the same + the second vendor is one that I've been using for years and has never screwed me before. So I guess 3,4-ctmp = crap for me. This made me wonder how a few simple modifications would affect it, hence the drawings.

The 5 and 6 MAPDBs are also something I'm interested in. I liked the benzofurans I tried (5 and 6 apb, 5 mapb, 5 apdb (this one more as a replacement for mdai)) and heard good things about 6-mapb and 6-apdb. The mapdbs are kinda a logical extension of that. The eapdb is something for people from the UK where the others are illegal (but I guess it's to late to try it, since all benzofurans will be illegal soon). The bk benzofurans are another thing I'd like to see tested, who knows, it may suck, be average or really good. Methylone and bk-2c-b turned out ok. And now knowing from bk-2c-b that bk primary amines can be stable enough we may see bk-mda.

And you don't really think that 6-allyl-6-nor-lysergic acid 2,4-dimethylazetidide or al-lsz is boring, right?

Oh, and thanks for the drawing program!


----------



## toastmann

5/6-MAPB are already available. The reports say it feels very similar to MDMA. 

The only problem I have with these saturated compounds, that if you look at 5-MA*D*PB for example, if you break up the tetrahydrofuran part you immediately get 4-methoxy-3-hydroxy-methamphetamine (HMMA) which is a known neurotoxic having its part in MDMA's neurotoxicity. But I don't know enough about metabolism to predict if this actually happens so maybe someone with more knowledge can shed some light on it. I also don't know if this happens in unsaturated compounds so I have to read a bit into 6/5-APB metabolism. If it does happen then 5/6-MAPDB would be safer than 5/6-APDB because the latter would then produce HMA which is more toxic then HMMA.


----------



## ebola?

babylon said:
			
		

> people have used [brephedrone] recreationally and not suffered horrendous neural damage.



Well, those involved in trials of PCA as an anti-depressant tolerated it well and didn't notice the horrendous neurotoxicity they incurred for a matter of years, if at all.

ebola


----------



## buildersoftime

Has this cyclisised version of MDEA been discussed before?


----------



## ebola?

I don't think that releasers fare well with cyclized groups added to the amine, though incorporation of the alpha-carbon tail is pretty novel, but it's not even clear whether it should be judged in terms of stimulant SAR of any sort.

ebola


----------



## SeenSoFar

Just a quick one here, I'm away from my computer and so I can't look this one up properly or draw it for you, but it's extremely straightforward. The previous compound brought up one I've been thinking about lately. I'm curious if benzylpiperidine or 3,4-methylenedioxy-benzylpiperidine have ever been studied. If not, why? It seems like the logical step in between amphetamine and BZP. Also, any results might be applicable to the 3,4-methylenedioxy-benzylpyrrolidine suggested by buildersoftime.


----------



## atara

Ethylphenidate is proof that NE activity is required for some people to have fun. We certainly learned something from it, most people who hated it were mad because it was promoted as a cocaine replacement. Oddly it seems to be a more practical therapeutic drug than MPH for this reason. Some people also thought the "legendary" amfonelic acid was boring. 

2-benzylpiperidine was apparently disappointing. 4-benzylpiperidine is an active NDRI. 3-benzylpiperidine has yet to be examined.

Ebola: such metabolic transformation of APDB compounds is unlikely. In addition, they were less toxic in rats than was MDA itself. This is another reason I'm annoyed the ACMD lumped these in with the APBs.


----------



## black53

toastmann said:


> 5/6-MAPB are already available. The reports say it feels very similar to MDMA.
> 
> The only problem I have with these saturated compounds, that if you look at 5-MA*D*PB for example, if you break up the tetrahydrofuran part you immediately get 4-methoxy-3-hydroxy-methamphetamine (HMMA) which is a known neurotoxic having its part in MDMA's neurotoxicity. But I don't know enough about metabolism to predict if this actually happens so maybe someone with more knowledge can shed some light on it. I also don't know if this happens in unsaturated compounds so I have to read a bit into 6/5-APB metabolism. If it does happen then 5/6-MAPDB would be safer than 5/6-APDB because the latter would then produce HMA which is more toxic then HMMA.



I know about 5/6 mapb. Only tried 5-mapb so far, but a 6-mapb sample is going to be here soon. For me the 5-mapb was a bit worse that a 5/6 apb combo, but then I like the trippyness of that. Guess I'm more of a mda person. For someone that doesn't want that, I can see 5-mapb being better. As far as 5/6 mapdb according to a few vendors they were in the plans but since the UK ban I guess it's not really that profitable any more (the vendors I talked with had the UK as their mayor market). So until some one rich pays for a synth it's an open question on how pleasurable the effects are. And I'd not be so fast to call things neurotoxic just buy speculations (note, a warning of the posssibility is of course totally different and fine) on their metabolism. As far as I know not much scientific research was done on any of the benzofurans. Not that I'm calling them safe, just saying more research is needed before saying either way. Besides, who knows, perhaps the mapdb compounds are crap effect wise and nobody would take them anyway. Personally 5/6 apb, 5-mapb and 5-apdb felt pretty benign to me but it's not like neurotoxicity from a few uses is that obvious unless huge.


----------



## black53

babylonboy said:


> ^It's been sold by UK vendors under the name 3,4-CTMP for over a year, quite a lot of EADDers have tasted it, the consensus is that it's even more rubbish than ethylphenidate. There's a thread here about it, there's probably others, but given the fondness of Brits for stimulant RCs, I think the fact that no-one's particularly bothered about it says a lot. My unscientific impression is that people would opt for methiopropamine or ethylphenidate over it, which makes me think it's not the best thing since sliced bread.
> 
> Very true.



Agree about 3,4 ctmp. Rubbish. None of the good sides of eph (yeah, I enjoy eph), not active in the low doses some claim... That's why I proposed some mods to it, perhaps ome would turn out nicer.


----------



## Dresden

3-carbomethoxymethcathinone


----------



## babylonboy

I don't get what you mean. 3-methoxymethcathinone with a carboxylic acid group hanging off the ether carbon, or the methyl ester of 3-hydroxymethcathinone, or what? Could you draw it in Symyx or ISIS?


----------



## Dresden

3-CO2CH3 methcathinone


----------



## babylonboy

This chappy? Don't know much about pharmacology but that seems way polar and bulky, ebola? or someone, are we even talking about stimulant SAR here? I feel like I'm very negative in this thread, I'm sorry, it's probably the manifestation of insecurity. Live the dream, be the change, have a Chinese national synthesise it. By the way, Dresden, I've said it before, you may just be on a phone or tablet or something, but ISIS/Symyx/Accelerys (I think it's all basically the same program, I'm unsure, it's not important) is free and serviceable, not quite as good as Chemdraw, but free and perfectly good with a little practice, you can get it here, it can draw anything you'd want, generate structures from text/SMILES and vice versa, worthwhile.


----------



## Transform

That ester will readily hydrolyse and leave you with something that will be very rapidly excreted. Additionally, it is unlikely to be active with such a polar substituent preventing BBB permeation.


----------



## Dresden

I got the aryl carbomethoxy idea from a new phenylethylamine nootropic which has a thread around here somewhere and also shares the Ar-3-CO2CH3.  I don't recall its name though, sorry.

Think of 3-CO2CH3 methcathinone as a more electronegative 3-MMC.  And then, of course, there is the possibility of the 4-CO2CH3 isomer.

If methylphenidate is any guide, the CO2CH3 moiety should last at least 2 to 4 hours.


----------



## atara

The 4-carboxylate function is believed to cause neurotoxicity in the case of 4-methylamphetamine. Probably best avoided.


----------



## Dresden

What about in the case of mephedrone?


----------



## Transform

Cathinones seem to display much less neurotoxicity. Presumably this is metabolite mediated as the B-ketone provides a "weak-point" which is easily metabolised to allow excretion and therefore this limits the potential to form dangerous metabolites through other routes cf. methylone, mephedrone


----------



## babylonboy

> Methcathinone and methylone were threefold less potent than MA or MDMA at inhibiting [3H]5-HT uptake into human platelets, with IC50's of 31.4 ± 7.3 uM and 5.8 ± 0.7 uM, respectively. In C6 glial cells stably expressing the rat dopamine transporter, methcathinone and methylone were similar in potency to MA and MDMA, with IC50's for [3H]DA uptake of 0.36 ± 0.06 uM and 0.82 ± 0.17 uM, respectively. Methcathinone and methylone were also similar in potency to MA and MDMA in C6 cells expressing the human norepinephrine transporter, with IC50's for [3H]NE accumulation of 0.51 ± 0.10 uM and 1.2 ± 0.1 uM, respectively. *The benzylic ketone moiety of methcathinone and methylone had a large (tenfold) negative impact on the abilities of these drugs to inhibit the vesicular monoamine transporter (VMAT2) compared to MA and MDMA.*
> 
> So, we see that the simple addition of a beta-ketone moiety to a PEA which normally had affinity for the VMAT2 drops the new compound's ability to interact with that receptor by 1000%!
> 
> For those unaware of the rather large implications of this:
> 
> 
> 
> VMAT2 is essential in the presynaptic neuron's ability to facilitate the release of neurotransmitters into the synaptic cleft.
> 
> 
> 
> 
> Therefore it seems these compounds, methcathinone and methylone [being literally 10x less efficient at interfacing with this receptor when compared to their monoamine releasing homologues methamphetamine and MDMA] are primarily re-uptake inhibitors, as they cannot bind to the VMAT2 with sufficient force as to facilitate release. Furthermore, these findings can almost certainly be applied to all the beta-keto compounds.
> 
> Got a knowledge bomb or two up my sleeve. Since we can assume brephedrone doesn't activate VMAT2, and therefore is a simple reuptake inhibitor, our conclusion regarding it's toxicity becomes increasingly clear. Drugs which only reuptake monoamines are generally much more benign as far as neurotoxicity. Even during simultaneous and strong serotonin release via MDAI, co-administration of a simple DARI resulted in *no* neurotoxicity. And THAT's straight from Nichols.
Click to expand...

From here. I don't know much credence to give it, but it was brought up in a discussion of brephedrone. It's essentially a bit beyond me, take it with a megadalton of halite.


----------



## black53

I know I sound annoying, but that al-lsz thing I posted a few pages back and the mapdbs are definitely something I'd like to see sold. If only I were rich and could just pay for having all sorts of weird chemicals I wanted ....


----------



## ebola?

> Therefore it seems these compounds, methcathinone and methylone [being literally 10x less efficient at interfacing with this receptor when compared to their monoamine releasing homologues methamphetamine and MDMA] are primarily re-uptake inhibitors, as they cannot bind to the VMAT2 with sufficient force as to facilitate release. Furthermore, these findings can almost certainly be applied to all the beta-keto compounds.



mmm...I don't see how a compound that effects transporter reversal with high efficacy could function primarily as a reuptake inhibitor though.  It might be less effective in maintaining tonic synaptic monoamine concentration increase in comparison to compounds that have significant affinity for VMAT2, but it's still different from mere reuptake inhibition.  Furthermore, controlling for general potency, another study found mephedrone to be highly effective at increasing synaptic monoamines, rivaling MDMA and amphetamine.  Methcathinone has also been observed to cause neurotoxicity qualitatively similar to methamphetamine though with reduced magnitude.



> Since we can assume brephedrone doesn't activate VMAT2, and therefore is a simple reuptake inhibitor, our conclusion regarding it's toxicity becomes increasingly clear.



No, it doesn't.  The specific mechanisms underlying the toxicity of PCA are unknown, beyond the fact that binding at SERT is necessary for such neurotoxic effects.  They seem somewhat distinct from those of other entactogens, as PCA exerts greater toxicity than MDMA at similar levels of serotonergic efflux.

ebola


----------



## babylonboy

Yeah, like I say, I'm not in any way able to critically evaluate those claims. They are not mine and I do not hold or advocate them. I was just reminded of this.


> Methcathinone has also been observed to cause neurotoxicity qualitatively similar to methamphetamine though with reduced magnitude.


Is this in clinical trials with pure compounds, or in street users? Only 'cos it seems like KMnO4 toxicity would be common in mcat users.


----------



## ebola?

IIRC, it was _in vivo_ assay in rats with post-mortem tissue examination. . . yeah, I believe that I was thinking of this study: http://jpet.aspetjournals.org/content/279/2/1043.short.

If there was KMnO4 present in their samples of compound, the researchers should have their degrees revoked. 

ebola


----------



## babylonboy

lulz

So I've hit a weird stride of finding novel RCs for sale. Earlier, 5-bromo-DMT and 5-isopropyl-DMT, pretty odd. Then, I said in EADD that no, I hadn't heard rumours of another lysergamide RC, and moments later, happened across a vendor offering "Lysergic acid 2-butylamide":




(My skeletal formulas, apologise if I've made a mistake, I'm so tired I just spent longer than I should scanning the list of forums, bemusedly unable to find Advanced Drug Discussion). It seems that AL-LAD and LSZ are definitely being sold, isobutylysergamide (I've just made that name up) is allegedly available, and the higher homologues of LSD seem to be natural candidates. LiHKAL, anyone?


----------



## atara

Lysergic acid sec-butylamide was mentioned several times by Nichols. It appears to be active. No reliable reports in humans exist.


----------



## SeenSoFar

Ok guys, here's one for you. I was thinking the other day about how much I really enjoy a mix of 2C-T-2 and 2C-T-7, and how that together they are more than the sum of their parts. I find the blend to be very entactogenic, and EXTREMELY visual. The compounds also potentiate each other, so that a dose of about 10mg of each is a very powerful and ecstatic experience, with a profoundly spiritual component being a semi-regular occurrence at this dose.

Since this combination is so enjoyable to me, I got to thinking, why not design a compound that could bring the experience of both? The most obvious way to do this, in my mind anyway, was an ester. However, there are no free hydroxyl groups in either compound. This brought me to the HOT series. I have as yet very limited experience with these compounds, but from my limited trials of each, I find them to be very comparable to their N-deshydroxy counterparts. So, without further ado, a compound that should break down to form HOT-2 and HOT-7 in vivo:






And here is a similar one for HOT-4 and HOT-7 that I did just for the hell of it as well:






Thoughts, anyone?


----------



## babylonboy

Why did you incide the isopropyl moiety og -t-4 and not the ethyl of t-2?


----------



## SeenSoFar

DUH!! Hahaha, I posted the wrong file! This was just another one I was messing with for fun. I'm going to update that to the right one right now.

EDIT: Ok, there we go! Thanks for pointing that out babylonboy!


----------



## MagickalKat777

Wouldn't that be potentially dangerous given the difference in dosage the two have and that 2C-T-7 is likely an MAOI?

I personally am so sensitive to 2C-T-7 that 15mg had me drifting in and out of consciousness while I have taken 38mg of 2C-T-2 and still kept my wits about me.

Cool idea though.


----------



## SeenSoFar

I have taken them together quite a few times and I've been fine. Like I said in the post though, I've never exceeded 10mg of each as a dose. There is definitely potentiation going on there, but the effects are much more magical and mystical than they are apart. I have yet to try mixing HOT-2 and HOT-7, but I imagine it will work  in a similar way, given the fact that, in myself at least, the HOT-X series seems very similar to their 2C-T-X counterparts. There's also the fact that this would be a totally dissimilar compound from a legal perspective...


----------



## Thanatos

No one has noticed the sulfonyl group has 6 bonds? From what I remember sulfur does have the capability to share that many electrons?


----------



## SeenSoFar

Thanatos said:


> No one has noticed the sulfonyl group has 6 bonds? From what I remember sulfur does have the capability to share that many electrons?



This is because this is compound is a sulfate diester. That is a common state for sulfate diesters. Compare with:

Diethyl Sulfate






Dimethyl Sulfate


----------



## sekio

sulfate esters are also generally considered to be incredibly reactive... dimethyl sulfate is a real nasty carcinogen.

a carbonate ester or methylene/ethylene linker (c.f. fenetylline) is the way this is traditionally done, I think.


----------



## Thanatos

^ yeah sorry guys, I was nodding off when I made that post. Not exqctlyban analytical state of mind.


----------



## SeenSoFar

sekio said:


> sulfate esters are also generally considered to be incredibly reactive... dimethyl sulfate is a real nasty carcinogen.
> 
> a carbonate ester or methylene/ethylene linker (c.f. fenetylline) is the way this is traditionally done, I think.



I thought the reason that the dialkylsulfates are particularly unpleasant is because they are alkylating agents. I considered a carbonate diester, but I chose a sulfate diester because I thought that in this case it would liberate the 2 parent compounds more readily than a carbonate diester and I could not see a mechanism for toxicity, since in this case it is not an ester of simple alkyl group and as such would not act as an alkylating agent. Was this not the correct line of thinking? I would appreciate the input!


----------



## pharmakos

saw this linked on a different forum (that i can't name) claimed that it will be the future should cathinone bans get even worse.  is there any actualy scientific reasoning behind this, or was the person just making stuff up?  seems like a pretty radical change from the parent compounds, idk how much activity it would retain:


----------



## babylonboy

My guess would be someone borked up drawing para-fluoro methcathinone. In any case, I'll not be imbibing.


----------



## MrKhazar

I can't lie about the fact that I made an account on BL just to post on this thread. Anyway, I wanted your opinion on a molecule that can potentially open the doors to a wide range of pharmaceutical analogues that act as pro-drugs for specific compounds. In common nomenclature (or Shulgin nomenclature, as I like to call it) the compound is called *L-4-Bromo-alpha-carboxyl-2,5-dimethoxyphenethylamine* (also known as *alpha-Carboxyl-2C-B*). It is the amino acid analogue of *2C-B*, and in my opinion this property allows it to be a pro-drug for 2C-B after it is ingested orally. There is a possibility that this molecule acts as a substrate to the enzyme known as *aromatic L-amino acid decarboxylase* (*AADC*), undergoing a reaction that ultimately removes the carboxyl group from the molecule thereby producing 2C-B. In addition, this molecule is most certainly not a substrate for another enzyme called *biopterin-dependent aromatic amino acid hydroxylase* (*AAAH*) because of the bromo functional group present on the 4-carbon position. Therefore, if this molecule acts as a substrate for AADC yet it does NOT act as a competitive inhibitor, we have ourselves a novel pro-drug that can have its own analogues! I wish I could post an attachment of a photo, but for some reason I cannot do so. I hope I presented this in a very clear and articulate manner.


----------



## babylonboy

So, analogous to:


----------



## MrKhazar

Well, they are not exactly analogous, but the first image represents *DL-4-Bromo-alpha-carboxyl-2,5-dimethoxyphenethylamine*, and the second image represents *DL-alpha-carboxyl-tryptamine* (*DL-tryptophan*). For them to be substrates of AADC, they must be levorotatory. Honestly, if I was a geneticist, I would create a gene that codes for aromatic D-amino acid decarboxylase. Oh, and right before I posted I learned that N-methylated amino acids are demethylated by N-methyl-L-amino acid oxidase, so I had to scrap the idea of making a pro-drug for DMT and Bufotenin.


----------



## babylonboy

Yeah, I'm not equipped or inclined to do anything involving polarised light nowm so there's the two absolute entantiomers, choose whichever you want. Oh, and should you ever muster a thanks, you're welcome.


----------



## MrKhazar

LOL I hope I didn't get under your skin. Trust me, I am very grateful for your help! I was tearing my hair out trying to attach an image to my post, and when I saw your post I was glad someone took the time to create some structural diagrams for me, albeit with some weird-looking double bonds in the phenyl ring haha. I presume the levorotatory stereoisomer is the one on the bottom? If so, that's the only one that would be useful as a pro-drug.


----------



## babylonboy

You didn't get under my skin, I just thought that a "thanks" was in order! They're aromatic bonds, rather than double bonds, but they do look weird, they can be changed. I prefer the circular notation, but cba right now.
IDK which one rotates light which way. Based on amphetamine stereochemistry, this should be the levo isomer


----------



## MrKhazar

Thanks a lot for the systematic name too! If this molecule can follow in the same footsteps as L-Phenylalanine, L-Tyrosine, and L-DOPA, what other compounds from the 2Cx family will follow suit? Earlier this week I was also working on pro-drugs for amphetamine and methamphetamine, but I scrapped that idea because either the resulting molecule would competitively inhibit the enzymes, or it would not act as a substrate for those enzymes.


----------



## babylonboy

^Check out symyx. It generates text from structure and vice versa, is easy to use and free. There are already loooods af amp/mamp prodrugs (Vyvansem isn't it?).


----------



## MrKhazar

The software is called Symyx Draw right? Thanks for that bro, I appreciate it. One thing I have noticed which completely boggles my mind, is the fact that L-alpha-methylphenylalanine, L-alpha-methyltyrosine, and L-alpha-methylDOPA competitively inhibit AADC and AAAH, yet L-alpha-methyltryptophan is metabolized into L-alpha-methyl-5HTP, and then into alpha-methyl-5HT! What is up with that?


----------



## babylonboy

Ask a pharmacologist, not a guy who learned to extract mesaline in his garage, is my advice. The software is ISIS/symyx/Accelerys (all same thing I think), then there's other things for smasing small drugs into proteins, which I presume you want to.


----------



## pharmakos

^ there are legit pharamcologists on this board, *Ba*bylon*Bo*y.


----------



## babylonboy

Yeah, by all means, ask them. I am not one of them. Ask me how to sort out an emulsion in your STB xtraction. Ask me that, I'll tell ya. All that shit up there is BEYOND ME. Took me 3 fucking cracks to draw the right structure,ffs. I do what I can, but I know when I'm out of my league. Also, I don't get the bold green bits in my UN in your post, explain them or leave them obscure, as you wish. Hope all is good, playa.

Also, does anyone know how I can make a phenyl ring appear with 6 single bonds and and unbroken internal ring, rather than alternating single and double order bonds? I prefer the former, but the latter seems to be the default. In Accelerys, or w/e it is these days. plz thx plur etc


----------



## pharmakos

one time awhile ago you (or someone else) made a joke comparing you to Breaking Bad.... the green bits are like the Breaking Bad logo =p


----------



## babylonboy

OOOOOOOH sorry

i was being dumb

think i prefer *Ba*bylo*Nb*oy, tho,


----------



## pharmakos

haha no prob   its obscure, i know.  i did the same thing with your user name immediately after that comment was made (i wanna say a month or two ago), dunno if anyone caught it then.


----------



## babylonboy

i tried yours. *Th*e*Ni*ght*W*a*Tc*h was my best shot, sorry. t*He*nig*H*tw*At*ch was seriously my second best shot. Here's a dollar, buy a vowel, yeah?


----------



## pharmakos

i'll take a U plz.


----------



## babylonboy

*Th*e*UunI*g*H*t*W*a*Tc*h

Uranium and ununtrium go for more than a dollar, btw. PM me.


----------



## pharmakos

we're getting offtopic, so here's some chemwank from a lay man






no idea if i could squeeze more fluorines on there

and i know my amine isn't quite right.  couldn't get it right with this lame online java chem sketch app i found.


----------



## babylonboy

So you thought, "2ct4, that's everyones fave, lets make it way more expensive"? Still not tried the legendary DO/2C-TFM meself, meant to be v. good and potent, perhaps something to this. Dunno why, just seems like a lot of electronegativity up on that 4-position, is that OK? Might it hinder BBB passage? Real scientists, say something sensible!


----------



## MrKhazar

At first I almost had a heart attack because the amine did not have 3 covalent bonds attached to it, but then I read your excuse and heaved a sigh of relief haha. I guess organic chemistry and OCD mix very well. Anyway, that molecule looks like 2C-TFM on steroids. I can't even name that thing! If it ends up being a viable compound, turn it into another NBOMe as well.


----------



## babylonboy

[4-2-[1,1,1,3,3,3-hexylluoryl]propyl- 2,5,dmpea, no? or 4-_sec_[1,1,1,3,3,3-hexafluoropropyl- 2,5,dmpea? tnw, GET ISIS DUDE! it'll generate IUPAC names and SMILES codes from structures, and vice versa. It's not chemdraw, but i can't find free chemdraw anymore, so it works fine. Might even prefer it now I'm used to it. 

Yeah, the 4-methyl that would be chiral if it didn't have identical groups on other side, that one doulc have one more F. For good measure or whatever.

Also, Fs all the way round the aryl ring, TFM groups on the Os, Fs on the amine nitrogen (is it even an amine then?), Fs on the aliphatioc chain. It's like you haven't even tried to make a highly fluorinated drug, If you see a hydrogen, or a higher-order bond, you can have more fluorine. Why, I dunno.

MrK, I didn't even notice that hypovalent N, I guess I'm just used to assuming that valencies are satisfied by H unless otherwise informed, with C atoms, and extrapolated without thinking. Did that really bother you? 

tnw, three marks down. No beta ketone, no methylendioxyring, no alpha methyl (well, a-TFM, ofc!). Very disappointed. See me after class.


----------



## pharmakos

babylonboy said:


> tnw, three marks down. No beta ketone, no methylendioxyring, no alpha methyl (well, a-TFM, ofc!). Very disappointed. See me after class.



if you look back many pages, i drew LSD with a methylenedioxy and an nbome on it =p

and that name you came up with looks right to me.


----------



## babylonboy

http://accelrys.com/products/informatics/cheminformatics/draw/no-fee.php

naming ain't hard, just methodical. at any rate, draw a chem, and the program will give you the IUPAC, and a smiles code so others can recreate it. DL it now, or we can;t be friends anymore


----------



## pharmakos

oh, just realized...



babylonboy said:


> [4-2-[1,1,1,3,3,3-hexylluoryl]propyl- 2,5,dmpea, no?



should be 4-2-[1,1,1,3,3,3,-hexafluoro]-*iso*propyl-2,5-dimethoxyphenethylamine i believe


----------



## babylonboy

Isn't that what the 2 at the very start means? Anyway, this is why names are shit, end up arguing over nomenclature more than anything else. Just draw the fucker, then we all know what we're talking about. Anyway... INSTALL BASTARD ISIS and it'll tell us.


----------



## sekio

im just gonna leave this here
http://web.chemdoodle.com/demos/iupac-naming


----------



## pharmakos

don't think that's what that 2 means.  in fact, i'm not entirely sure that 2 belongs there at all.

see: the name of 2C-T-21, 2,5-DIMETHOXY-4-(2-FLUOROETHYLTHIO)PHENETHYLAMINE






i hope our bumbling isn't annoying the true scientists that read this thread

i suppose thats why us amateurs get quarantined to these stickies =p



sekio said:


> im just gonna leave this here
> http://web.chemdoodle.com/demos/iupac-naming



with that i get:

2-{2,5-Dimethoxy-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]phenyl}ethylamine


----------



## babylonboy

2-[2,5-dimethoxy-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]phenyl]ethanamine. More important than a name refers to one compound than that a compound has one name; were my tweeky creations ambiguous? With 2Cs, the 2- means the ortho position relative to the alkylamine chain. With alkanes, I understood the meaning of the two was equivalent to _sec_, to show that it bonded at the central, secondary C, not either terminal primary C.

Yeah, I was taught to find the longest alkane chain present (the (iso)propyl) and name from there. Oh well. I had hoped sekio might, being a chemist, help others who are obviously trying to learn to understand their mistakes. Any chance, dude, please?

Also- just fuckin' draw the thing. Always FTW!


----------



## pharmakos

wish i could just email sasha and ask him what he would name it 

2,5-dimethoxy-4-(2,3-hexafluoroisopropyl)phenethylamine?


----------



## babylonboy

You prolly can. I reckon di-TFM-2C-D, or hexafluoro-2C-iP. He's more a man of the people, likes to share, prefers to get knowledge out there than use esoteric jargon as an exclusive cant to preserve privilege to the ingroup. Heck, let's just call it Ununbabohellahalonium. Sasha was partial to a whimsical name himself (Beatrice? Flea? Iris?) See, names are so unimportant, they're just a way for those in academia and research to try to keep the little people, like us, out. I mean, we all knew what chemical we were talking about; isn't that the sole purpose of a name, at least for a chemical that hasn't even been synthesised, to identify it unambiguously? If one likes not a name, I suggest they explain why it is wrong, y'know, take a moment to explain and help understand. I think we've probably come up with several unambiguous names here, and unless the IUPAC are a-knocking, we'll be ok.


----------



## SwampFox56

^^

Thanks for that, I've been playing around with it. But I've got a few questions if someone wouldn't mind answering them for me. Specficially - I was playing around with the idea of "Methylenedioxypropylhexedrine", but noticed that the tool wouldn't allow me to positively charge the carbon off of the amide. Why is this? 



Spoiler: Molecule











I think it has something to do with the Nitrogen bond, and the fact that doing so would make the molecule way more polar, or non-polar than physically possible. But I don't know... that's why I'm asking.


----------



## sekio

Maybe you need to put hydrogens on it?
*NSFW*:


----------



## babylonboy

sekio, do you use that? it seems like it sucks so hard next to ISIS


----------



## SeenSoFar

First off, the IUPAC name of the compound under discussion is 2-(4-(1,1,1,3,3,3-hexafluoropropan-2-yl)-2,5-dimethoxyphenyl)ethanamine. Here is it drawn by ChemDraw Pro:

*NSFW*: 













babylonboy said:


> ... With alkanes, I understood the meaning of the two was equivalent to _sec_, to show that it bonded at the central, secondary C, not either terminal primary C...



When you're refering to a branched proply structure, it is referred to as iso, not sec. There is no sec-Propyl, only n-propyl and isopropyl. It's only when you extend the alkyl chain to butyl that you can have the option of n-, iso-, sec- and tert- butyl. 



SwampFox56 said:


> ^^
> 
> Thanks for that, I've been playing around with it. But I've got a few questions if someone wouldn't mind answering them for me. Specficially - I was playing around with the idea of "Methylenedioxypropylhexedrine", but noticed that the tool wouldn't allow me to positively charge the carbon off of the amide. Why is this?
> 
> 
> 
> Spoiler: Molecule
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> I think it has something to do with the Nitrogen bond, and the fact that doing so would make the molecule way more polar, or non-polar than physically possible. But I don't know... that's why I'm asking.



Why would you like to have a carbonium cation on your N-methyl? I don't understand why this is something you would want... It would be far too polar to cross the BBB from what I know...

Also, the aromatic ring is required for SERT and DAT affinity. You would probably end up with something that was NE specific, if active at all I would think.


----------



## sekio

I use Chemdraw, but for IUPAC naming the little doodle tool is fine.


----------



## babylonboy

> When you're refering to a branched proply structure, it is referred to as iso, not sec. There is no sec-Propyl, only n-propyl and isopropyl. It's only when you extend the alkyl chain to butyl that you can have the option of n-, iso-, sec- and tert- butyl.


Yeah, duh, put that down to me being better at smoking speed than doing ochem (orchemwank or whatever this is we do here). Of course, when you 0 0r 1, there's no 2 option.

sekio, I've said it many times, but if you can't get chemdraw, ISIS is a decent and much freer second. I gave up on that doodler, why bother when this:
http://accelrys.com/resource-center/downloads/freeware/index.html
is free? 

SSF, like I said, I was always told to find the longest alkane, so I was surprised not to see "prop" anywhere. I really appreciated your post- not being afraid tto tell me where I'd made stupid mistakes, and explaining the theory so I can learn for another time. Thanks, dude/tte. Sometimes people who know more than us come in, scoff, tell us we're stupid, and don't take the the time to explain where we've gone wrong. What I learn in ADD, I then use in other forums, so there's a trickle-down of  knowledge, and a couple minutes of time spent explaining chem or something here can really help the community. Not everyone does it, not even staff sometimes, so thanks man, it really is appreciated that you take the time to help amateurs like us grasp these concepts.


----------



## MrKhazar

Another molecule that peaked my interest is called *L-5-MeO-alpha-methyltryptophan*. In the same vein as *L-4-Bromo-2,5-dimethoxyphenylalanine*, it would act as a pro-drug, but this time it would be metabolized into *L-5-MeO-aMT* when ingested orally. Since the 5-carbon position on the phenyl ring has a methoxy group on it, the compound will not act as a substrate for AAAH, therefore this enzyme cannot add a hydroxyl at the 5-carbon position. For some odd reason, alpha-methylation of tryptophan does not make it a competitive inhibitor of AADC yet it still acts as a substrate for that enzyme, therefore the enzyme will catalyze the decarboxylation reaction of L-5-MeO-alpha-methyltryptophan to yield L-5-MeO-alpha-methyltryptamine (L-5-MeO-aMT). This will only work if the molecule acts as a substrate for AADC and is levorotatory. Once again I cannot add attachments, so I hope everything is clear.


----------



## sekio

methylenedioxypropylhexidrine might not even be stable - non-aromatic methylenedioxy rings are not the most stable.


----------



## MagickalKat777

MrKhazar said:


> Another molecule that peaked my interest is called *L-5-MeO-alpha-methyltryptophan*. In the same vein as *L-4-Bromo-2,5-dimethoxyphenylalanine*, it would act as a pro-drug, but this time it would be metabolized into *L-5-MeO-aMT* when ingested orally. Since the 5-carbon position on the phenyl ring has a methoxy group on it, the compound will not act as a substrate for AAAH, therefore this enzyme cannot add a hydroxyl at the 5-carbon position. For some odd reason, alpha-methylation of tryptophan does not make it a competitive inhibitor of AADC yet it still acts as a substrate for that enzyme, therefore the enzyme will catalyze the decarboxylation reaction of L-5-MeO-alpha-methyltryptophan to yield L-5-MeO-alpha-methyltryptamine (L-5-MeO-aMT). This will only work if the molecule acts as a substrate for AADC and is levorotatory. Once again I cannot add attachments, so I hope everything is clear.



That sounds like a bad idea all the way around... The last thing that needs to be going into the human body is something that turns into 5-MeO-aMT in an unknown and likely widely variable amount. I've got a lot of experience with that substance, a lot more than I would like to admit, and a couple milligrams is the difference between a blissful and intense trip that rivals the likes of DMT and a trip to the ER.

Also, your attachment issue? Go to tinypic and upload pics there then use the IMG code it gives you for forums. Problem solved.


----------



## MrKhazar

Wow, I guess I was way too lazy to even think about uploading them on tinypic haha. Oh well, thanks a lot for your help! Anyway, everyone's body is different, so it would be stupid to expect that 2mg of the pro-drug will metabolize into 2mg of L-5-MeO-aMT and vice versa, but because it has a slightly higher molecular mass the amount of L-5-MeO-aMT that is ingested will be slightly lower. Couple that with different rates of enzymatic action, and you're looking at an amount that ranges from almost nothing to almost 2mg. Oh yeah, and the onset of action might take a very long time therefore a user will take more thinking the dosage wasn't enough.


----------



## SkyblueMolly

Here's a new image. It's 2C-BU(or 2C-Bu)! It's a fake molecule. If it became real, it might produce only vague hallucinogenic effects while being more mental and longer lasting with stimulating effects.


----------



## babylonboy

Would it not follow the pattern of increasing duration and intensity of D-E-P? Mind you, "butyl is futile".


----------



## pharmakos

shulgin made DOBU (the 3-carbon homologue of that molecule), and it didn't show much activity up to 2.8mg.  seems like he quit exploring it there, though.  he assumed it would not have activity past that, but who knows.  https://www.erowid.org/library/books_online/pihkal/pihkal063.shtml


----------



## MrKhazar

I started thinking about proteins and peptides recently, so I thought of making a polypeptide chain of the amino acid versions of 2C-B and 5-MeO-aMT. This is the result. The brackets denote a continuation of peptide linkages between individual amino acids, which would result in an extremely long chain of molecules. These are just two examples representing the phenethylamine class and the tryptamine class. Imagine being given a prescription for a protein form of 2C-B by your physician haha! When you ingest it orally, the enzyme protease and hydrochloric acid in your body breaks it down into smaller polypeptide chains, and it continues to do so until you are left with single 2C-B molecules entering your bloodstream. The same thing would happen with the protein form of 5-MeO-aMT. Pretty neat, eh?


----------



## Munroe

Can anyone name this molecule? Trying to find some more information about it but it's proving difficult.


----------



## pharmakos

^ isn't that cocaine?


----------



## SeenSoFar

thenightwatch said:


> ^ isn't that cocaine?



 Yes indeed it is. However, and mind you there is a good chance I am wrong since this is right off the top of my head, I believe its one of the "unnatural" isomers of cocaine.



MrKhazar said:


> I started thinking about proteins and peptides recently, so I thought of making a polypeptide chain of the amino acid versions of 2C-B and 5-MeO-aMT. This is the result. The brackets denote a continuation of peptide linkages between individual amino acids, which would result in an extremely long chain of molecules. These are just two examples representing the phenethylamine class and the tryptamine class. Imagine being given a prescription for a protein form of 2C-B by your physician haha! When you ingest it orally, the enzyme protease and hydrochloric acid in your body breaks it down into smaller polypeptide chains, and it continues to do so until you are left with single 2C-B molecules entering your bloodstream. The same thing would happen with the protein form of 5-MeO-aMT. Pretty neat, eh?



If that did indeed work, which is never guaranteed when it comes to predicted pharmacokinetics, we're back to the same problem of variable metabolism to a substance with a low dose and steep dose-response curve. I personally am a lover of 5-MeO-aMT and I think it gets an unfairly bad rep, but I would never take it without being positive that I knew my exact dose down to a sub-milligram margin of error. I've had one or two very uncomfortable experiences with very slight increases in dose, and it has given me a strong respect for this compound. I would rather rip my dick off and throw it in the river than take a dose of any 5-MeO-aMT prodrug. On the other hand, the 2C-B version would be something that I'd like to explore....


----------



## MrKhazar

Man, to hell with 5-MeO-aMT amino acid! I don't know if you've tried 5-MeO-aET, but this is what its L-amino acid counterpart looks like. The thing is, the addition of an ethyl group on the alpha-carbon might turn this molecule into a competitive inhibitor of AADC, or it might simply nullify its potential to act as a substrate altogether. If it does act as a pro-drug to 5-MeO-aET, the sky's the limit. I've already compiled the amino acid versions of mescaline, 2C-B, 2C-E, 2C-T-2 and 2C-T-7, so this one might be added to my ever-growing collection of pro-drugs. Honestly, if none of these pro-drugs work in vitro or in vivo, I wouldn't bat an eye. Instead, I'll just focus on N-hydroxylated analogues of our favourite chemicals.


----------



## Munroe

thenightwatch said:


> ^ isn't that cocaine?





SeenSoFar said:


> Yes indeed it is. However, and mind you there is a good chance I am wrong since this is right off the top of my head, I believe its one of the "unnatural" isomers of cocaine.




Hmm.. I think I've lifted the wrong diagram then. Trying to avoid posting the IUPAC nomenclature as it leads straight to a vendor page.

It's cocaine but 2,3-dicarboxylate rather than 2-carboxylate from what I can tell.


----------



## MrKhazar

I've been scratching my brain for two whole days trying to understand something. The drug *Fenclonine*, also called *para-chlorophenylalanine* (*PCPA*) acts as a substrate for the enzyme *tryptophan hydroxylase*. First off, how can a phenylalanine-derivative act as a substrate for an enzyme that normally binds to a tryptamine? In addition to being a substrate, PCPA also acts as a *competitive inhibitor *for tryptophan hydroxylase. How is this kind of thing even possible? My hypothesis is the molecule cannot be a substrate for phenylalanine hydroxylase because of the chloro- group on the 4 carbon position, therefore tryptophan hydroxylase tries to add a hydroxyl group onto some other carbon in the aromatic ring. The thing is, why wouldn't it try to add a hydroxyl group onto any aromatic ring it encounters? This all doesn't make logical sense, but it just goes to show how complex this stuff really is. Anyway, I'm pretty sure all my amino acid pro-drugs will likely be competitive inhibitors of both enzymes. Meaning, if you take 2C-B amino acid your serotonin levels will plummet because you just took a reversible tryptophan hydroxylase inhibitor! Sigh...

EDIT: I made a mistake. PCPA does NOT act as a substrate for tryptophan hydroxylase because it does not bind to the active site. Instead, it binds to the allosteric site which makes it an irreversible (noncompetitive) inhibitor. PCPA is in fact a substrate for tyrosine hydroxylase, according to this article: http://www.ncbi.nlm.nih.gov/pubmed/8679520


----------



## AromaticNitrogen

Furan analogue of etizolam? 
Geometric optimization shows similar geometry to the thiophene.


----------



## SeenSoFar

AromaticNitrogen said:


> Furan analogue of etizolam?
> Geometric optimization shows similar geometry to the thiophene.



It's a good idea, but the thing that might end up being a problem is the fact that furan rings are not aromatic whereas thiophene rings are. I'm not sure off the top of my head how loss of aromaticity at this position will change affinity and efficacy at the BZD allosteric site, so maybe someone else can fill in that blank...


----------



## sekio

> furan rings are not aromatic whereas thiophene rings are



Furan is aromatic.


----------



## AromaticNitrogen

^
Also, I ran optimization for this "etfuralam" as well as etizolam an alprazolam. Angles and bond distances were similar between all with little variation in the diazepine and triazine rings. I think it's viable. I can post values if desired.


----------



## atara

C1=CC=C2CC(N(C)CC(C)C(=O)N(CC)CC)CC3=CNC1=C23

asfasdfafasdfsaowoejriowjrowejrowewow
such molecule
oiawoeirjlkwlekrjlkllkmlkma.mlwkemlkwmr.,malkmslkdmflkmwerill make you smiles
aowjojoijojoijoijijiiejrojvery chemical

ajjwfused rings bling bling
aiweojrowjrojlaklaldkfoijooijoijjiojoijlkmalamaze

aoiwoejrojweorjwomuch structure


----------



## sekio

such seco-LSD?


----------



## SeenSoFar

sekio said:


> Furan is aromatic.



Derp. I feel stupid. You're totally right. I don't know where THAT came from. Serves me right for posting after vaporizing 50mg of 5-MeO-DALT.


----------



## SeenSoFar

Here's one for everyone. I got the inspiration from the BOX series and phenmetrazine. The first one is BOB with the beta-methoxy lengthened by one carbon and bonded to the amine nitrogen to form a kind of 2C-B-phenmetrazine. The second one came from an observation that 2C-B took on a significantly different 3D structure than my analogue did. By cyclizing the 2-methoxy onto the position that is analogous to the alpha-carbon in PEAs, I ended up with a compound that is almost a perfect 3D overlay with 2C-B. I would be VERY interested in trying either of these out. I have a hunch that either or both may be active, and interesting...


----------



## MrPorter

Interesting about that last one because DFLYs methyl from methoxys are fixed to the other side of the ring so that the carbon sits kind of above the C2-C3 bond, but in yours it's the other side (C1-C2). Don't know if it's comparable though because of DFLYs aromatic rings


----------



## atara

MrPorter said:


> Interesting about that last one because DFLYs methyl from methoxys are fixed to the other side of the ring so that the carbon sits kind of above the C2-C3 bond, but in yours it's the other side (C1-C2). Don't know if it's comparable though because of DFLYs aromatic rings



The chromanamines are interesting, but I wouldn't expect them to be potent psychedelics. Jimscaline and TCB-2 (and Br-DFLY) seem to more closely represent the optimal spatial relationship between the nitrogen and the methoxys. In chromanamines the nitrogen is too close to the oxygen -- in TCB-2 the ring closure pushes the N _away_ from the ring and increases potency, whereas the chroman brings the N closer.

However, they could still be active SERT ligands. There's some similarity to e.g. MDAT.


----------



## SeenSoFar

atara said:


> The chromanamines are interesting, but I wouldn't expect them to be potent psychedelics. Jimscaline and TCB-2 (and Br-DFLY) seem to more closely represent the optimal spatial relationship between the nitrogen and the methoxys. In chromanamines the nitrogen is too close to the oxygen -- in TCB-2 the ring closure pushes the N _away_ from the ring and increases potency, whereas the chroman brings the N closer.
> 
> However, they could still be active SERT ligands. There's some similarity to e.g. MDAT.



I noticed this as well, that the conformation changes significantly in the chromamines. However, when I combined the chromamine and morpholine structure, I ended up with a conformation extremely close to the 2C-Xs, even more of a match than when I modeled the BOX series and compared them to various 2Cs. I am not implying that they will be equipotent to the unsaturated FLYs or the beta-cyclized PEA analogues, but I think there may be potential there for something interesting. Then again, you could very well be absolutely correct. Predicting the 3D conformations of novel compounds _in silico_, even using something like Chem3D is incredibly inexact! You did bring up an excellent point about the tetralins and related compounds though. I will do some comparison to their conformation and see what comes up.


----------



## Roger&Me

atara said:


> C1=CC=C2CC(N(C)CC(C)C(=O)N(CC)CC)CC3=CNC1=C23
> 
> asfasdfafasdfsaowoejriowjrowejrowewow
> such molecule
> oiawoeirjlkwlekrjlkllkmlkma.mlwkemlkwmr.,malkmslkdmflkmwerill make you smiles
> aowjojoijojoijoijijiiejrojvery chemical
> 
> ajjwfused rings bling bling
> aiweojrowjrojlaklaldkfoijooijoijjiojoijlkmalamaze
> 
> aoiwoejrojweorjwomuch structure



i lol'd seriously hard when i got to "fused rings bling bling" :D


----------



## SwampFox56

MrKhazar said:


> Man, to hell with 5-MeO-aMT amino acid! I don't know if you've tried 5-MeO-aET, but this is what its L-amino acid counterpart looks like. The thing is, the addition of an ethyl group on the alpha-carbon might turn this molecule into a competitive inhibitor of AADC, or it might simply nullify its potential to act as a substrate altogether. If it does act as a pro-drug to 5-MeO-aET, the sky's the limit. I've already compiled the amino acid versions of mescaline, 2C-B, 2C-E, 2C-T-2 and 2C-T-7, so this one might be added to my ever-growing collection of pro-drugs. Honestly, if none of these pro-drugs work in vitro or in vivo, I wouldn't bat an eye. Instead, I'll just focus on N-hydroxylated analogues of our favourite chemicals.



My understanding is that the only way to produce a prodrug is if the molecule is simply cleaved off into the active chemical. Correct?


----------



## dingophone

SwampFox56 said:


> My understanding is that the only way to produce a prodrug is if the molecule is simply cleaved off into the active chemical. Correct?



Not necessarily. 1,4-butanediol is a prodrug to GHB through dehydrogenation and hydroxylation. Similarly, primidone is metabolized into phenobarbital through dehydrogenation and hydroxylation. In regards to the post about 5-meo-aet amino acid, there's some info on using a-methyltryptophan as a prodrug for a-methylserotonin, so the concept is definitely a good one! However, I don't know how the 5-methoxy group would affect metabolism. Could it inhibit tryptophan hydroxylase (which wouldn't be fun)?

Also, here is death on a stick:


----------



## immad

^An irreversible MAOi and strong serotonin releaser?


----------



## dingophone

immad said:


> ^An irreversible MAOi and strong serotonin releaser?



Precisely the idea!


----------



## immad

Nice, now we need to tag on some gaba antagonism for teh lulz!


----------



## dingophone

immad said:


> Nice, now we need to tag on some gaba antagonism for teh lulz!



How about kainate agonism too? 

Also, fluordiazepoxide anyone?






Bonus stupid lysergamide:


----------



## black53

Don't know if it's already been posted, just wanted to test out the chemdraw I just installed 






isopropyl version of eph






mdai like version of 6-apb

this chem draw stuff is fun


----------



## pharmakos

i would try it, but i think it would make you very jittery/hypothermic


----------



## black53

the eph or apb?

also:









sulfur analogues of mdma













allyl versions of 2c-p and 2c-e along with their sulfur analogues


----------



## pharmakos

the isopropylenidate i would try

the rest are fairly sketchy imo


----------



## black53

The allyl stuff shouldn't be too bad imo, the sulfur analogues... who knows could be anything from inactive to dangerous.


----------



## pharmakos

in particular imo you should lose the methyl from the nitrogens on those

i think n-alkylated MDMA analogues is barking up the wrong tree.  hard to top that one.


----------



## black53

You mean make them MDA analogues instead?


----------



## black53

like this?


----------



## pharmakos

those sure are gonna smell, but i think they'll be winners


----------



## black53

benzofuran version of 4-ho-met, idea from http://en.wikipedia.org/wiki/Dimemebfe





al-lad + lsz + ald-52 modification of lsd, because why not if i'm already making shit up




o-desmethylethyltramadol




2cd-fly




2c-e-fly




2c-al-fly




difmdma


----------



## MrPorter

DiFMDA has been made
I think don't think fluorination is the way forward to 'beat' MDMA. I think MDMA is may just be the pinnacle.


----------



## black53

That's where I got the idea from 



 

 



MBDB sulfur analogues





lsb + eth lad




and this would be 3-meo-2-oxo-pcp, right 




flutoprazepam


----------



## overstoned

*Would you take this? Pyridine vs phenyl*






2-METHYL-1-(3-PYRIDINYL)-1-PROPANONE 

Niacin/nicotinamide tweaked out. I presume this would do nothing?

Can someone explain the difference the pyridine vs phenyl would make? I'm sure it's been thought of many times but I am retarded when it comes to certain aspects of biochemistry.

What about 3-isobutylpyridine??


----------



## sekio

It looks like a cut down analogue of metyrapone, a compound that messes with liver enzymes. It's hard to accurately guess what activity the compound would have based upon its structure alone.

I probably wouldn't go eating random pyridine compounds. Some of them can be carcinogenic or otherwise toxic. 



> Can someone explain the difference the pyridine vs phenyl would make?



Pyridine has a nitrogen which can hydrogen bond and coordinate to things, it's also polar because of this. 

Isobutylpyridine would be a corrosive, nasty liquid that probably has no use as a drug either.


----------



## blueberries

4-HO-N, N Dimethyl-methoxy Tryptamine

http://imgur.com/KNuju8n


----------



## blazR

blueberries said:


> 4-HO-N, N Dimethyl-methoxy Tryptamine
> 
> http://imgur.com/KNuju8n



Nice.. I wonder if it would be active


----------



## sekio

I'd expoect the methoxy groups to fall off under acidic conditions, they are hemiaminal ethers. At least when it's 2 oxygens, it decomposes to formaldehyde + 2 alcohols.


----------



## black53

What we really need is for science and engineering to advance to a point where you'd draw a molecule in chemdraw, run a simulation (in reasonable time on a single pc), and it would calculate all of it's binding affinities, downstream effects, metabolites, ...


----------



## pharmakos

black53 said:


> What we really need is for science and engineering to advance to a point where you'd draw a molecule in chemdraw, run a simulation (in reasonable time on a single pc), and it would calculate all of it's binding affinities, downstream effects, metabolites, ...



i hope that doesn't happen any time soon.... at least not until drug laws are less barbaric.

if that ever happens it would be way too easy for blanket bans to happen.... i.e. "any synthetic molecule that binds to the 5HT-2A receptor at a nM below XX is hereby considered a Schedule I compound"

i mean, bans like that are already happening with synthetic cannabinoids, but still.... being able to quantify this legal gray area we enjoy might not be such a blessing just yet.


----------



## black53

Once we're that advanced machines that will synth anything from basic ingredients + power shouldn't be far off 

So instead of porn you'd be downloading drugs.

Yeah, I believe in science.


----------



## SeenSoFar

black53 said:


> Once we're that advanced machines that will synth anything from basic ingredients + power shouldn't be far off
> 
> So instead of porn you'd be downloading drugs.
> 
> Yeah, I believe in science.



This is a lot closer than you might think. I was reading an article the other day where someone was conjecturing that, within the next decade or two, 3D printers will become available to print on an atomic scale. It will be so fascinating when it progresses to the point that you load a print cartridge of carbon, hydrogen, nitrogen, and oxygen into your printer, along with any other raw atomic material you need, load in a ChemDraw file, specify the molar weight to be synthesized, and click print. I can imagine that such technology will render current drug laws obsolete, since anyone with access to such a device will be able to create whatever they desire. 

Its actually a bit of a frightening prospect. Some teenager with little to no chemical knowledge starts loading things from this thread into his molecular printer and then doses them to see what happens. What a brave new world...


----------



## black53

I didn't know about general ones, but some peptides are already machine made


----------



## ShaggyFin

*Could Beta Ketones be the future?*

I have read somewhere that you can add an "aromatic" beta ketone compound to tons of different terpenes and other alkaloids using acetone, and I was wondering if anyone had any more information on that.
Acetone is also called "Beta-Ketopropane"
http://en.wikipedia.org/wiki/Beta-ketopropane
And it has sisters.

So even if acetone can't do it, maybe one of these can.
http://en.wikipedia.org/wiki/Ketone_bodies
http://en.wikipedia.org/wiki/3-hydroxybutanal
http://en.wikipedia.org/wiki/Mannich_base
http://en.wikipedia.org/wiki/Damascone
The three endogenous ketone bodies are acetone, acetoacetic acid, and beta-hydroxybutyric acid.[4] Other ketone bodies such as beta-ketopentanoate and beta-hydroxypentanoate may be created as a result of the metabolism of synthetic triglycerides such as triheptanoin

I know there are things like bk-MDMA, bk-MBDB, etc in existence. Is there a possibility of something like a bk-DMT or bk-DXM or bk-THC bk-Etizolam bk-Mescaline bk-JWH bk-Kavalactones bk-Cocaine bk-PEA (alpha-ethyl PEA is active, so why not)?

If you read here this guy says bk-DET exists, but I can't find an example online.
http://www.bluelight.org/vb/threads/...=1#post5146876

I also found a PDF book online that has one reference to a 5-MeO-bk-DiPT

And this
http://www.bluelight.org/vb/threads...methylenedioxy-group-to-an-ephedrine-molecule

Beta-Meo-MDMA
http://www.bluelight.org/vb/threads/686964-MeO-MDMA

And this
http://www.bluelight.org/vb/threads...enzofurans?p=12195710&viewfull=1#post12195710


black53 said:


> So I went and drawn some of them
> Sulfur analogues and their bk versions:
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> MDAI like versions and some new ideas still to come, eapb versions omitted, because there's enough drawings as is




Also this
http://en.wikipedia.org/wiki/Aldol_adduct
http://en.wikipedia.org/wiki/Ketogenesis
http://www.bluelight.org/vb/threads/357814-Beta-keto-amphetamines-(cathinones)-amp-stability
http://www.bluelight.org/vb/threads/306522-alpha-keto-tryptamines-3-acetamideindoles
http://www.bluelight.org/vb/threads...enethylamines-Beta-MeO-PEA-s-BM-PEA-s-(BMP-s)
http://www.bluelight.org/vb/threads/688503-Alpha-Ethyl-Psychedelic-Amphetamines-(Aephetamines)
AMT is really just a-MT or alpha-MethylTryptamine. So there is probably a bk- and a- for everything, and I think they are available through Aldol reaction methods.

bk-2c-B exists... Why not bk-2c-I, or bk-25I-NBOMe, bk-MDA, bk-Mescaline, etc?


----------



## sekio

> I have read somewhere that you can add an "aromatic" beta ketone compound to tons of different terpenes and other alkaloids using acetone, and I was wondering if anyone had any more information on that.



Acetone will react in e.g. aldol condensations, but no it can't be used to just "add a beta ketone", nor can any of those other compounds listed. Aldol condensations are something totally different, they form carbon-carbon bonds.



> I know there are things like bk-MDMA, bk-MBDB, etc in existence. Is there a possibility of something like a bk-DMT or bk-DXM or bk-THC bk-Etizolam bk-Mescaline bk-JWH bk-Kavalactones bk-Cocaine?



Considering many of those aren't phenethylamines/tryptamines, no, there can't be "BK-cocaine". All that the term means is there's a ketone on the second carbon away from the amine in a PEA/tryptamine.


----------



## Solipsis

The above image of bk-2C-B-NBOMe is missing the letter "r" next to the "B". Br stands for bromine / colliquially bromo (which is the prefix name for the element bromine), B stands for boron which is another element.

bk-MDA, if at all active, would probably need a ridiculous dose like something along the lines of 400 mg if there is ~4x potency loss when beta-ketonating 2C-B. I really don't think it is a smart idea to put that kind of strain on your vitals.
bk-Mescaline even worse, a dose may be over a gram, though it wouldn't be a subbed cathinone like bk-MDA.

The term beta ketone refers to putting that carbonyl oxygen on the beta position. The term beta position (wiki search substituted phenethylamine to find out what it is) is only meaningful in a limited context***. So on terpenes you can certainly 'design' an additional =O carbonyl oxygen, but that doesn't magically create an interesting structure. It only makes sense if you depart from a certain drug that would benefit from the modification.

bk-2C-B may have its fans and the prospect of other bk-2C-X compounds can be fascinating as long as the starting material is not too weak to begin with (which would yield the problems I listed at the start of this post), but that may mostly be by the virtue of cathinone (again look up the structure) being an active compound itself. So there may be some crossover pharmacodynamics - which often don't work well by the way - and quite frankly the dimerisation problem giving inconsistent responses to dosage and the general impotency are a pain in the ass. These problems (not sure which exactly) seem to be causing the drop in potency.
Also prepare to be told by people that cathinones are categorically shitty.

If you like methylone then obviously beta-ketone versions of the MAPBs / MAPDB should be fun, yes I would expect those surfacing first and foremost. Those actually make sense and don't go so far out on a limb.
No offense, I applaud the enthousiasm, but you need to either learn some more chemistry and/or stay more close to home regarding drug design. Ketonating the shit out of random chemicals does not mean anything per se, it is a trivial thing in organic chem and there are other considerations if it's going to be worth investigating any bit.***

(What Sekio said plus where I marked *** are reasons why bk-etizolam, bk-kavalactones, etc don't make sense. With some exceptions perhaps, for example 'beta-keto tryptamines' apparently have been discussed, just BL-google that)


----------



## ShaggyFin

*A New Class of Drugs*

This idea started in this thread
http://www.bluelight.org/vb/threads/716103-Could-Beta-Ketones-be-the-future

http://en.wikipedia.org/wiki/Damascone
It's in Roses, and it's already a Cyclohexyl and Beta Ketone.


OR

http://en.wikipedia.org/wiki/Myrcene
A strange maybe "ready" molecule.


Now, looking at those and these.
http://en.wikipedia.org/wiki/Acetone


http://en.wikipedia.org/wiki/Chloroform


http://en.wikipedia.org/wiki/Cyclohexylamine


http://en.wikipedia.org/wiki/Nitroethane


http://en.wikipedia.org/wiki/Naoh


I feel like something is here...


----------



## JWills20

MED ---> NPD. Chemistry really isn't our thing in MED, perhaps the neuroscience and pharmacology guys can provide some insight.


----------



## Solipsis

What makes you think any of these suggest a new class of drugs?

I thought I was clear earlier in the 5-HO-DMT thread about oversimplifying cut and paste style chemistry Lego-ing?


----------



## ShaggyFin

JWills20 said:


> MED ---> NPD. Chemistry really isn't our thing in MED, perhaps the neuroscience and pharmacology guys can provide some insight.



I'm reading up on the chemistry myself right now. I'm not at all sure what it would be like as far as effects, but I think I can hypothesize on things that can be formed.


----------



## Solipsis

So you just "guess" out of the blue that they could be drugs if you would modify them in one of the countless ways.

Continuing on the lego analogy, that would be the same as dumping a metric ton of lego somewhere and picking a few pieces randomly and saying: I might be onto something.

Err, we're gonna need a little more than that. 8)




Granted, myrcene appears to be mildly psychoactive but it is only very mild and therefore not really promising.
Damascone is a cyclohexene and terpenoid but is it psychoactive to begin with?

And again: slapping carbonyl oxygens or chloro's onto some chemicals willy nilly is not drug design, you kind of need an aim - and other than that if something like myrcene were promising then yes what big pharm company labs might do is investigate analogues by modifying the structure. Still nowadays this isn't done at random, it is modelled based on what receptors you wish to agonize or antagonize.


----------



## ShaggyFin

Solipsis said:


> The above image of bk-2C-B-NBOMe is missing the letter "r" next to the "B". Br stands for bromine / colliquially bromo (which is the prefix name for the element bromine), B stands for boron which is another element.



I actually got that image from a page that was proposing NEW NBOMe molecules that have not been made yet. I am actually not sure what it is meant to be.



			
				Solipsis;12212683
bk-MDA said:
			
		

> [/B]. So on terpenes you can certainly 'design' an additional =O carbonyl oxygen, but that doesn't magically create an interesting structure. It only makes sense if you depart from a certain drug that would benefit from the modification.



I am not suggesting we may find some miracle drug, just a likable non-dangerous one.



Solipsis said:


> No offense, I applaud the enthousiasm, but you need to either learn some more chemistry and/or stay more close to home regarding drug design. Ketonating the shit out of random chemicals does not mean anything per se, it is a trivial thing in organic chem and there are other considerations if it's going to be worth investigating any bit.***
> 
> (What Sekio said plus where I marked *** are reasons why bk-etizolam, bk-kavalactones, etc don't make sense. With some exceptions perhaps, for example 'beta-keto tryptamines' apparently have been discussed, just BL-google that)



I am not like sitting at a work bench ready to pour these things, I am just proposing a discussion that could lead to something larger.


----------



## ShaggyFin

Solipsis said:


> So you just "guess" out of the blue that they could be drugs if you would modify them in one of the countless ways.



Is that not how everything was made int he first place? Without Pihkal and Tihkal, you could say the same about Phenethylamines and Tryptamines.



Solipsis said:


> Granted, myrcene appears to be mildly psychoactive but it is only very mild and therefore not really promising.
> Damascone is a cyclohexene and terpenoid but is it psychoactive to begin with?



Pepper is not psychoactive and we use it to make Ecstasy.


----------



## Solipsis

ShaggyFin said:


> I actually got that image from a page that was proposing NEW NBOMe molecules that have not been made yet. I am actually not sure what it is meant to be.



It would be the hybrid of bk-2C-B and 25B-NBOMe. And it seems like a _disastrous_ idea.



> I am not suggesting we may find some miracle drug, just a likable non-dangerous one.



And I am suggesting the idea is flawed in a way that will theoretically make potentially dangerous or at the very least uneconomical drugs. I for one wouldn't like to be around when it is released on unwitting people who will try anything.


----------



## ShaggyFin

Solipsis said:


> It would be the hybrid of bk-2C-B and 25B-NBOMe. And it seems like a _disastrous_ idea.


Not my idea, and I don't plan on making it. I am just trying to open people's minds to the possibilities.



Solipsis said:


> And I am suggesting the idea is flawed in a way that will theoretically make potentially dangerous or at the very least uneconomical drugs. I for one wouldn't like to be around when it is released on unwitting people who will try anything.


You are being very general.

I am again not certain of the possibilities, but what about something like a weaker version of LSD (bk-LSD, bk-LSA) or a weaker version of Mescaline. Can you not see how this could lead to a more widespread acceptance of psychedelic use? You are already blowing them off as if they will be too weak for the value, what if that is the form of psychedelics society NEEDS.




Solipsis said:


> Please start at the beginning and learn introductory chemistry, organic chemistry and medicinal chemistry first (and also ideally drug design).



I started with Marijuana extraction (at 14 years old), then things like Kava extraction and at this time I am studying natural products and marine natural products. I will get to organic chemistry eventually, but I have a lot of books to read.


----------



## Solipsis

No. Pihkal compounds started out from mescaline which was found in nature (in cactus species) and Tihkal started out from psilocin which was also found in nature in mushrooms. Both are already psychoactive so modifying them to see if you come up with compounds that are still psychoactive but in a different way is logical and it has a reasonable chance of succeeding.

We don't really use pepper to make ecstasy. MDMA is made from saffrol compounds found in sassefras. Piperine which is a compound found in pepper, is indeed related to those saffroles but that is all.

You can't magically expect to depart from an unactive compound and modify it until you end up with something active. The chances of that happening are mindbogglingly small. Therefore it is an unrealistic approach.

Do you understand?


----------



## ShaggyFin

Solipsis said:


> No. Pihkal compounds started out from mescaline which was found in nature (in cactus species) and Tihkal started out from psilocin which was also found in nature in mushrooms. Both are already psychoactive so modifying them to see if you come up with compounds that are still psychoactive but in a different way is logical and it has a reasonable chance of succeeding.
> 
> We don't really use pepper to make ecstasy. MDMA is made from saffrol compounds found in sassefras. Piperine which is a compound found in pepper, is indeed related to those saffroles but that is all.
> 
> You can't magically expect to depart from an unactive compound and modify it until you end up with something active. The chances of that happening are mindbogglingly small. Therefore it is an unrealistic approach.
> 
> Do you understand?



Ok, you are right about the Tryptamines, and Mescaline. I hadn't thought about the fact that he started with a known. I agree that we can not assume that what is made will do anything at all, I never said that something would for sure come out. And that it would be like Ecstasy or Mescaline.

But... What I did say is that this would be a new class of drug. And I have a feeling that I can NOT shake that tells me that there is something here.

And I feel like if we started adding Phenethylamine and Tryptamine structures to these 2 things, all bets would be off. Myrcene alone crosses the Blood brain barrier like a MOTHER FUCKER.

What do you think about a discussion that includes things that are KNOWN to be active. Now this thread can make everyone happy.

DXM
http://en.wikipedia.org/wiki/DXM


Morphine
http://en.wikipedia.org/wiki/Morphine


LSA
http://en.wikipedia.org/wiki/Lysergic_acid_amide


Erythravine
http://en.wikipedia.org/wiki/Erythravine


Tryptophan
http://en.wikipedia.org/wiki/Tryptophane


Tropane
https://en.wikipedia.org/wiki/Tropane


Scopolamine
http://en.wikipedia.org/wiki/Scopolamine


Coumarin
http://en.wikipedia.org/wiki/Coumarin


Lactucopicrin
http://en.wikipedia.org/wiki/Lactucopicrin


Lactucin
http://en.wikipedia.org/wiki/Lactucin


Phenethylamine
http://en.wikipedia.org/wiki/Phenethylamine


Isopropyl Alcohol
http://en.wikipedia.org/wiki/Isopropyl_alcohol


Isopropyl Nitrate
http://en.wikipedia.org/wiki/Isopropyl_nitrate


Benzaldehyde
http://en.wikipedia.org/wiki/Benzaldehyde


Cinnamaldehyde
http://en.wikipedia.org/wiki/Cinnamaldehyde


Furfural
http://en.wikipedia.org/wiki/Furfural


1,4-Benzoquinone
http://en.wikipedia.org/wiki/1,4-Benzoquinone


Allyl Hexanoate
http://en.wikipedia.org/wiki/Allyl_hexanoate


Benzyl Acetate
http://en.wikipedia.org/wiki/Benzyl_acetate


Butyl Acetate
http://en.wikipedia.org/wiki/Butyl_acetate


Ehtyl Buyrate
http://en.wikipedia.org/wiki/Ethyl_butyrate


Ethyl Formate
http://en.wikipedia.org/wiki/Ethyl_formate


Isobutyl Acetate
http://en.wikipedia.org/wiki/Isobutyl_acetate


Ethyl Heptanoate
http://en.wikipedia.org/wiki/Ethyl_heptanoate


----------



## Solipsis

Not much knowledge is required to pull off extractions, well done tho and no offense, but it is basically similar to making tea. I've done plenty of extractions myself.

Why would weaker versions of existing psychoactives be what society needs? There are mild psychedelics like 2C-D already if you want people to have more acceptable and controllable experiences. Besides I am not against semi-weak compounds, I am against compounds that would be so weak that the dosages would become unresponsibly high.

Have fun dreaming about weak lysergic amides, but there are plenty or well at least a number of them already I think. But there are also reasons why they are not desirable most of all being that they are not as selective in action and may tend to produce a host of very unwelcome or dangerous side effects like lethal vasoconstriction. That is why you only see a few LSD analogues yet. It has to actually be worth it.
And please stop saying bk-this and bk-that, did I not explain how that doesn't make sense?

There are already too many people producing random RC drugs that may be bad for public health and HR, so no I don't have a lot of patience for opening up people's minds to all kinds of random ideas. I like to stick to what seem like trustworthy plans.

If I am being more super general: I think you dream a lot and your imagination runs wild with all the possibilities, but it is a formless sea at this point. I am not saying stop dreaming entirely, but balance it with a healthy dose of skepsis and apprehension. If you are going to dabble in science, don't be careless because if you DO happen to influence the world and other people's lives there may be dire consequences. So take it more seriously. Talking about slapping chemical groups on stuff in a careless way is actually a slap in the face of some people.

Also, there have been numerous threads on beta-ketones already I'm quite sure. Be so good to search for them. Again, I assure you there will be plenty of people complaining about beta-ketone drugs very often being nasty sons a bitches.


----------



## sekio

> I am again not certain of the possibilities, but what about something like a weaker version of LSD (bk-LSD, bk-LSA) or a weaker version of Mescaline. Can you not see how this could lead to a more widespread acceptance of psychedelic use?



... a compound that's dosed at half a gram is not weak enough for you?


----------



## ShaggyFin

Solipsis said:


> Not much knowledge is required to pull off extractions, well done tho and no offense, but it is basically similar to making tea. I've done plenty of extractions myself.
> 
> Why would weaker versions of existing psychoactives be what society needs? There are mild psychedelics like 2C-D already if you want people to have more acceptable and controllable experiences. Besides I am not against semi-weak compounds, I am against compounds that would be so weak that the dosages would become unresponsibly high.
> 
> Have fun dreaming about weak lysergic amides, but there are plenty or well at least a number of them already I think. But there are also reasons why they are not desirable most of all being that they are not as selective in action and may tend to produce a host of very unwelcome or dangerous side effects like lethal vasoconstriction. That is why you only see a few LSD analogues yet. It has to actually be worth it.
> And please stop saying bk-this and bk-that, did I not explain how that doesn't make sense?
> 
> There are already too many people producing random RC drugs that may be bad for public health and HR, so no I don't have a lot of patience for opening up people's minds to all kinds of random ideas. I like to stick to what seem like trustworthy plans.
> 
> If I am being more super general: I think you dream a lot and your imagination runs wild with all the possibilities, but it is a formless sea at this point. I am not saying stop dreaming entirely, but balance it with a healthy dose of skepsis and apprehension. If you are going to dabble in science, don't be careless because if you DO happen to influence the world and other people's lives there may be dire consequences. So take it more seriously. Talking about slapping chemical groups on stuff in a careless way is actually a slap in the face of some people.
> 
> Also, there have been numerous threads on beta-ketones already I'm quite sure. Be so good to search for them. Again, I assure you there will be plenty of people complaining about beta-ketone drugs very often being nasty sons a bitches.



I didn't say extractions were especially educational, my point was that I have been doing them since I was 14. And with different things. So I have done a lot of reading about things like Acetone, and Naphtha and Chloroform.

Weaker forms can be better because some people don't want to trip for hours, or trip hard.

I did a search for beta ketone threads and included most of them in my post. I am not doing this willy nilly, I am simply opening up discussion. People do not realize that Acetone is not just a solvent, and people do not realize that chemistry like this will soon be part of every day life. I am simply bringing research together and saying "So what do you think we can do with this?" and if no one is on board, I will just do it myself when I have the time, money and have read a few more books.


----------



## ShaggyFin

sekio said:


> ... a compound that's dosed at half a gram is not weak enough for you?



"Does it last longer than 30 minutes? And will I still be able to function on it? I have to be to work in an hour, and I still have to get dressed"

The sentence we must worry about if we ever want this shit to be legal.


----------



## Solipsis

ShaggyFin said:


> I have read somewhere that you can add an "aromatic" beta ketone compound to tons of different terpenes and other alkaloids using acetone, and I was wondering if anyone had any more information on that.



Yes acetone can be a reagent. But quote what you read and elaborate.

Otherwise, good luck with that.


----------



## Bagseed

^ dosing psychedelics prior to responsibilities is not a wise thing to do and should be discouraged. why do you think there is a need for a psychedelic drug you can take before work?


----------



## ShaggyFin

Solipsis said:


> Yes acetone can be a reagent. But quote what you read and elaborate.
> 
> Otherwise, good luck with that.



I can't quote it, I have no idea where it is. I am looking right now for what I was talking about though. I was reading through like 1000+ terpenes to see which ones were active for humans, when I came across some stuff about turning terpenes into their Beta Ketone form using acetone. 

I'm looking for something to qualify it, hold on.


----------



## ShaggyFin

Bagseed said:


> ^ dosing psychedelics prior to responsibilities is not a wise thing to do and should be discouraged. why do you think there is a need for a psychedelic drug you can take before work?



Because if they ever legalize anything like this, it will be because it's not dangerous to the roads and kids.


----------



## ebola?

On average, bk-phenethylamines tend to be less potent and more adrenergic than their parent compounds.  There hasn't been much of a case to be made for any beta-ketone being superior to its parent compound (perhaps with the exception of mephedrone, but only because it lacks the gross neurotoxicity of 4-methyl-amphetamine).

ebola


----------



## ebola?

You present a variety of compounds with little mutual relation in terms of structure or activity  I'm not sure what constitutes this "new class" of compounds you think is emerging.  This conversation could be enriched if you were to elaborate on the rationale behind what you're doing.

ebola


----------



## sekio

"Myrcene analogs" have lovely scents (geraniol, nerol, linalool etc), but aren't drugs as far as I know. The only reason myrcene crosses the BBB is because it's essentially turpentine, it's super fat soluble... doesn't mean it has any strong activity.

Like others have said, most drug discovery in this day and age is directed, not purely serendipity-based. The "hit rate" for coming up with workable drugs for a particular need from random atom-smashing is pretty much nil. That's not to say it doesn't happen, but I think you need to clarify what exactly you're trying to say here. "I have a hunch that compounds derived from XYZ will be active some way" is not really how this works and isn't ground for running around shouting Eureka.


----------



## ShaggyFin

ebola? said:


> On average, bk-phenethylamines tend to be less potent and more adrenergic than their parent compounds.  There hasn't been much of a case to be made for any beta-ketone being superior to its parent compound (perhaps with the exception of mephedrone, but only because it lacks the gross neurotoxicity of 4-methyl-amphetamine).
> 
> ebola



I have a theory about beta ketones, I think there has to be a way to unlock them, so that they are active simply by smelling them. Like how cats get high on catnip (absorption, inhalation etc), but for humans.

Imagine if the store could sell you a gas dispensing mask that would make you trip while it was on, then stop when you took it off. Helium and/or Acetone could be the key. Like, a canister that has bk-xxxx in water and a tank of helium underneath. The helium is bubbled through the water creating a release of aromatic bk-xxxx with the helium. Maybe some kind of helium/oxygen mixture as long as that won't cause a reaction with whatever the xxxx is. There just needs to be a bk liquid so that it is ready to go airborne as particles.

Or even like a bk-xxxx hooka pen with no heat just air flow, where you put a puck in and it blows stuff out for you to breath in, maybe even just a vicks thing for your nose.


----------



## ShaggyFin

ebola? said:


> You present a variety of compounds with little mutual relation in terms of structure or activity  I'm not sure what constitutes this "new class" of compounds you think is emerging.  This conversation could be enriched if you were to elaborate on the rationale behind what you're doing.
> 
> ebola



Give me a little while, I apologize. I understand that everyone here is living a real life, and when they read something they expect it to be fully formed. Call this a "Hunch" because I won't call it an educated guess. I am under-educated and under-furnished, but I read a LOT and I have been thinking about and researching things around this since I was 14 (I am 22 now).

So sometimes I may be a little off about this stuff, but I am coming at it from a COMPLETELY different perspective than anyone that decided to traditionally educate themselves about this in any way. I have no organic chemistry degree, but I have been reading and trying to work out how what everything in Pihkal and Tihkal mean since I was 14, and I have a pretty good understanding at this point (compared to most people that I have met).

I am getting an Organic Chemistry 1 and a regular chemistry book, as well as reaction guides. So over the next few years I will use that knowledge and my past experience as a base.

Rose isolates (as well as a few other plant materials) and Myrcene will be the main compounds in the "New Class". Mainly Myrcene and Damascone will be the back bones of EVERYTHING.

I want to combine Myrcene with Damascone and see what happens. I assume this will create an *extremely* aromatic compound. Then based on what I have broken and added at that point, I will start adding and tearing more of the structure apart (using some of the things listed) and we will have a new family


----------



## ShaggyFin

sekio said:


> "Myrcene analogs" have lovely scents (geraniol, nerol, linalool etc), but aren't drugs as far as I know. The only reason myrcene crosses the BBB is because it's essentially turpentine, it's super fat soluble... doesn't mean it has any strong activity.
> 
> Like others have said, most drug discovery in this day and age is directed, not purely serendipity-based. The "hit rate" for coming up with workable drugs for a particular need from random atom-smashing is pretty much nil. That's not to say it doesn't happen, but I think you need to clarify what exactly you're trying to say here. "I have a hunch that compounds derived from XYZ will be active some way" is not really how this works and isn't ground for running around shouting Eureka.




Sure, Myrcene and it's little tweaks don't do much for anyone. But slap a DMT molecule on there, and things might change.

Also, I have been toying with the idea of "Drugs that are active through room temperature vapor inhalation" a "Sublime drug" or "a Smell that can get you high". Human pheromones may even come into play.

I just found/realized another key player in the family, I think.
http://en.wikipedia.org/wiki/Methanol


----------



## ebola?

> Mainly Myrcene and Damascone will be the back bones of EVERYTHING.



Okay.  So I can now see what said hunch is, but I don't see the logic that could underlie it.





> I want to combine Myrcene with Damascone and see what happens. I assume this will create an extremely aromatic compound.



I know this is not what you meant, but please remember that in chemistry, aromaticity means something other than its common meaning, something very specific.  Aromaticity is the presence of delocalization of electrons in a functional group, among different nuclei.  You commonly see this with hydrocarbon rings with alternating double and single bonds, and they cause the functional group to be more planar.

ebola


----------



## ebola?

> I have a theory about beta ketones, I think there has to be a way to unlock them, so that they are active simply by smelling them.



I see no basis for this being plausible, and I think that any according personal experience you've had can be explained by classical conditioning.

ebola


----------



## ShaggyFin

ebola? said:


> Okay.  So I can now see what said hunch is, but I don't see the logic that could underlie it.
> 
> 
> 
> 
> 
> I know this is not what you meant, but please remember that in chemistry, aromaticity means something other than its common meaning, something very specific.  Aromaticity is the presence of delocalization of electrons in a functional group, among different nuclei.  You commonly see this with hydrocarbon rings with alternating double and single bonds, and they cause the functional group to be more planar.
> 
> ebola



There is no logic, other than the fact that Damascone is basically a form of acetone, and Myrcene is extremely good at crossing the blood brain barrier. Other than that, they both have smells. That's it.

I apologize, when I said aromatic I just mean I want it to have some sublime qualities.

http://en.wikipedia.org/wiki/Chloroform



Chloroform + (b or a not sure)-Damascone + Lye = Stable compound if I am not mistaken. With plenty of room for attachment.

If it works and has not been done before, I call it "Chloroscone"

Also just found this: 4-Acetoxy-b-Damascone


And according to a perfume ingredients supplier, these exist.
3-hydroxy-.BETA.-damascone, 3-hydroxydihydro-.BETA.-damascone

And perfume rules (no idea who makes those rules) say that Damascones can make up no more than .1% of the perfume. So making these Myrcene compounds could actually be a loophole for fragrance makers. And this family might be considered designer perfumes and not designer drugs, LOL. This could revolutionize the perfume industry.

Once I do a little more reading, I am going to put something together here with Damascone too:

http://en.wikipedia.org/wiki/5-Hydroxytryptophan


http://en.wikipedia.org/wiki/L-DOPA


http://en.wikipedia.org/wiki/Tetrahydrocannabinol


http://en.wikipedia.org/wiki/Phenethylamine


http://en.wikipedia.org/wiki/Anandamide


http://en.wikipedia.org/wiki/Tryptophane


http://en.wikipedia.org/wiki/Lysergic_acid_amide


http://en.wikipedia.org/wiki/Isopropyl_alcohol


http://en.wikipedia.org/wiki/Benzaldehyde


http://en.wikipedia.org/wiki/Cinnamaldehyde


http://en.wikipedia.org/wiki/Isobutyl_acetate


----------



## ShaggyFin

ebola? said:


> I see no basis for this being plausible, and I think that any according personal experience you've had can be explained by classical conditioning.
> 
> ebola



I am not saying that I have experienced this. I have never tried it. They have yet to be "Unlocked", I think that MeOH and things like Myrcene could be the key to unlocking it though.


----------



## sekio

> I have a theory about beta ketones, I think there has to be a way to unlock them, so that they are active simply by smelling them. Like how cats get high on catnip (absorption, inhalation etc), but for humans.



The reason cats are effected by the volatiles in catnip is because they are analogues of odorants in cat urine that activate the vomeronasal organ, not because they are magical beta ketones.

In fact most of these "ketones" are absorbed into the body and circulation and even brain quite well, it's just that they have no effect at most of the receptors responsible for altering concsiousness. 

Acetone-aldol condensation products are usually fragrance compounds anyway. You can huff damascenone all you like but it won't get you stoned.

I'm going to close this since it seems to be going nowhere fast.


----------



## ShaggyFin

sekio said:


> The reason cats are effected by the volatiles in catnip is because they are analogues of odorants in cat urine that activate the vomeronasal organ, not because they are magical beta ketones.
> 
> In fact most of these "ketones" are absorbed into the body and circulation and even brain quite well, it's just that they have no effect at most of the receptors responsible for altering concsiousness.
> 
> Acetone-aldol condensation products are usually fragrance compounds anyway. You can huff damascenone all you like but it won't get you stoned.
> 
> I'm going to close this since it seems to be going nowhere fast.



Damascone + Chloroform + Lye = "Huff" that


----------



## sekio

I forgot to close this thread, silly me.

Dichlorocarbene addition products of damascenone would be gnarly, I'd rather not huff them.


----------



## SwampFox56

ShaggyFin said:


> Sure, Myrcene and it's little tweaks don't do much for anyone. But slap a DMT molecule on there, and things might change.



It's not anywhere near the simple unfortunately. 'Slapping' a DMT molecule onto another chemical wouldn't make that chemical a psychoactive drug perse. It all depends on many factors, not just what one part of a molecule has known activity. Also, think about this - what if you combined two drugs? What if you too DMT and 'slapped' it onto Morphine? What would happen then? Do you see the point I'm trying to make? 



ShaggyFin said:


> Also, I have been toying with the idea of "Drugs that are active through room temperature vapor inhalation" a "Sublime drug" or "a Smell that can get you high". Human pheromones may even come into play.
> 
> I just found/realized another key player in the family, I think.
> http://en.wikipedia.org/wiki/Methanol



Methanol is not a key player in human biology. Methanol is quite toxic and while it DOES have sedative effects - ingesting incredibly low amounts (I believe even as low as 20 mL) can be fatal. Do not ingest Methanol. It WILL kill you.


----------



## ShaggyFin

SwampFox56 said:


> It's not anywhere near the simple unfortunately. 'Slapping' a DMT molecule onto another chemical wouldn't make that chemical a psychoactive drug perse. It all depends on many factors, not just what one part of a molecule has known activity. Also, think about this - what if you combined two drugs? What if you too DMT and 'slapped' it onto Morphine? What would happen then? Do you see the point I'm trying to make?
> 
> Methanol is not a key player in human biology. Methanol is quite toxic and while it DOES have sedative effects - ingesting incredibly low amounts (I believe even as low as 20 mL) can be fatal. Do not ingest Methanol. It WILL kill you.



I have actually read of C30-NBOMe, which is just 2 drugs slapped together. And the rest of the NBOMe series too if I am not mistaken, it's just Mescaline on 2c-x's right? I'm not using that to qualify a morphine DMT combo, but that doesn't mean Myrcene and Damascone can't change the game.

And even if I don't make a drug, this WILL make a perfume. And that is just as valuable to the world.

I didn't mean methanol was a key player in Human biology, I just meant now I can make MeO forms of these things. I know about methanol as a thing on the planet, but I never new it was MeOH, I just never looked at what it was.


----------



## sekio

> There is no logic, other than the fact that Damascone is basically a form of acetone, and Myrcene is extremely good at crossing the blood brain barrier. Other than that, they both have smells. That's it.



There are lots of other chemicals that fulfill those criteria as well. Not sure why those stick out at you. 2-pentanone is a fat solubler acetone anlogue but I don't see anyone claiming it's a revolution in drugs/perfume.



> Chloroform + (b or a not sure)-Damascone + Lye = Stable compound if I am not mistaken. With plenty of room for attachment.
> 
> If it works and has not been done before, I call it "Chloroscone"



If you can't provide a structure and reaction pathway (better still look at the literature and find someone who has done this before), this is meaningless masturbation. More importantly, if this is just on paper or in your head or in a simulation of any sort, there is absolutely no guarantee it will actually happen in your flask in a lab unless you try it first and characterise the products.



> And perfume rules (no idea who makes those rules) say that Damascones can make up no more than .1% of the perfume.



... because it has such a low detection threshold, and anything above that would overpower everything else in the perfume. Same with some sulfide compounds and other strong odorants. These are rules of thumb, not some sort of legal restriction.



> I have actually read of C30-NBOMe, which is just 2 drugs slapped together. And the rest of the NBOMe series too if I am not mistaken, it's just Mescaline on 2c-x's right? I'm not using that to qualify a morphine DMT combo, but that doesn't mean Myrcene and Damascone can't change the game.



C30-NBOMe and the others are not "two drugs slapped together", they are modifications of phenethylamines which have a group that makes them bind better to the 5ht2a receptor. It's not "mescaline on a 2cx" because it's substituted with a benzyl group (1 carbon + phenyl ring) rather than a phenethylamine (2 carbons + phenyl ring, like mescaline).

At the same time, there is nothing that points to damascenone or myrcene being promising leads for drug development. Drugs like the NBOMe series and the synthetic cannabinoids were derived from a compound that had weak activity of the type that scientists were looking for, and many derivatives were characterised (N-benzyl, N-2-methoxybenzyl, N-3-methoxybenzyl etc) to find those that had the best activity. If you start with a compound that has no activity at your target then you're not really guaranteed anything. 

You should really get a solid foundation of organic chemistry before you go around thinking you can do whatever synthesis work you desire. There's really more art to this than mixing reagents A, B, C, and you make new compound D.

More importantly, we're not a perfume design conglomerate, we're a drug harm reduction board... I don't see how this relates. I can however tell you to give some of the pages at Leffingwell and Givaudan a look. The field of synthetic odorants is relatively well covered, especially in today's age of chiral gas chromatography and NMR... people have gas chromatographs that pipe the vapours to your nose, for instance, so you can smell pure isolated compounds. Very cool.


----------



## ShaggyFin

sekio said:


> C30-NBOMe and the others are not "two drugs slapped together", they are modifications of phenethylamines which have a group that makes them bind better to the 5ht2a receptor. It's not "mescaline on a 2cx" because it's substituted with a benzyl group (1 carbon + phenyl ring) rather than a phenethylamine (2 carbons + phenyl ring, like mescaline).



Ok. Well again, I apologize.

I am not saying to slap drugs together, or that we can.

But to me, it sure looks like I can put a few of these things together, and the same basic fragrant structure will remain. Like with the Chloroscone combo, that would be something like Chlorobutanol I am pretty sure. And from there you have plenty of room to attach things. And even if that doesn't lead to desired compounds, we could start another branch using Cinnamaldehyde (If I am not mistaken), which would open up a whole slew of opportunities to attach molecules and design fragrances.

If that doesn't work, something can probably be made with that 4-Acetoxy form, or with the Methanol.

There is an ENTIRE realm of possibility here. And, there is both a-Damascone and b-Damascone.

This could definitely be helpful
http://en.wikipedia.org/wiki/Allyl_hexanoate





'



sekio said:


> There are lots of other chemicals that fulfill those criteria as well. Not sure why those stick out at you. 2-pentanone is a fat solubler acetone anlogue but I don't see anyone claiming it's a revolution in drugs/perfume.



Myrcene sticks out because I use it to potentiate my Marijuana. Damascone stands out because it just kept coming up in my Beta Ketone searches.

I never claimed a "Revolution" in drugs, just a new family. And it's only a revolution in fragrance because we can make micro available forms of Damascone that can meet and be under the .1% criteria, and set new standards. As well as compounds that could effect the senses in ways never before seen in a perfume.


----------



## sekio

Now that this is established as wholly irrelevant to drugs, it's closing merging time.



> Myrcene sticks out because I use it to potentiate my Marijuana.



As someone who works with the stuff (to make terpenes ), I assure you this is 100% placebo. But, that's for another publication.



> But to me, it sure looks like I can put a few of these things together, and the same basic fragrant structure will remain. Like with the Chloroscone combo, that would be something like Chlorobutanol I am pretty sure. And from there you have plenty of room to attach things. And even if that doesn't lead to desired compounds, we could start another branch using Cinnamaldehyde (If I am not mistaken), which would open up a whole slew of opportunities to attach molecules and design fragrances.



The problem you'll quickly run into is: the bigger the molecule, the heavier and less volatile it is. Especially if it has any polar functionality or relatively heavy halogen atoms. Once you get to ~25 carbons then all bets are off regarding volatility, chances are it will only be slightly volatile at room temp. Even stuff like the freebase of 2CC-NBOMe is solid. So trying to get any sort of prodrug for a psychoactive to be volatile is a losing game. Bigger ain't always better with volatiles. 

Also, volatility does not correlate with odor any more it does with, say, UV absorbancy or any other characteristic of a chemical. There can be intensely scented steroid molecules which just have a really, really low detection threshold, or very volatile compounds that don't smell all that strong compared to others. (Most terpenes e.g. myrcene are like this when you compare them to the highly active odorants like damascenone).

Curiously, amphetamine used to be administered this way (as a freebase it exists as a volatile, stinky, cat-pee-and-fish odor liquid) adsorbed onto cotton, as Benzedrex. The Vicks inhalers do this too with laevomethamphetamine (whose freebase is also a liquid too).

On a fragrance sort of vibe here, check out this table of esters (pdf). Odor chemistry is wonderfully complex.


----------



## ShaggyFin

sekio said:


> Now that this is established as wholly irrelevant to drugs, it's closing merging time.
> 
> 
> 
> As someone who works with the stuff (to make terpenes ), I assure you this is 100% placebo. But, that's for another publication.
> 
> 
> 
> The problem you'll quickly run into is: the bigger the molecule, the heavier and less volatile it is. Especially if it has any polar functionality or relatively heavy halogen atoms. Once you get to ~25 carbons then all bets are off regarding volatility, chances are it will only be slightly volatile at room temp. Even stuff like the freebase of 2CC-NBOMe is solid. So trying to get any sort of prodrug for a psychoactive to be volatile is a losing game. Bigger ain't always better with volatiles.
> 
> Also, volatility does not correlate with odor any more it does with, say, UV absorbancy or any other characteristic of a chemical. There can be intensely scented steroid molecules which just have a really, really low detection threshold, or very volatile compounds that don't smell all that strong compared to others. (Most terpenes e.g. myrcene are like this when you compare them to the highly active odorants like damascenone).
> 
> Curiously, amphetamine used to be administered this way (as a freebase it exists as a volatile, stinky, cat-pee-and-fish odor liquid) adsorbed onto cotton, as Benzedrex. The Vicks inhalers do this too with laevomethamphetamine (whose freebase is also a liquid too).
> 
> On a fragrance sort of vibe here, check out this table of esters (pdf). Odor chemistry is wonderfully complex.



It seems that Phenethylamine would be available for attachment then, only 8 carbons. And Methanol or Chloroform, Isopropyls will too.

I'll keep that in mind. Thank you.

And on the Myrcene, I have tried it and it's not just a maybe, it's full blow higher for sure. If it's placebo, it's a DAMN good placebo.


----------



## sekio

If you haven't run any blind tests, you can't for sure say it's placebo.

The other issue you're likely to run into with phenethylamine derivatives (really most amines): they smell like a selection of shit, stale fish, decaying fish, fermented urine, rotting meat, ammonia, and the like - in general they are better off avoided as, er, 'body notes' of fragrances. The amine group tends to ruin things in the odor department.

Leffingwell for instance talks about the enantiomers of amphetamine being "musty" and "fecal" smelling. Wonderful.


----------



## ShaggyFin

sekio said:


> If you haven't run any blind tests, you can't for sure say it's placebo.



I have read about it outside of the plant I tried, and without extractions. They say Mangoes have Myrcene and do the same thing.

I eventually plan on doing tests, but as I said before, I am under-furnished to do such things.

And thank you for this
http://jameskennedymonash.files.wordpress.com/2013/12/table-of-esters-and-their-smells-v2.pdf


----------



## ShaggyFin

sekio said:


> Leffingwell for instance talks about the enantiomers of amphetamine being "musty" and "fecal" smelling. Wonderful.



I honestly do not care for Amphetamines, my hopes are to hopefully make one or two MeO PEAs that are something like Ecstasy or Dissociatives, and then take a step back and let others do that field of continuation.

I want to make something MUCH more subtle, maybe like some form of Tropane or a Cannabinoid, or even a Benzo if possible. Maybe some kind of soft trip, or sleeping aid, or Nootropic. Caffeine could have applications as well in the modern world.

And I want to maybe explore DXM, it seems like it wants someone to take a look at it.

I am VERY unlearned in organic chemistry, my "expertise" from the past (if you can call it that) is more on that "taking and comparing" side of drugs. I ordered some books so I will be able to draw other molecules soon. But unless we can Isomerize this stuff, or Decarboxalyze it, or whatever. All I know that is possible is to attach it to a Chloroform, because after Ana Nicole smith died I read about Chlorobutanol (the stuff that killed her from OD, it's a Barbiturate I believe) and making that is the same as making this.

Original Molecule: Dramascone

So, unless someone has made this molecule before, I invented the first Drug (probably active because of the Chloroform) from Rose essence. And I hope to create more soon that aren't based on attaching a Chloroform molecule.


I call it (unless someone out there already made this one, because it does seem to simple to have not been made)
*Chloroscone*
Damascone + Chloroform + Lye = Chloroscone
(I messed up a tiny bit on the drawing on one of the little bottom arm things, but it's mostly right)





And correct me if I am wrong, but does this not look like with a few rings completed (either side of the Cl's, plus a few tiny additions) it could be an opiate?


----------



## MrKhazar

Reading what ShaggyFin wrote put me in a bad mood. Here's a hint for ya: start with a pharmacophore!


----------



## Solipsis

^ me too, but I can't look away...

Chlorobutanol is not a barbiturate. Barbiturates are derivates of barbituric acid. Look them both up and consider how they do not look alike.
These are both blunt and dirty old school sedatives though. Barbiturates are a bit more sophisticated, they are one or two generations later than stuff like chloral hydrate.

I thought we already established that jamming chloroform onto a molecule (that isn't even psychoactive to begin with) does not magically lend it psychoactive properties just because it happens to be the case with chlorobutanol synthed from acetone. Chlorobutanol is psychoactive because it has a structure that allows it to be so (this is related to what is just said about a pharmacophore - I told you earlier: start from something you have reason - one you can explain, not a gut feeling FFS - to believe or know to be psychoactive. If not, it deserves to be ignored). Chloroform is not psychoactive because of something nucleophilic addition with chloroform does universally.
People have also already told you that joining a DMT or mescaline molecule onto another molecule is not a way to lend it psychoactivity, this is the same thing. You don't seem to be getting the hint for someone with that much ambition.

Also there can be several problems with nucleophilic addition of chloroform to damascone if I am not mistaken. The chloroformic anion might also bind with the left double bound cyclohexene carbon if a conjugate is formed trough the terpene pi system.
Put simply: there are side-reactions to consider when designing a synth reaction or strategy. The amount of oversimplification is staggering and indirectly an insult to chemists.

This compound is a far way from being an opiate and closing rings really isn't as easy as you would make it out to be.

It wouldn't be such a bitch to help you if you were being a bit more modest and realistic.


----------



## pharmakos

"if i weld a motorcycle to a sports car, i assume i'll have a new vehicle that will go twice as fast!"


----------



## sekio

> I am VERY unlearned in organic chemistry, my "expertise" from the past (if you can call it that) is more on that "taking and comparing" side of drugs.



That makes you about as qualified to design drugs as a dude that flies in lots of different airliners as a passenger is qualified to design stealth bombers.



> But unless we can Isomerize this stuff, or Decarboxalyze it, or whatever. All I know that is possible is to attach it to a Chloroform [...] So, unless someone has made this molecule before, I invented the first Drug (probably active because of the Chloroform) from Rose essence.



Excellenty job throwing words around without knowing what they mean. By the by, I don't think you've "made" anything yet, you've just posted on a forum a whole bunch. There is also no guarantee at all that the chloroform addition product of higher ketones would be either druglike or even nontoxic. And the fact remains, damascone is not the same thing as acetone... most organic chemists would tell you that damascones are "alpha, beta unsaturated ketones" whereas acetone is just a simple ketone, so they react differently. Like Solipsis said: There's no guarantee that chloroform would even add. You may end up with a bunch of tar, or the damascone falling apart on you...



> And correct me if I am wrong, but does this not look like with a few rings completed (either side of the Cl's, plus a few tiny additions) it could be an opiate?



Considering it is neither related to a compound that has opioid activity and doesn't fit the "Morphine Rule", I'm going to say no, you don't know what you're talking about.


----------



## ShaggyFin

Solipsis said:


> ^ me too, but I can't look away...
> 
> Chlorobutanol is not a barbiturate. Barbiturates are derivates of barbituric acid. Look them both up and consider how they do not look alike.
> These are both blunt and dirty old school sedatives though. Barbiturates are a bit more sophisticated, they are one or two generations later than stuff like chloral hydrate.
> 
> I thought we already established that jamming chloroform onto a molecule (that isn't even psychoactive to begin with) does not magically lend it psychoactive properties just because it happens to be the case with chlorobutanol synthed from acetone. Chlorobutanol is psychoactive because it has a structure that allows it to be so (this is related to what is just said about a pharmacophore - I told you earlier: start from something you have reason - one you can explain, not a gut feeling FFS - to believe or know to be psychoactive. If not, it deserves to be ignored). Chloroform is not psychoactive because of something nucleophilic addition with chloroform does universally.
> People have also already told you that joining a DMT or mescaline molecule onto another molecule is not a way to lend it psychoactivity, this is the same thing. You don't seem to be getting the hint for someone with that much ambition.
> 
> Also there can be several problems with nucleophilic addition of chloroform to damascone if I am not mistaken. The chloroformic anion might also bind with the left double bound cyclohexene carbon if a conjugate is formed trough the terpene pi system.
> Put simply: there are side-reactions to consider when designing a synth reaction or strategy. The amount of oversimplification is staggering and indirectly an insult to chemists.
> 
> This compound is a far way from being an opiate and closing rings really isn't as easy as you would make it out to be.
> 
> It wouldn't be such a bitch to help you if you were being a bit more modest and realistic.




I never said that there was a guraentee, and I was just guessing at Chlorobutanols family based on its effects and time period of public popularity.

Again, I said these compounds would be aromatic and that most of them would be inactive.

If you are insulted, it's your own problem.



sekio said:


> Excellenty job throwing words around without knowing what they mean.



I know what removing carbon and changing magnetic structure are, ass. And I can tell you how to utilize them with different molecules (THC, Tryptophan and Morphine)



sekio said:


> That makes you about as qualified to design drugs as a dude that flies in lots of different airliners as a passenger is qualified to design stealth bombers.


Well, get ready for some stealth bombers, because I will be a designer soon.


----------



## pharmakos

no one is trying to get offensive on either side, shaggy... but you really are trying to jump into the deep end of the pool before you've even learned to swim.

i admire your passion and zeal, though

trying to think of another good analogy....  its like you're trying to build the roof on a house before you've even laid the foundation.

small steps, broseph.... you're not going to stumble on the next big chemical discovery before you even understand what "beta position" means, and that it means different things on different molecules.


----------



## ShaggyFin

thenightwatch said:


> no one is trying to get offensive on either side, shaggy... but you really are trying to jump into the deep end of the pool before you've even learned to swim.
> 
> i admire your passion and zeal, though
> 
> trying to think of another good analogy....  its like you're trying to build the roof on a house before you've even laid the foundation.
> 
> small steps, broseph.... you're not going to stumble on the next big chemical discovery before you even understand what "beta position" means, and that it means different things on different molecules.



Again, I do not care if I make anything that gets anyone high. This is HOW I learn.
I am a very hands on learner.

And if I make some new fragrances, I will be happy. And other people that are smarter than me can take it from there when they read about it in 10 years.


----------



## pharmakos

ShaggyFin said:


> Again, I do not care if I make anything that gets anyone high.



you must have changed your mind then, because you very much were talking about psychoactive effects in the last couple pages.

you've got good drive and zest, man, i just worry that you're wasting your efforts by spreading yourself too thin.

are you in school?  if not, i think you should be.  you've definitely got the motivation for it.


----------



## ShaggyFin

thenightwatch said:


> you must have changed your mind then, because you very much were talking about psychoactive effects in the last couple pages.
> 
> you've got good drive and zest, man, i just worry that you're wasting your efforts by spreading yourself too thin.
> 
> are you in school?  if not, i think you should be.  you've definitely got the motivation for it.



That is because I plan on attaching L-DOPA and 5-HTP, etc molecules to it, and I assume that at that point we will start seeing some new effects. Maybe not, but I would say probably.

No money for school, but I read a lot of textbooks. Usually not chemistry, Pihkal and Tihkal have been my chemistry textbooks until now.


----------



## pharmakos

its not so hard finding money to go to school, depending on where you live.  if there's a local community college near you, you should make an appointment to talk to the financial aid office.  they'll be more than willing to help you figure out what your options for funding are.


----------



## ShaggyFin

thenightwatch said:


> its not so hard finding money to go to school, depending on where you live.  if there's a local community college near you, you should make an appointment to talk to the financial aid office.  they'll be more than willing to help you figure out what your options for funding are.



I do not want to go to community college, I learn plenty, I'd rather sit and read textbooks. I would rather go to like Yale or Harvard when I'm like 30-35.


----------



## pharmakos

don't put the cart before the horse

the longest journey starts with a single step

you may think you're learning plenty, but without proper direction you will end up spreading yourself too thin

earlier in this thread you got upset when people told you the things you were saying were incorrect, and your response was "i don't have an organic chemistry schooling background like you guys"

well, thats something you can fix.

if money is an issue, it makes a lot more sense to start out at a community college, get your 2-year associates degree, then transfer to a larger school (perhaps Yale or Harvard like you said).  if you get good grades on your associates then it becomes a LOT easier to find the funding for a more expensive school.


----------



## ShaggyFin

thenightwatch said:


> earlier in this thread you got upset when people told you the things you were saying were incorrect, and your response was "i don't have an organic chemistry schooling background like you guys"



I never got mad, and I never compared my education to anyone here, so I think you are mistaken. I apologized for my lack of knowledge, but that is all.



> you may think you're learning plenty, but without proper direction you will end up spreading yourself too thin



When I say I "am learning plenty" I mean I would rather come back here in a week with some organic chemistry textbooks and just start drawing molecules and discussing them with you guys. That would be MUCH more stimulating than sitting in a classroom learning from a failed DOW chemist or wanna-be Meth chef.

BTW, I am not just talking out of my ass. I plan on making designer smells, and I will need chemists to advise me and invent their own things.



> well, thats something you can fix.
> 
> if money is an issue, it makes a lot more sense to start out at a community college, get your 2-year associates degree, then transfer to a larger school (perhaps Yale or Harvard like you said). if you get good grades on your associates then it becomes a LOT easier to find the funding for a more expensive school.



I am already fixing that, and it won't take me 2 years (the learning part, money still may take some time)


----------



## pharmakos

ShaggyFin said:


> I never got mad



you may claim to have not gotten mad, but you accused others of feeling insulted when no one was insulted.... which is typically a sign of being mad oneself



ShaggyFin said:


> If you are insulted, it's your own problem.



you even resorted to tossing out insults yourself:



			
				ShaggyFin said:
			
		

> I know what removing carbon and changing magnetic structure are, *ass*.



----------------------------------



			
				ShaggyFin said:
			
		

> and I never compared my education to anyone here



you certainly did that as well, here:



ShaggyFin said:


> So sometimes I may be a little off about this stuff, but I am coming at it from a COMPLETELY different perspective than anyone that decided to traditionally educate themselves about this in any way. I have no organic chemistry degree



-------------------------------



			
				ShaggyFin said:
			
		

> That would be MUCH more stimulating than sitting in a classroom learning from a failed DOW chemist or wanna-be Meth chef.



^ more insults, not directed at anyone on this board this time, at least =/

------------------------------------------------



			
				ShaggyFin said:
			
		

> I am already fixing that, and it won't take me 2 years.



your plan is to teach yourself with used Organic Chemistry textbooks and Wikipedia, and then somehow convince Yale or Harvard to accept you despite having no prior degrees to present to them?  i suppose its possible if you manage to get some groundbreaking papers published, but i hate to tell you -- its a long shot.


----------



## ShaggyFin

thenightwatch said:


> you may claim to have not gotten mad, but you accused others of feeling insulted when no one was insulted.... which is typically a sign of being mad oneself



I did not "accuse", he told me that when I talk about this stuff, it is "insulting to real chemists". I was just reiterating his statement.

I did not think of that as comparing myself educationally, I said my perspective was different because of my differing background, but I did not mean it as a direct comparison. Just a statement to help people understand where I am coming from.

You can't just pretend you are counting insults that don't exist, then include a real one that was directed at bad teachers, not anyone here. And act like it justifies your fake counted insults.



thenightwatch said:


> your plan is to teach yourself with used Organic Chemistry textbooks and Wikipedia, and then somehow convince Yale or Harvard to accept you despite having no prior degrees to present to them?  i suppose its possible if you manage to get some groundbreaking papers published, but i hate to tell you -- its a long shot.



Again I am not a chemist, so this is not my life's work. I just stumbled in to this. I've got plenty of things that I am working on that colleges will be looking at.

Example, here is one of MANY things I am working on currently. I want categorize EVERYTHING in a way that is more compatible to recreational use. Still making the list, so categorizing has not even started yet. And I also plan on using this possibly in the fragrance building.



> I have recently made the decision to not allegedly take any more grey area RCs as long as I am in the US anymore, and since I will never again be in the possession of anything that could be considered an analogue of anything, I decided I will start an “Alkaloids 101” type thing where I teach other people that might hurt themselves if they don't know better. And maybe help someone sitting in a hospital room with a dieing relative.
> It will start as like 1-10 minute videos where I talk about each individual chemical, plant or animal. So far I have 1000+ individual chemicals, plants and animals listed. Then, once those videos have all been made, I will make a giant smashed together film with all 1000+ in 1 long video. So it will be something like 10+ hours long.
> From there I will at some point begin showing extractions on individual plants, and testing different methods to see which plants extract best with which methods. Then I will start making novel chems and eventually add those processes on to the video as well.
> So, we are basically going to have a video version of Pihkal and Tihkal (PLUS a video Pharmaceutical Encyclopedia) soon enough.
> This list is not an endorsement, it is simply a list of Bio-Active Alkaloids. Let's cure cancer, let's cure AIDS (some of these are KNOWN to treat Cancer, AIDS, brain swelling, Head Trauma, Alzheimer's Disease, Broken Relationships/Marriages, Depression, Boring Sex lives, Addiction, ADD/ADHD, Sleep Disorders, Alcoholism (even some things on the list that can clear up drunkenness, cocaine/meth highs, and even trips) and other things, but not all doctors know about them, or care to acknowledge them), let's find the chemical that lets us transition into the next big metal alloy or microchip. If you need a molecule that doesn't exist, check this list before you give up. Research these things, some are poisons, some are said to bring on Godly experiences, some are just good for you. People can DIE from things on this list, so again, this list is not an endorsement, but people can also be SAVED by things on this list. And the future can be built on this list, because I believe that the personal identity of a human being is heavily dependent on the nitrogen bonds they put in their body occasionally (THC, Opiates, Nootropics, Hallucinogens etc.) and nitrogen bonds they put in their body every day (Nicotine, Caffeine, Opiates, etc)
> 
> (Two Great Online Resources: Erowid Vaults, Bluelight Big and Dandy and of course Wikipedia has tons of info. Some of these will not be listed some places though) L-Tyrosine, L-DOPA, Apomorphine, CPZ, BPAP, PPAP, Cabergoline, DAR-0100, Lisuride, Pergolide, Pramipexole, Rotigotine, Biopterin, PLP, Aminepetine, MAO-B Inhibitor, Isoflavones, Citicoline, Arecoline, Paraxanthine, a-GPC, Acetylcarnitine, Cluracetam, AR-R17779, GTS-21, Ispronidine, PHA-543,613, SSR-180,711, WAY-317,538, Hopantenic Acid, IDRA-21, Propentofylline, PRL-8-53, Trytophan, Picamilon, Betahistine, A-349,821, Cipoxifan, Creatine, Mildronate, Pregnenolone, Nisoxetine, Orexin, CP-39,332, Esreboxetine, Daledalin, AM-1248, Phenoxybenzamine, Symbescaline, Phentolamine, Isomescaline, Tolazoline, a-Methylfentanyl, Paraflourofentanyl, 3-Methylfentanyl, Metofoline, Buscaline, O-DT, Nortilidine, Thiobuscaline, Dizocilpine, Rolicyclidine, Phenescaline, Tenocyclidine, Methoxyketamine, pFPP, 5-me-MDA, 4-MAR, 1,4-Butanediol, 2-Methyl-2-Butynol, GHV, GVL, Mebroqualone, Benzylbutylbarbituates, Phenylacetylindoles, Benzoylindoles, Napthoylindoles, Adamantoyindoles, Pineapple Sage, Kokum, Brahmi, Artic Weed, Skullcap, Salvia Splendens, Coriander, Rhodiola Rosea, Velvet Bean, Bitter Orange, St. john's Worth, Grape Seed Extract, Tulsi, Blessed Thistle, 3-Desoxy-MDA, Skatole, Isoindole, Indole, Benztropine, Diphenhydramine, Niaprazin, Doxylamine, Alaproclate, Zopiclone, Ifoxetine, Methylmethaqualone, Panuramine, Meta-Tyramine, Para-Tyramine, 2M2B, Pirandamine, SB-649,915, Epinephrine, Mepyramine, Octopamin, Delucemine, Oxidopamine, β-Methylphenethylamine, Mesembrine, Psuedoephedrine, Etolorex, Cathine, Cathinone, Ethcathinone, Norfenfluramine, Fenfluramine, Phentermine, Metaescaline, n-Ethylbuphedrone, Naphyrone, Pyrovalerone, Isopropylamphertamine, Clobenzorex, Pholedrine, Chlorphentermine, Xylopropamine, DON, DOPR, TMA, Methyl-BOB, Tetramethoxyamphetamine, 4-MTA, Bromatane, Hydroxyzine, BNC-210, CL-218,872, L-838,417, SL-651,498, S32212, 6-CAT, TAP, ETAI, IMP, Lorxaserin, Cisapride, Tegaserod, AS-19, E-55888, LP-12, LP-44, LP-211, Etoperidone, Lorpiprazole, Lubazodone, Mepiperazole, 5-TASB, TB, 3-TE, 4-TE, 2-TIM, 3-TIM, 4-TIM, 3-TM, 4-TM, TMA, TMA-2, TMA-3, TMA-4, TMA-5, TMA-6, 3-TME, 4-TME, 5-TME, 2T-MMDA-3a, 4T-MMDA-2, TMPEA, 2-TOET, 5-TOET, 2-TOM, 5-TOM, TOMSO, TP, TRIS, 3-TSB, 4-TSB, 3-T-TRIS, 4-T-TRIS, 44-BMAR, 3-MOMC, Prolintane, SDB-001, AB-FUBINACA, Dichloromethylphenidate, AB-PINACA, MN-24, 5F-MN25, A-836,339, ADBICA, 5F-NNEI, RCS-4, RCS-8, MPHP, 6-APDB, 4-HMP, EDMA, a-PBP, Methylhexamine, a-PPP, 4-FMD, EIDA, Phenylphrine, UWA-101, MPBP, RH-34, F-2, F-22, MR-2096, Adrenochrome, AET, Carbogen, DOB, DOM, Desmorphine, Ethylcathinone, Ehylene, GHV, Hypocretin, mCPP, MDPR, Methaqualone, TFMPP, CPP, MeoPP, A2, Salvinorin A, Scoplamine, TMA-2, BDO, 2c-B-FLY, 4-Flouromethcathinone, 4-HO-MPT, U4EA, 4-MTA, Phenylpiracetam, Melatonin, NRG-3, Theobromine, A834-735, Oxytocin, NZT-48, Heroine, 3-HO-PCP, MAOIs, 4-MeO-PCP, 3c-P, 5-IAI, Atropine, 5-IT, Bufotenin, 5-MAPB, 4-Aco-MiPT, 6-MAPB, ALD-52, AMMI, MET, D2PM, DET, CBD, CBN, LY-2183240, SF-SDB-005, AM-404, EG-018, DXM, FDU-PB22, AL-LAD, 3-MeOMC, 2-MeO-Diphenidine, 4-MPD, bk-MDMA, 4-MeO-a-PVP, GHB, 4-MeO-PBP, MBDB, 4-MeO-PV9, Fentanyl, 4F-PV8, Aniracetam, a-PBT, BDB, a-PVT, 2-FMA, Dibutylone, 5-Meo-DiPT, Diclofensine, Methcathinone, DL-4662, MDEA, MDPPP, Methylone, Butylone, NEB, Phenibut, PV-8, GABA, 25B-NBF, Etaqualone, 5-API, Ethylone, Pentadrone, 4F-PVP, 25C-NBF, BZ-6378, C30-NBOMe, RH-34, MDAT, MDMAI, Dimethocaine, Synthacaine, 3β-FBT, 5-MeO-BFE, 3,4-DMMC, AM-1248, MTTA, AM-2233, URB-597, AM-694, AM-087, BAY-38-7271, AB-005, A-796260, URB-754, 2-DPMP, a-PVP, 25N-NBOMe, 5-MeO-NiPT, Dexmethylphenidate, Buphedrone, RTI-111, Pentylone, 25I-NBF, Flourotropacocaine, Flourococaine, Cocaethylene, 25D-NBOMe, 25E-NBOMe, DMT, 5-Meo-DMT, 2c-I, 2c-E, 25I-NBOMe, 25I-NBOH, 25C-NBOMe, MXE, LSD, MDA, MDE, Mescaline, Ibogaine, Bromo-DragonFLY, Salvinorum, RU-28306, 2NE1, Psilocybin, HOT-7, JWH-018, JWH-250, 5-Meo-EiPT, AM-2201, 5-APDI, BZP, BZ, 4-MEC, MDPV, Bakers Ammonia, THC, THCv, Chloral, Chlorabutynol, MT-45, 5-Methyl-Ethylone, Methylphenidate, 6-APB, 5-APB, Muscimol, 5-MeO-MALT, AKB48, 3,4-CTMP, PB-22, Diphenidine, UR-144, Flubromazepam, HU-210, MPA, XLR-11, MN-18, Naltrexone, STS-135, Gabapentin, 5-MAPB, Nitrous, Etizolam, Mephedrone, Pyrazolam, Methedrone, AH-7921, Phenazepam, AMT, OxyNEO, DPT, 5-MeO-AET, 4-Aco-DMT, EAM-2201, 5-MeO-DALT, 5-MeO-AMT, Acefentanyl, Ehylphenidate, 4-HO-MiPT, THJ-2201, 5-APDB, 5-EAPB, 4-HO-DPT, DOC, bk-2c-B, Escaline, THJ-018, 4-HO-MET, 2-AI, 2-MeO-Ketamine, Methoxphenidine, Ketamine, 2c-EF, Methamphetamine, Dextro-Amphetamine, Cocaine, Nitracaine, DALT, IAP, 4-fa, 2-Me-DMT, 4-fcocaine, Isopropyl Nitrate, 5-MeO-TMT, Piracetam, Amatadine, Choline, Memantine, 5-HTP, Camfetamine, Methallyescaline, LSZ, LSA, NBOMe-Mescaline, Loperamide, LSB, 25P-NBOMe, 25G-NBOMe, 3-MeO-PCE, MAM-2201, PCP, MPTP, MDAI. 2c-T-2, DOI, BB-22, EA-3167, BDF, L-Theanine, Dimethylone, Hydrocodone, Codeine, Morphine, Dilaudid, Oxycontin, Xanax, Valium, Fentanyl, Soma, Suboxone, Adderall, Barbituates, Marinol, Seroquell, Trazodone, Lithium Bicarbonate, Abilify, Methadone, Amitriptyline, Strattera, Chloral Hydrate, Bromazepam, Buperonorphrine, Bupropion, Chlordiazepoxide, Clonidine,Clonazepam, Cyclobenzaprine, Dramamine, Benadryl, Ethchlorvynol, Fluoxetine, Flurazepam, Metaxalone, Mirtazapine, Nalaxone, Nimetazepam, Oxymorphone, Paroxetine, Zopidone, Pregabalin, Promethazine, Risperadone, Selegiline, Sertraline, Sumatripan, Tiagabine, Propofol, Propanolol, Tiletamine, Zolpidem, Lotus, Aloe, Datura, Calendula, Chacruna, Galangal, Chaliponga, Chamomile, Damiana, Fever Few, Nightshade, Ginseng, Foxglove, Lavender, Henbane, Mugwort, Hemlock, Monkshood, Dream Herb, Capsaicin, Amanita, Hawaiian Baby Woodrose, Ergot, Hops, Imphepho, Indian Warrior, Kanna, Dagga, Kratom, Mandrake, Valerian, Nicotiana Tobacum, Nicotiana Rustica, Mimosa Hostilis, Morning Glory, Nutmeg, Opium Lettuce, Poppy, Sinicuichi, Syrian Rue, Tree Tobacco, Wormwood, Yohimbe, Yopo, Khat, Peyote, Cannabis, Catnip, Phalaris, San Pedro, Soma (ancient), Chacruna, Acacia, Ephedra, Mulungu, Mullet Fish, Siganus Spinus, Fugu, Sting-ray Venom, Bufo Alvarius, Epipedobates Tricolor, Waxy Monkey Frog, Salamandra Salamandra, Cobra & Scorpion Venom, Reindeer Urine, Glomeris Marginata, Sergeant Major, Grouper, Bluefish, Brass Beam, Flathead Mullet, Golden Goatfish, Rabbit Fish, Goat Fish, Adrafinil, DHEA, Aniracetam, Dilantin, DMAE, Fipexide, Gerovital, Ginko, HGH, Hydeigine, Meclofenoxate, Modafinil, Oxiracetam, Phenyton, Pramiracetam, Vasopressin, Vinopocetine, Bee Venom, Monkey Frog, UCM-707, AM-1172, VDM-11, VDM-13, OMDM1, OMDM2, LY-2318912, O-2093, OL-135, URB-597, URB-532, AEM, AL, ALEPH, ALEPH-2, ALEPH-4, ALEPH-6, ALEPH-7, ARIANDE, ASB, B, BEATRICE, BIS-TOM, BOB, BOH, BOHD, BOM, 4-Br-3,5-DMA, 2-Br-4,5-MDA, 2C-B, 3C-BZ, 2C-C, 2C-D, 3C-E, 2C-F, 2C-G, 2C-G-3, 2C-G-4, 2C-G-5, 2C-G-N, 2C-H, 2C-N, 2C-O-4, 2C-P, CPM, 2C-SE, 2C-T, 2C-T-4, 2C-T-2, 2C-T-7, Ψ-2C-T-4, 2C-T-8, 2C-T-9, 2C-T-13, 2C-T-15, 2C-T-17, 2C-T-21, 4-D, β-D, DESOXY, 2,4-DMA, 2,5-DMA, 3,4-DMA, DMCPA, DMMDA, DMMDA-2, DMPEA, DOAM, DOBU, DOEF, DOET, Ψ-DOM, DON, DOPR, E, EEE, EEM, EME, EMM, ETHYL-J, ETHYL-K, FLEA, G-3, G-4, G-5, GANESHA, G-N, HOT-2, HOT-17, IDNNA, IM, IP, IRIS, J, LOPHOPHINE, M, 4-MA, MADAM-6, MAL, MDAL, MDBU, MDBZ, MDCPM, MDDM, MDHOET, MDIP, MDMC, MDMEO, MDMEOET, MDMP, MDOH, MDPEA, MDPH, MDPL, MDPR, ME, MEDA, MEE, MEM, MEPEA, META-DOB, META-DOT, METHYL-DMA, METHYL-DOB, METHYL-J, METHYL-K, METHYL-MA, METHYL-MMDA-2, MMDA, MMDA-2, MMDA-3a, MMDA-3b, MP, MME, MPM, ORTHO-DOT, P, PE, PEA, PROPYNYL, SB, TA, 3-TASB, 4-TASB, Tropane, Vomeronasal Organ, Tropine, Hyosyamin, Dihydrokavain, Hyoscine, Myrcene, Ecgonine, 7-OH-DPAT, Benzoylecgonine, Sunifiram, Hydroxytropacocaine, Estrogen, Methylegonine Cinnamate, Estradiol, Catuabines, Estratetraenol, Phenyltropane, Androstenone, Civetone, Adrostenol, 5F-PB-22, Androstadienone, CBG, THCa, CBC, CBDa, Anandamide, 2-AG, CBL, CBDv, CBCv, CBGv, CBGm, Ibogaine, Noribogaine, Tabernanthine, Coronaridine, Ibogamine, Vaocangine, 18-MC, 5-MeO-Alkyltryptamine, β-Carboline, Tryptoline, Pinoline, Harmane, Harmaline, Harmine, Harmalol, Harmalan, Harmanamide, Acetylnorhormine, Bufotenin Oxide, DMT-N-Oxide, 5-MeO-Tryptamine, 5-OH-DMT, 5-MeO-DMT-Oxide, 3,4-Dimethoxyphenylamine, 6-MeO-Harman, Anethole, Safrole, Estragole, Monolignol, Pukateine, Glaucine, THP, Nantenine, Thujone, Lagochilin, Nicotine, Carbachol, Methacholine, ME-18-MC, 18-MAC, Tryptamine, β-Methyl-Phenethylamine, NMT, Voacanga Africana, Vachellia Farnesiana, Duboisia Hopwood, Acacia Victoriae, Anadenanthera Penegrina, Phalaris Aquatica, Echinopsis Lageniformus, Cylindropuntia Echinocarpa, Leptactina Densiflora, Fennel, Justica Pectoralis, Lactucarium, Glacium Flavum, Zornia Latifolia, Argemone Mexicana, Silene Undulata, Catharanthus Roseus, Desfontainia, Heimia Salicifolia, Lophophora, Sea Urchin Eggs, Bethanechol, Muscarine, Pilocarpine, Oxotremorine, Aporphine, Leonurine, Bungacotoxin, Tetrodotoxin, Taurine, Opiod Peptide, Streamlined Spinefoot, Blue-Spotted Spinefoot, Dusky Spinefoot, Marbled Spinefoot, Little Spinefoot, Salema, Phyllomedusa, Blue Sea Chub, Brow Chub, Conuict Surgeonfish, Yellowstipe Goatfish, Finstripe Goatfish, Acute Jawed Mullet, Coral Grouper, Platypus Venom, Slow Ioris Venom, Pygmy Slow Ioris Venom, Giant Leaf Frog, Gluten Exorphin, Soymorphin-5, Dermophin, 7-PET, Dimethyliambutene, Proopiomelanocortin, β-Endorphine, Dynorphin, Adrenorphin, Salvinorin B Methoxymethyl ether, Amindophin, Enkephalins, Salvinorin B ethoxymethyl ether, Opiorphin, Herkinorin, RB-101, DPI-221, Spinorphin, Kelatorphan, Delta-Pheylalanine, Thiorphan, Tynorphin, Hemorphon-4, valorphin, casomorphin, Gliadorphin, Rubiscolin, Deltorphin, MG6, MT-45, Myrophine, Acetorphine, Acetylmorphone, Actiq, Benzethidine, BU-48, BRL-52537, Pethidine, Naloxol, Betacetylmethadol, Methorphan, Bezitramide, RAM-378, Bromadol, Eriadoline, BW373U86, Thebaine, C-8813, Menthol, 8-CAC, Capperidine, Matrine, Chloromorphide, a-Chlorocodide, HZ-2, Codeinone,  LPK-26, Codoxime, AD-1211, Conorfone, DADLE, Butorphanol, DAMGO, Semorphone, Dextromoramide, Sutentanil, Diampromide, Zenazocine, Difenoxin, Thebacon, Dihydroetorphine, Tilidene, Dimenoxadol, Xorphanol, Dipipanone, Dipropanoylmorphine, Doxpicomine, DPI-3290, Drotebanol, Endomorphin, Eseroline, Ethoheptacine, 14-Ethoxymetopon, Ethylmorphine, Etorphine, Etoxerdine, Furethidine, Heterocodeine, RAM-320, IBNtxA, IC-26, 1-Iodomorphine, Isomethadone, Ketobemidone, Ketorfanol, Lefetamine, Levorphanol, Loperamide, Meprodine, Metofoline, Metopon, Morpheridine, Morphine-N-Oxide, Morphinone, MR-2096, Nicocodeine, Nicomorphine, Normethadone, Ocefentanyl, Ohmefentanyl, Oxpheneridine, Oxymorphazone, Oxymorphol, Oxymorphone, Pentamorphone, PEPAP, Pericine, Phenadoxone, Phenempromide, Phenazocine, Pheneridrine, Phenomorphan, Picenadol, Piminodine, Piritramide, Proclilidine, Prodine, Proheptazine, Properidine, Prosidol, R-30490, R-4066, Ro4-1539, RWJ-394674, Sameridine, SC-17599, Methyldesorphine, Hydroxypethidine, 4-Fluouropethidine, Cannabis Indica, Cannabis Sativa, Cubensis, Hash, BHO, Delta-9-THC, 25TFM-NBOMe, 2C-B-BZP, 2CBFLY-NBOMe, 2CD-5Et0, 5-I-R91150, A-372,159, 2-Bromo-LSD, a-5IA, PWZ-029, L-655,708, TB-21007, 5-Ethoxy-DMT, 5-Ethyl-DMT, 7,N,N-TMT, VER-3323, YM-348, Alnespirone, 8-OH-DPAT, Aminorex, Batoprazine, 5-BT, BIMU-8, BMY-14802, BRL-54443, BW-723C86, 5-CT, CGS-12066A, Cinitapride, CJ-033,466, CP-135,807, CP-809,101, CP-93,129, CP-94,253, N,a,-DEPEA, Dimemebfe, RA-7, E-6801, E-6837, Eltoprazine, EMD-386,088, EMDT, ST-1936, Fluprazine, Indorenate, Jimscaline, L-694,247, Lasmiditan, APD-356, MMDPEA, LY-293,284, LY-310,762, LSD-pip, LPD-824, LSM-775, 5-MT, MBZP, Methyl-MMDA-2, a-MS, MK-212, Mosapride, Org 12,962, Org 37,684, Quipazine, 6-Nitroquipazine, NBUMP, 1-NP, 5-(Nonyloxy)Tryptamine, PHA-57378, PNU-181731, PNU-22394, Propylhexedrine, Prucalopride, PRX-03140, Psilocin, RDS-127, RH-34, Ro60-0175, Ro60-0213, RS-56812, RS-67,333, RU-24,969, RU-28306, SKF-97,541, SR-57227, Tandospirone, Tegaserod, TFMFly, pTMFPP, U-92,016A, SCA-136, TD-5108, Vortionetine, WAY-161503, WAY-208,466, WAY-629, Xaliproden, YM-31636, Zacopride, A-423,579, A-84,543, Abercarnil, 5-Br-DMT, Sugar, Acetildenafil AMMI 4C-D, AS-8112, Astemizole, Asymbescaline, Azapride, BAY-38-7271, BAY-59-3074, BAY-60-6583, Benproperine, Benzylmorphine, Berberine, 2-Pyrrolidone, JBIR-03(1), 1'-O-Acetylpaxilline, Penijanthine A, Emindole DA (1), Petromindole, Emindole SA (2), JWH-133, Napthylmethylindoles, Napthyolpyrroles, Napthylideneindenes, Cyclohexylphenols, Indole-2-Carboxamides, C3 Amino-Indoles, Cymserine, Hodgkinsine, Physostigmine, Psychotridine, Psychotria Colrata, Yuremamine, Gevotroline, Latrepirdine, BMY-7,378, Boldine, BP-897, Brexpiprazole, 4-Bromo-3,5-Dimethoxyamphetamine, Bromopride, Caroverine, CGS-20625, Cinchocaine, DAA-1097, DAA-1106, DOTFM, DMPEA, DMCM, Dyclonine, Ethylvanilin, Evoxine, Furoquinoline Alkaloids, Gabazine, GBLD-345, Rapacuronium, Mivacurium Chloride, Cisatracurium Besilate, DTC, Cloroqualone, Diproqualone, Mecloqualone, Methylmethaqualone, Eszopiclone, TP-003, TP-13, TPA-023, Y-23684, Pagoclone, Pazinaclone, Suproclone, Suriclone, Zapiclone, CGS-9896, NS-2664, NS-2710, Pipequaline, RWJ-51204, SB-205,384, ELB-139, Acamprosate, GABOB, N4-Chloroacetylcytosine Arabinoside, (+)-CAMP, CACA, AZD-3355, 1,4-Butanediol, XP19986, Atagabalin, Gabapentin Enacarbit, Hopantenic Acid, Imagabalin, 4-Methylpregabalin, PD-217,014, Afloqualone, Rocuronium Bromide, Vecuronium Bromide, Pipecuronium Bromide, Pancuronium Bromide, Amyl Nitrate, Atracurium Besilate, BWA444, Benzylisoqualone, Papaverine, Protopine, HS-342, HS-347, HS-310, Emylcamate, Eperisone, Febarbamate, Flavoxate, Inaperisone, Acamprosate, Progabide, Tiagabine, Lanperisone, Mephenesin, HS-692, HS-693, HS-704, HS-705, HS-626, Chlorzoxazone, Cisatracurium Besilate, Curare, Cyclobenzapine, Dantrolene, Decamethonium, Difebarbamate, Dihydrochanclonium, Doxacurium Chloride, Gallamine Triethiodide, Gantacurium Chloride, Hexafluronium Bromide, Meprobamate, Metaxalone, Methocarbamol, Norgesic, Orphenadrine, Pancuronium Bromide, Phenprobamate, Pipecuronium Bromide, Premazepam, Promoxolane, Quazepam, Rocuronium Bromide, Silperisone, Sulazepam, Suxamethonium Chloride, Suxethonium Chloride, Tetrabamate, Tizanidine, Tolperisone, Gigantine, BAY-73-6691, Indiplon, Nitrosoprodenafill, Zaleplon, Udenafil, Sulfoaildenafill, Sildenafil, Ocinaplon, Alpidem, Bamaluzole, DS-1, Fadrozole, Fazadinium Bromide, Imidazopyridine, Minodronic Acid, Bisphosphonate, Miroprofen, Necopidem, AL-LAD, DBT, a.O-DMS, 2,a-DMT, a,N-DMT, ETH-LAD, a-ET, 4-HO-DBT, 4-HO-pyr-T, MBT, 4,5-MDO-DIPT, 5,6-MDO-DIPT, 4,5-MDO-DMT, 5,6-MDO-DMT, 5,6-MDO-MIPT, 5,6-MeO-MIPT, 5-MeO-pyr-T, 5-MeO-NMT, 6-MeO-THH, 5-MeS-DMT, PRO-LAD, pyr-T, a,N,O-TMS, Olprinone, Telcagepant, Febrifugine, Halofuginone, MK-0249, LY-156,735, Ramelteon, Tasimelteon, SL-164, Quinazoline, Albaconazole, Altaserin, ATC-0175, Canertinib, Cediranib, Doxazosin, Fluproquazone, Gefitinib, Katanserin, Lapatinib, Agmatine, Amantadine, AP-7, AP5, Aptiganel, CGP-37849, 7-CTKA, DCKA, DXO, MK-801, SL-82.0715, Esketamine, Ethanol, NEFA, Besonprodil, Gacyclidine, Gavestinel, Huperzine A, Ifenprodil, Indantadol, Metaphit, Memantine, LY-235,959, Lubeluzole, Levomethadone, Kynuretic Acid, Midafotel, Neramexane, Nitromemantine, PEAQX, Perzinfotel, 8A-PHDQ, Remacemide, Rhynchophylline, Sabeluzole, Tiletamine, Tramadol, Xenon, Hydroxchloroquine, Antrafenine, Bedaquiline, GSK-299423, JTC-801, JTE-907, LGD-2226, PBT-2, PF-2545920, SB-215,505, SB-277,011-A, SB-742,457, BHF-177, BHFF, BSPP, Cartazolate, CGP-7930, Clomethiazole, Etazolate, Etomidate, Felbamate, Fospropofol, Gaboxadol, Glutethimide, GS-39783, Ibotenic Acid, ICI-190,622, Isoguracine, Isonipecotic Acid, Loreclezole, Methyprylone, Allopregnanolone, 5a-Dihydroprogesterone, Progesterone, THDOC, Alfadolone, Alfaxalone, Ganaxolone, Hydroxydione, Minaxolone, Org-20599, Pregnane, Piperadone, Propanidid, Propofol, Pyrithyldione, ROD-188, Stiripentol, Thiomuscimol, Thymol, Tybamate, QNB (BZ), Scopolamine, Midazolam, Sodium Pentathol, Amobarbital, Blue 88, Adinazolam, Alphenal, Bentazepam, Bromisoval, Camazepam, Carbromal, Centalun, Chloralodol, Chronobiotic, Cinolazepam, Clorazepate, Cloxazolam, Cyclopyrrolones, Delorazepam, Dichloralphenazone, DPH, Doxefazepam, Doxylamine, Embutramide, Eplivaserin, Ethinamate, Ethyl Ioflazepate, Fludiazipam, Heptabarb, Oleamide, Org 21465, Org 25435, Paraldehyde, Phenobarbital, Propiomazine, Promethazine, Propylbarbital, QH-II-66, Quetiapine, SH-053-R-CH3-2'F, Sulfonmethane, Tetrabarbital, Tetronal, Trional, Trytophol, Acaprazine, Acebrochal, Acetylglycinamide Chloral, Almorexant, Detomidine, Bromouriede, Benzoctamine, Barakol, Bekhterev's Mixture, Fasiplon, Fenadiazole, Fluperlapine, JM-1232, Inebriating Mint, Ro41-3696, Methapyrilene, Minitran, Nisobamate, Oxanamide, Oxomemazine, Panadiplon, Pazinaclone, Pentabamate, Petrichloral, Potassium Bromide, Procymate, Saripidem, Vinybital, Vinbarbital, Valofane, Validolum, Valeric Acid, Unisom, U-90042, U-89843A, Triclofos, 2,2,2-Trichloroethanol, TCS-OX2-29, SX-3228, Suvorexant, Sigmodal, SB-649,868, 6-APA, 77-LH-28-1, Adimolol, Alfentanil, Amedanil, Amedalin, BMS-564,929, Binospirone, Carburazepam, Clazolam, Clobazam, Clobenzepam, Clotiazepam, Thienodiazepine, Brotizolam, CP-14145, Cyclazodone, CSP-2503, Cycloserine, Cytisine, Demoxepam, Chlordizepoxide, Dibenzepin, Dihydroergocorine, Dihydroergocristine, DHEC, Dihydroergotamine, 17-DMAG, Dimiracetam, Doliracetam, Droperidol, Dihydrotestosterone, Dutasteride, Edaravone, EGIS-12,233, Elfazepam, Elzasonan, Enilospirone, Ergoloid, Ergotamine, Ergocrytine, Ergocristine, Ergovaline, Etazepine, Evodiamine, Fenmetramide, Fenozolone, Flunitrazepam, Flutazolam, Flutemazepam, Flutoprazepam, Fosazepam, GW-803,430, Halazepam, Haloxazolam, Herbimycin, Horsfiline, HT-0712, Icilin, Clazepam, Indoprofen, Ipsapirone, Isatin, Ketazolam, KF-26777, Lofendazepam, Lopirazepam, Loprazolam, Lorazepam, Lormetazepam, Menitrazepam, Meclonazepam, Menitrazepam, NMSP, Mexazolam, THCI, THCII, THCIII, THCIV, THCV, Mosapramine, Motrazepam, NBQX, Nevirapine, Nimetazepam, Nitrazepam, Nitrazepate, Nitroxazepine, Nordazepam, Nortetrazepam, Oxazepam, Oxatomide, Paliperidone, Prazepam, Pivoxazepam, Pirquinozol, Pirenzepine, Pinazepam, Pemoline, Paraxazone, Palonosterone, Proflazepam, Propizepine, Razobazam, Revospirone, Ripazepam, Ro15-4513, Ro48-6791, Ro48-8684, Ro5-2904, Ro5-4864, Ro64-6198, Ropinirole, RPL-554, RS-102,221, SL65.0155, Spiroxatrine, Temazepam, Tetrazepam, Thozalinone, Tolufazepam, Triflubazam, Vardenafil, Ziprasidone, Zolazepam, Zomebazam, Zometapine,  Pyrazolodiazipines, Triazolodiazipines, Estazolam, Flubromazolam, Triazolam, Nitrobenzodiazepines, Pentazocine, 8-HO-PBZI, A-366,833, ABT-202, Sympathomimethies, ABT-239, ABT-418, Aniracetam, Almotriptan, BD-1008, LR-132, BD-1031, Singma Agonists, BD-1018, 4-PPBP, Alazocine, BD-1052, Butinoline, Clemizole, CPHPC, Desoxy-D2PM, Citalopram, Ditolyguanidine, Escitalopram, Fluoxetine, Fluvoxamine, Tgmesine, L-697,384, PRE-084, S33005, SA-4503. Siramesine, Venlafaxine, Clonidine, VUT-8430, UR-AK49, Moroxydine, Altinicline, Anabasine, 3-Bromocytine, Bradanicline, Cotinine, Desformylflustrabromine, Dianicline, DMPP, Epibatidine, Epiboxidine, Lobeline, Myosmine, Phenylpiracetam, PNU-120,596, PNU-282,987, ABT-089,Rivanicline, RJR-2429, Phantasmidine, Sazetidine A, SIB-1553A, TC-1698, TC-1827, TC-2216, Tebanicline, 2,3,4,5-Tetrahydro-1,5-Methano-1H-3-Benzazepine, UB-165, Varenicline, FE-β-CPPIT, FB-β-CPPIT, RTI-336, NVP-AUY922, Pleconaril, RTI-177, RTI-371, Calea Ternifolia, African Dream Herb, Ambutonium Bromide, Hyoscamine, Ilex Guayusa, Abediterol, Aclidinium Bromide, Benzilycholine Mustard, Bevonium, Bornaprine, Cyanodothiepin, Darifenacin, Dexetimide, Dicycloverine, Etybenzatropine, Fenpiverinium, Fesoterodine, Homatropine, Hydroxyzine, Imidafenacin, Ipratropium Bromide, Methylatropine, Methylhomatropine, Octatropine Methylbromide, PD-0298029, PD-102,807, Pipenzolate, Piperidolate, Tiotropium Bromide, Anisodine, Benacytazine, Butylscopolamine, CAR-226,086, CAR-301,060, CAR-301,196, Caramiphen, Clidinium Bromide, Ditran, EA-3167, EA-3443, EA-3580, EA-3834, JB-318, JB-336, Methylscoplamin Bromide, Oxapium Iodide, Oxitropium Bromide, Polyfothine, Propiverine, Pyrrobutamine, Timepidium Bromide, Tridihexethyl, Tropatepine, WIN-2299, Amrutanjan, Abstral, Acetylmethadol, Acetyldihydrocodeine, Alletorphine, Anilopam, Axomadol, BC Powder, Befiradol, Benorilate, Betamethadol, Bicifadine, Butinazocine, Carbazocine, Celadrin, Chlorodyne, Cinchophen, Co-dydramol, Co-codamal, Cogazocine, Conolidine, Deltorphin I, Dezocine, Dimepheptanol, Dipyrocetyl, TRPV1 Receptor, Capsazepine, Dosulepin, Electroanalgesia, Epideral Steroid Injection, Eptazocine, Equianalgesic, Efazocine, Fedotozine, Filenadol, Fioricet, Fiorinal, Frakefamide, Hemprenorphine, 3-HM, Ibazocine, Levallorphan, Levomepromazine, Lufuradom, Magnesium Salicylate, Blue Prickly Poppy, Menabitan, A-40174, Dimethylhepylpyran, Metamizole, Metkefamide, Moramide, Morphiceptin, Moxazocine, Nafoxadol, Malmexone, Naproxen, Nefopam, Nimesulide, Naracymethadol, Norlevorphanol, Norpipanone, NS-11394, Panadol, Penthox Inhaler, Phenacetin, Phenazone, Phenazopyridine, Propyphenazone, Proxorphan, Resiniferatoxin, Rimazolium, Romifidine, RUB-A535, Salecylamide, Salonpas, Tectin, Tolfenamic Acid, Tenazocine, Ufenamate, Volazocine, Xylazine, Yangonin, Zinda Tilismath, Ziconotide, Anazocine, Bremazocine, Cyclazocine, EKC, Fluorophen, Gemazocine, Ketazocine, Metazocine, Quadazocine, Azocine, Benzazocine, 0-2545, DOU-216,303, Phenylethylpyrrolidine, GR-89696, HA-966, ICI-199,441, ICI-204,448, NNN, Nornicotine, Clemastine, PF-03654746, RTI-229, SB-269,970, U-50488, U-69,593, Bombesin, Bivaracetam, Cebaracetam, DEABL, Coluracetam, Cromakalim, Doxapram, Dupracetam, Etiracetam, Fasoracetam, Imuracetam, Levetiracetam, Lidanserin, Nebracetam, Nefiracetam, Nicoracetam, Oxiracetam, Piperacetam, Pramiracetam, Seletracetam, MOPPP, MPBP, MPHP, MDPDP, MDPPP, Pyrovalone, a-PBP, a-PPP, Neuropeptides, Galanin, Neuropeptide Y, Enkephalin, Somatoslatin, CCK, Substance P, Neurotensin, TRH, Acepramazine, Aceprometazine, Acetanisol, Acetohexamide, Acetophenazine, Acetophenone, Acetosyringoine, 2-Acetylpyridine, Adrenalone, Anthrone, Apocynin, Avobenzone, Benzbromarone, Benziodarone, Benzoin, Butaperazine, CB-13, AM-6545, AZ-11713908, WIN-54,461, JWH-200, WIN-56,098,S-796,260, AM-1220, AM-1221, AM-1241, AM-2233, AM-630, AAI's, CPE, GW-405,833, JWH-193, JWH-198, JWH-007, 3-Acetyl-6-Methoxybenzaldehyde, Aflobazole, AR-A000002, Azasestron, Bazinaprine, 3-Benzhydrylmorpholine, BML-190, Cobicistat, CYT387, Desmethylmoramide, Dioxaphetyl Butyrate, Edivoxetine, Epelsiban, Demoxytocin, Carbetocine, WAY-267,464, Atosiban, Eprobemide, L-371,257, L-368,899, Quinagolide, Terbutaline, 2CB-ind, 5-APDI, APICA, Donepezil, ICI-118,551, Indatraline, Indinavir, Ladostigil, Mutisianthol, PNU-99,194, S-15535, TAI, Zicronapine, Aleglitazar, Thromboxame Receptor Agonist, Verruculogen, Brevianamide, 2,5-DKP, Fellutanine, Phenylahistine, Plinabulin, Rugulosuvine, Fedrilate, Fenbutrazate, L-733,060, G-130, HC3, Indeloxazine, Levomoramide, Metostilenol, Molindone, Molracetam, Nimorazole, O-1057, O-1812, AM-2232, O-774, AM-2389, HHC, HU-243, Canbisol, Nabilone, 11-OH-THC, 2-AGE, Paxahexyl, THC-C4, AMG-36, AMG-41, AM-1235, AM-906, AM-365, O-2694, O-2372, O-2113, O-2050, VCHSR, TM-38837, PiplSB, PF-514273, MK-9470, LY-320,135, O-2545, PD-128,907, PF-219,061, ABT-670, ABT-742, UK-414,495, OSU-6162, Melanotan II, Oxaflozane, PF-592,379, 2-Phenyl-3,6-Dimethylmorpholine, Pramocaine, SCH-50911, 4-HTMPIPO, A-41988, AB-001, AB-005, ADBICA, AM-087, AM-411, KM-233, AM-679, AM-694, AM-855, AM-905, AM-919, AM-4030, AM-938, AM-251, AMG-1, AR-231,453, PSN-375,963, PSN-632,408, (C6)-CP-47,497, CCH, O-1871, CP-55,940, CP-47,497, CP-50,556'1, CP-55,244, Otenabant, (C9)-CP-47,497, CBS-0550, AVE-1625, GW-842,166x, HU-308, HU-336, HU-331, HU-320, Ajulemic Acid, JTE-7-31, A-834,735, MDA-19, S-444,823, JTE-907, JWH-015, JWH-019, JWH-030, JWH-047, JWH-048, JWH-051, JWH-057, JWH-081, SLV319, 2-Isopropyl-5-Methyl-1-(2,6-dihydroxy-4-nonphenyl)cyclohex-1-ene, HU-345, JWH-098, JWH-116, JWH-120, JWH-122, JWH-147, JWH-148, JWH-149, JWH-161, JWH-164, JWH-167, JWH-175, JWH-176, JWH-184, JWH-185, JWH-196, JWH-203, JWH-249, JWH-302, JWH-307, JWH-359, JWH-398, JWH-424, L-759,633, L-759,656, GW-405,833, Leelamine, NESS-0327, NESS-040C5, NMP-7, Nonabine, O-1125, O-1238, O-1269, O-806, O0823, Org-27569, Org-28312, LBP-1, Org-28611, Otenabant, Perrottetinene, PF-03550096, RCS-4, RCS-8, Rosonbrant, SDB-001, SDB-006, SER-601, Serinolamide A, THC-O-Phosphate, Tinabinol, VDM-11, Virohamine, A77636, Adafenoxate, Adapromine, Adatanserin, Bolmantalate, Bromantane, SR-142,948, 25B-NBOMe, 25I-NBMB, 25TFM-NBOMe, 5-MeO-NBpBiT, 2CBCB-NBOMe, 25CN-NBOH, Juncosamine, TCB-2, 6-Br-APB, Agelferin, Cridazepam, Meta-DOB, NGD-4715, Nicergoline, P7C3, SB-357,134, Sclerotia Truffle, 5-Flouro-aMT, 6-Flouro-aMT, Telepathine, AMDA, Amperozide, Cinaserin, Deramciclane, Fenanserin, Flibanserin, Glemanserin, Iferanserin, KML-010, LY-367,265, Pruvanserin, Rauwolscine, Setoperone, Spiperone, Volinanserin, Xlamidine, Altropane, ATI-2042, PIA, RTI-121, RTI-353, Tramethinib, SB-258,585, Lu-AE58054, MS-245, Ro04-6790, SB-271,046, SB-399,885, RTI-55, AC-262,356, 2'-Acetoxycocaine, Bemestron, Benzoylthiomethylecogine, Brasofesine, 2-CMT, Clobenztropine, Cocaethylene, Deptropine, Dichloropane, Diflouropine, Granisetron, 3-(p-Flourobenzoyloxy)tropane, p-ISOCOC, Methylvanillylecogonine, Norcocaine, NS-2359, RTI-126, WF-23, WF-33, WF-31, WF-11, BRL-46470, RTI-112, RTI-113, RTI-120, RTI-150, RTI-171, RTI-274, RTI-31, RTI-32, RTI-51, RTI-83, Thiophenyltropanes, MAT Inhibitor, Salicylmethylecgonine, Tesofesine, Troparil, WIN-35428, Amfonelic Acid, Oxolinc Acid, Tropisetron, Zatosetron, Dichloropane, RTI-336, RTI-126, Tropoxane, Poyo (Palm Wine), Tropicamide, Caffetin, Formic acid, Monocled Cobra, Sisa, Tramadol, Dazopride, Dolasetron, Amylocaine, Articaine, Bupivacaine, Butacaine, Chloroprocaine, Cyclomethycaine, Etidocaine, Hexylcaine, Levobupivacaine, Mepivacaine, Meprylcaine, Prilocaine, Proxymetacaine, Risocaine, Ropivacaine, Tetracaine, Trimecaine, Piperocaine, Metabutoxycaine, Adipiplon, Almitrine, ARRY-520, AZD5423, Cisapride, CP-226,269, CRL-40,941, DBL-583, Dexamethasone, DFMD, Methyldopa, Carbidopa, d-DOPA, L-DOPS, Octaflourocyclobutane (for alloys), DFB (for alloys), Didesmethylcitalopram, Elopiprazole, Phenylpiprazine, F-15,599, FGIN-127, Fletazepam, Flucindole, GR-159,897, LY-503,430, MPPF, PEPA, RS-127,445, S-23, SHA-68, SNAP-7941, SNAP-94847, TP-003, TPA-023, UH-301, Calycosin, Flavinoids, Psi-Tectorigenin, Blochanin A, Formononetin, Glyciten, Irigenin, Methoxyisoflavone, 5-O-Methylgenistein, 7-O-Methylluteone, Ononin, Pratensein, Prunetin, Retusin, Tectoridin, Tectorigenin, Barbigerone, Daidzein, Derrubone, Genistein, Ipriflavone, Irilone, Luteone, Orobol, Psuedobaotigenin, Wighteone, AMG-3, Nabazenil, Naboctate, a-Napthoflavone, 11-Nor-9-Carboxy-THC (How Drug Tests Work), Pirnabine, Apiol, Dillapiol, 1,3-Benzodioxole, Piperonal, beta-Asarone, Eleicin, Homovanyllyl Alcohol, Myristicin, 2-Bromo-4,5-Methylenedioxyamphetamine, Californidine, Chavicine, Cinoxacin, Dibutylone, Fenoverine, Befuraline, MDIP, MDMAI, MDPR, MDAL, ORTHO-MDA, MDP1P, MDP2P, Omiloxetine, Osemozotan, Piclozotan, Robalzotan, Ebalzotan, Sarlzotan, Piperine, Protokylol, Isoprenaline, Rhoeadine, MDMPEA, MMDPEA, MMDMPEA, MDIP, MDHOET, MDPL, GYKI-52895, Ungiminorine, NADA, ECG, EGCG, EGC, Levonantradol, Cone Snail Venom, A-836,339, Abacavir, CYP-LAD, 2-Bromo-LSD, BU-LAD, DAM-57, DAL, Epicriptine, Ergometrine, Ergometrinine, Ergostine, ETH-LAD, LEA-32, Methylergometrine, MLD-41, LSP, LSH, MIPLA, PARGY-LAD, PRO-LAD, DCG-IV, DOV-102,677, MDCPM, MNTX, Amfonelic acid, J-113,397, SB-612,111, VUF-6002, DBM, Piberatine, Ilercimide, Dithranol, Divaplon, Ebastine, Flopropione, Iloperidone, Ketorolac, Melperone, NNC-38-1044, Tetralone, Cuscohydrine, Hygrine, 4-NEMD, Aceburic Acid, Amfecloral, Aprobarbital, Arfendazam, Benzobarbital, Benzylbutylbarbituate, Brallobarbital, Brophebarbital, Buthalitol, Carbubarb, Climazolam, Cyclobarbital, Cyclopentobarbital,
> 
> Everyone should look up "Digital Biological Converter" and "Biological Teleportation" Medicine and Industry can both completely move like 100 steps forward if tons of people learn about Biological Teleportation and the things on this list.
> 
> Also, if you want to learn more about Alkaloids go on Amazon and look up "Alkaloids", "Organic Chemistry", "Biochemistry", "Biosynthesis", "Epigenetics" and "Natural Materials"  and look at the textbooks.
> 
> Sasha Alexander Shulgin Scale +, ++, +++, ++++ or +1, +2, +3, +4
> 1= Tipsy
> 2= High/Drunk, etc. But you could still go to the store
> 3= If you went in public, people would say "I think that person is on something"
> 4= Seeing God
> 
> And now a days people say "Threshold/Weak", "Medium", "Strong" in terms of instant mental effects, but Shulgin had things like "Museum Doses" where he would take like 10mg of 2C-I so that the Museum would come alive.
> 
> Psychedelic, Deleriant, Entactogen, Stimulant, Dissociative, Sedative/Anti-Psychotic, Anti-Depressant/Mood Stabilizer, Nootropic, Vitaman, Sleep Aid, Sex Aid, Addiction Aid, Antidote
> Isomerization, Polarization, Chromatography
> 
> When Aliens come to Earth and openly land somewhere for everyone to see, and it turns out they don't have vocal cords and they have insect eyes. Shouldn't we have a bio-active alkaloid that represents how we want them to feel about us? The way a poison plant is saying "Go away" and Marijuana is saying "Hello" we can tell the aliens whatever we want. I vote we brew some Ayahuasca to take with them, OR take some Lisuride (LSD without any visuals).


----------



## pharmakos

also, these two quotes from you are pretty contradictory:



ShaggyFin said:


> When I say I "am learning plenty" I mean I would rather come back here in a week with some organic chemistry textbooks and just start drawing molecules and discussing them with you guys. That would be MUCH more stimulating than sitting in a classroom learning from a failed DOW chemist or wanna-be Meth chef.





ShaggyFin said:


> I am a very hands on learner.




if you are a hands-on learner, then going to school and learning in a classroom / laboratory setting would be ideal.  perhaps you have the wrong notion of what learning chemistry in college is like -- you will actually be in a laboratory from the first week of your freshman year, starting with Chemistry 101.


----------



## pharmakos

ShaggyFin said:


> I did not "accuse", he told me that when I talk about this stuff, it is "insulting to real chemists". I was just reiterating his statement.



also, the person you called an ass was not the same person that accused you of being an insult to real chemists


----------



## ShaggyFin

thenightwatch said:


> if you are a hands-on learner, then going to school and learning in a classroom / laboratory setting would be ideal.  perhaps you have the wrong notion of what learning chemistry in college is like -- you will actually be in a laboratory from the first week of your freshman year, starting with Chemistry 101.



Again, I don't have the money to do avid schooling, so I would probably be doing basics, like math and lit. Not lab after lab. So pondering and drawing my own structures is as "hands on" as I can get for now.

But within months I will be creating my own ghetto lab, where I can do this directly without following their curriculum.



thenightwatch said:


> also, the person you called an ass was not the same person that accused you of being an insult to real chemists



Yeah, that was the guy that pretended I said words I didn't know, so I had to spell it out for him.
Is there a point to my replying to you now, or is this just fun for you?


----------



## pharmakos

the people in this thread are trying to help you, dude.  we're not just correcting you for shits and giggles.  we are legitimately trying to steer you on the right course.

you insulted the failed DOW chemist or the wanna be Meth-chef, but you want to have your own ghetto lab in a few months?

i tell you this for your own good -- you are incredibly far away from being able to start your own laboratory.  for the good of you and the people you live nearby, i hope to god that you do not attempt it.



			
				ShaggyFinn said:
			
		

> I am VERY unlearned in organic chemistry, my "expertise" from the past (if you can call it that) is more on that "taking and comparing" side of drugs. I ordered some books so I will be able to draw other molecules soon. But unless we can Isomerize this stuff, or Decarboxalyze it, or whatever. All I know that is possible is to attach it to a Chloroform, because after Ana Nicole smith died I read about Chlorobutanol (the stuff that killed her from OD, it's a Barbiturate I believe) and making that is the same as making this.



he was right when he said you were just throwing out words without knowing what they meant.  "isomerize" and "decarboxylate" make absolutely no sense in the context you were using them in.


----------



## ShaggyFin

thenightwatch said:


> the people in this thread are trying to help you, dude.  we're not just correcting you for shits and giggles.  we are legitimately trying to steer you on the right course.
> 
> you insulted the failed DOW chemist or the wanna be Meth-chef, but you want to have your own ghetto lab in a few months?
> 
> i tell you this for your own good -- you are incredibly far away from being able to start your own laboratory.  for the good of you and the people you live nearby, i hope to god that you do not attempt it.



See, you say you are not doing this for fun, then you TRY not to understand where I am coming from.

Is it not OBVIOUS that when I said "failed DOW chemist" and "Wanna-be meth chef" I am talking about people that CALL themselves chemists because they "know procedure" but they have NO alchemical spirit, which DRIVES chemistry.

I am not making a lab in my house or anything, my family is interested in this fragrance stuff. So we will probably rent a place specifically for this, maybe with an herbal supplement shop.


----------



## pharmakos

ShaggyFin said:


> See, you say you are not doing this for fun, then you TRY not to understand where I am coming from.



i don't even think you know where you are coming from.  you have contradicted yourself an astounding number of times in the last three pages.


----------



## ShaggyFin

thenightwatch said:


> i don't even think you know where you are coming from.  you have contradicted yourself an astounding number of times in the last three pages.



I think you are just confused about what is being said.


----------



## pharmakos

i'm not going to lie -- deciphering your posts is quite confusing.  that is no fault of mine, though.

i already have pointed out several of your contradictions to you.  i could point out more, but if your past responses are any indicator of what your future responses will be, you will just backpedal and say you meant something other than what you actually said.

like i said, though, shaggy -- i admire your zeal and drive.  i really think you need to go a lot slower, though.  you are approaching dangerous territory if you are talking about starting up your own lab within a few months.

part of me thinks that you might just be an internet troll.  that's how nonsensical you are being, dude.


----------



## ShaggyFin

thenightwatch said:


> i'm not going to lie -- deciphering your posts is quite confusing.  that is no fault of mine, though.
> 
> i already have pointed out several of your contradictions to you.  i could point out more, but if your past responses are any indicator of what your future responses will be, you will just backpedal and say you meant something other than what you actually said.
> 
> like i said, though, shaggy -- i admire your zeal and drive.  i really think you need to go a lot slower, though.  you are approaching dangerous territory if you are talking about starting up your own lab within a few months.
> 
> part of me thinks that you might just be an internet troll.  that's how nonsensical you are being, dude.



Honestly, I have had the thought that you are just trolling too.

I am not a troll, people may say that, but again I am just under-educated and under-furnished. I know a LOT from reading textbook after textbook, but I DO NOT claim to know everything and try to work with people. But people would rather see you have something completed than be part of getting there and reap the benefits of being involved. It is a pattern that has cycled over and over nice I joined the interneting community.

I may seem like a troll, but only because I am broke and full of ideas and thoughts that cost money. 

I really think you are over expecting me. When I say "Lab" I mean ghetto lab. We will be making Chloroscone, and an Isopropyl form. Other than that, there are no plans for anything yet (some more may pop up in the next few weeks, but nothing drastic). So whatever idea of a lab is in your head, please re-equate it.


----------



## pharmakos

i think you are overexpecting of yourself.  i'm done, though -- you obviously are beyond reason.  enjoy blowing up your neighborhood mixing volatile chemicals together.


----------



## ShaggyFin

thenightwatch said:


> i think you are overexpecting of yourself.  i'm done, though -- you obviously are beyond reason.  enjoy blowing up your neighborhood mixing volatile chemicals together.



Lol, we will be getting a fume hood and other safety materials, so we probably won't blow up the neighborhood with our Isopropyl alcohol and Chloroform, but thank you for your concern.


----------



## pharmakos

i said i was done, but damn it...



you can afford a fume hood but you can't afford $400 to take a Chemistry 101 class at your local community college?  you are bonkers.


----------



## ShaggyFin

thenightwatch said:


> i said i was done, but damn it...
> 
> 
> 
> you can afford a fume hood but you can't afford $400 to take a Chemistry 101 class at your local community college?  you are bonkers.



My parents suck a little. They want to see money before they spend money. Opening a Perfume production "center" would make more money than me sitting in a classroom. Plus YouTube videos of this will make money as well.

So they have money for this, but have not ever had money for school.


----------



## pharmakos

somehow i doubt that you are 22 years old like you claimed


----------



## ShaggyFin

thenightwatch said:


> somehow i doubt that you are 22 years old like you claimed



I am. And I am so broke I have never bought alcohol in America or been to a bar in America (I did in Mexico when I was 18 ), but I do ferment my own wine like a fucking inmate.


----------



## pharmakos

why don't you get a job?  are you here illegally?


----------



## ShaggyFin

thenightwatch said:


> why don't you get a job?  are you here illegally?



Basically.

I have a misdemeanor (they can't cross state lines for it) warrant in Texas for Marijuana possession. So that shows up on my record for any job as an open warrant, plus I don't have money which perpetuates the problem. If I were in my home town it would be no problem, I would just have a friend help me get a job. But I live in a state where no one knows who I am (and weed is legal, so they can't wrap their heads around a weed charge for someone that did nothing), and therefor no one trusts me like that. And since I have no money, I can't go hang out anywhere and get to know anybody that can offer me a job.

So, I am stuck earning Adsense money and Bitcoins. Which are actually two amazing programs once you are forced to figure out what they are.


----------



## pharmakos

so you are making money?  i thought you were broke?

btw the powers that be pay attention when people order chemistry supplies like fume hoods and reagents.  i wouldn't be surprised if you get an unfriendly knock on the door if you go through with this plan of yours.


----------



## ShaggyFin

thenightwatch said:


> so you are making money?  i thought you were broke?
> 
> btw the powers that be pay attention when people order chemistry supplies like fume hoods and reagents.  i wouldn't be surprised if you get an unfriendly knock on the door if you go through with this plan of yours.



I am broke. I eat most of my money, the rest goes to working towards creating a stable USD income online (which is not stable yet).

I am sure they are already looking at me for the lists I make of alkaloids and stuff. But my assumption is that they can see that I am not dangerous, I am not stockpiling weapons or ammo, I am hopeful for the future, and no one listens to me. So I am not a threat.

I am sure they watch me, but more in wonder than in a sense of security probably. Like, I sent a tweet to the president asking if the Situation Room's (a private line in the white house for emergency stuff) phone number was the same, then I tweeted the number at him (I found it online in highschool and we used to call it for fun and say we had cats in a tree and stuff, so I know it is real), and he didn't reply. And I have been sending tweets to various politicians and political pundits.

But I actually kinda HOPE they come knock on our door, we won't be doing anything illegal. And I want to talk to someone in the DEA about how to get a DEA license.


----------



## pharmakos

i think your definition of dangerous and their definition of dangerous are two totally different things.  someone who obviously has next to no knowledge about synthesis is talking about ordering volatile chemicals and doing experimental reactions with them.  they're going to consider that dangerous, dude.  and i'm pretty sure they'll just laugh in your face if they come knocking on your door with a warrant and you start asking them about how to get a license to work with scheduled/controlled chemicals.

i don't mean this as an insult at all, so please don't take it as one -- do you realize how delusional you're being?  you're a fugitive with barely any educational background trying to scrape together a digital income, and you think that you'll be able to convince the DEA to give you a license and convince Yale to accept you as a student?  seriously?

you remind me of my IRL friend Brandon.  he wouldn't shut up one night about how he could convince NASA to accept him as an astronaut if he just had a chance to talk to them.  so the morning came, and i found a phone number for NASA.  he gave them this huge speech about "why can't a guy, if he's willing to give the shirt off his back for his country, go to space if he wants to?"  the person on the phone was straight up laughing at him, but he was so manic and delusional that he thought he actually was being convincing.

Brandon is now getting disability checks for "debilitating Bipolar disorder," and he is court ordered to take his antipsychotics or be forced to go back into a mental institution.


----------



## pharmakos

you need to get your ducks in a row, man -- take care of that warrant.  its not going to go away if you ignore it, and you will never be able to make anything worthwhile of your life if you don't deal with it.


----------



## ShaggyFin

thenightwatch said:


> i think your definition of dangerous and their definition of dangerous are two totally different things.  someone who obviously has next to no knowledge about synthesis is talking about ordering volatile chemicals and doing experimental reactions with them.  they're going to consider that dangerous, dude.  and i'm pretty sure they'll just laugh in your face if they come knocking on your door with a warrant and you start asking them about how to get a license to work with scheduled/controlled chemicals.
> 
> i don't mean this as an insult at all, so please don't take it as one -- do you realize how delusional you're being?  you're a fugitive with barely any educational background trying to scrape together a digital income, and you think that you'll be able to convince the DEA to give you a license and convince Yale to accept you as a student?  seriously?
> 
> you remind me of my IRL friend Brandon.  he wouldn't shut up one night about how he could convince NASA to accept him as an astronaut if he just had a chance to talk to them.  so the morning came, and i found a phone number for NASA.  he gave them this huge speech about "why can't a guy, if he's willing to give the shirt off his back for his country, go to space if he wants to?"  the person on the phone was straight up laughing at him, but he was so manic and delusional that he thought he actually was being convincing.
> 
> Brandon is now getting disability checks for "debilitating Bipolar disorder," and he is court ordered to take his antipsychotics or be forced to go back into a mental institution.



Woah woah woah, slow down. Again, you are looking at this like I am jumping into everything.

When we start a lab, and make Chloroscone and the Isopropyl form and any other simple form we can make (Many of which would just be two natural oils bonded together), our next step will not be to start doing more chemistry. At that point we just start selling our designer smells. 

If the DEA comes, I am not going to try to "convince them to give me a DEA licence" I will simply ask how that works, and let them know about my interest in Shulgin, who they have probably heard of and most people haven't. So that could lead to some good discussion.

Again, you are not at all trying to see where I am coming from and automatically jump to Brandon, which is not a case like mine at all.

And I do not plan on living in America forever, or even very long. I have made that clear to just about everyone on the internet, it just has not come up here.



thenightwatch said:


> you need to get your ducks in a row, man -- take care of that warrant.  its not going to go away if you ignore it, and you will never be able to make anything worthwhile of your life if you don't deal with it.



I don't plan on breaking the law again, and after 7 years it goes away. It's been 4.


----------



## sekio

Reading a few textbooks does not a qualified chemist make.



> I really think you are over expecting me. When I say "Lab" I mean ghetto lab. We will be making Chloroscone, and an Isopropyl form. Other than that, there are no plans for anything yet (some more may pop up in the next few weeks, but nothing drastic). So whatever idea of a lab is in your head, please re-equate it.








Yeah, have fun making money selling uncharacterised "perfumes". Especially when you can't provide data on purity, toxicity, etc. Doubly so when there's a fucking trichloro group on them, which is generally Not Good For Cells. If you can't afford to live on your own you're not going to get rich quick making "novel designer perfumes" when you have no fucking idea what you're doing at all.



> Like, I sent a tweet to the president asking if the Situation Room's (a private line in the white house for emergency stuff) phone number was the same, then I tweeted the number at him (I found it online in highschool and we used to call it for fun and say we had cats in a tree and stuff, so I know it is real), and he didn't reply.



Words fail me.



> I will simply ask how that works, and let them know about my interest in Shulgin, who they have probably heard of and most people haven't. So that could lead to some good discussion.



Yeah, somehow, I doubt much good discussion is going to come from telling DEA agents you're interested in this Shulgin guy. Expect a warrant for illicit posession of a category B precursor, acetone....

Less discussion of perfumery and more of drugs plz.


----------



## pharmakos

ShaggyFin said:


> Woah woah woah, slow down. Again, you are looking at this like I am jumping into everything.



you ARE jumping into everything.



			
				ShaggyFin said:
			
		

> If the DEA comes, I am not going to try to "convince them to give me a DEA licence" I will simply ask how that works, and let them know about my interest in Shulgin, who they have probably heard of and most people haven't. So that could lead to some good discussion.



"oh hey, one of my idols is a man who is considered an enemy of the DEA.  wanna chat about it?"

/facepalm.


----------



## ShaggyFin

sekio said:


> Reading a few textbooks does not a qualified chemist make.


I never said it did, I literally said I am not a chemist and that I would need help.




sekio said:


> Yeah, have fun making money selling uncharacterised "perfumes". Especially when you can't provide data on purity, toxicity, etc. Doubly so when there's a fucking trichloro group on them, which is generally Not Good For Cells.


That is the  FIRST thing I thought of, I can start with a plain Damascone and figure out how to attach Myrcene, or Ethyl Formate, or Butyl Acetate or whatever. I just don't know how yet, in a week or so I will be drawing up all kinds of new (simple) compounds that don't have a Chloroform.






sekio said:


> Yeah, somehow, I doubt much good discussion is going to come from telling DEA agents you're interested in this Shulgin guy. Expect a warrant for illicit posession of a category B precursor, acetone....


I don't see why not, he has basically shaped our modern laws with his categorizations. So they probably are interested in him.

And if they take me to court for acetone I don't even need a lawyer, 
Ab abusu ad usum non valet consequentia
A conclusion as to the use of a thing because of its abuse is invalid

Plus I won't be using acetone, Damascone has the same properties.


----------



## ShaggyFin

thenightwatch said:


> "oh hey, one of my idols is a man who is considered an enemy of the DEA.  wanna chat about it?"
> 
> /facepalm.



He's not an enemy, he is a FRIEND, that is my point. They don't hate him, they are just confused by him because he won't teach them anything more. He just says "I am a modest chemist at my work bench".


----------



## pharmakos

ShaggyFin said:


> I never said it did, I literally said I am not a chemist and that I would need help.



and yet when we try to help you, you don't listen



ShaggyFin said:


> He's not an enemy, he is a FRIEND, that is my point. They don't hate him, they are just confused by him because he won't teach them anything more. He just says "I am a modest chemist at my work bench".



so when the DEA raided Shulgin's house they were just coming over for tea and cookies?


----------



## ShaggyFin

thenightwatch said:


> so when the DEA raided Shulgin's house they were just coming over for tea and cookies?



No, they were making sure he wasn't doing anything illegal because they had no leads for anything anywhere and they know what he does.



thenightwatch said:


> and yet when we try to help you, you don't listen



I don't want help tearing myself a new asshole. I want help pondering what we can do with this. Ex: Medicine with better access across the BBB


----------



## pharmakos

ShaggyFin said:


> I don't want help tearing myself a new asshole.



no one is trying to tear you a new asshole.  if we're telling you that you're not ready to be attempting novel organic syntheses in your basement it is for your own good.  perhaps sad to you, but it is true.


----------



## ShaggyFin

thenightwatch said:


> no one is trying to tear you a new asshole.  if we're telling you that you're not ready to be attempting novel organic syntheses in your basement it is for your own good.  perhaps sad to you, but it is true.



Ok, thank you. 

I solemnly swear that I am not going to be attempting organic synthesis in my basement. I have a bible or a qu'ran or Pihkal and Tihkal if you would like me to swear on one of them.

You have brought that point home, can we move on now.


----------



## Solipsis

You can't expect to learn and get ahead if you are not able to tell right from wrong. That is absolutely necessary for the scientific / experimental method to find answers, otherwise there is no way of telling what is true or not.

If you refuse to accept all the things that are wrong here (which we have sound arguments for), it is hopeless. You would just be feeding your own fantasies, deluding yourself that things like alchemy are going to help you find what you are looking for.

So which is it? Are you just talking to yourself and convincing yourself that all of this will really work, evidence to the contrary? Or are you actually open to criticism?

Also LMAO @ acetone charges, that would be brilliantly ironic - cheers sekio


----------



## ShaggyFin

Solipsis said:


> You can't expect to learn and get ahead if you are not able to tell right from wrong. That is absolutely necessary for the scientific / experimental method to find answers, otherwise there is no way of telling what is true or not.
> 
> If you refuse to accept all the things that are wrong here (which we have sound arguments for, it is hopeless. You would just be feeding your own fantasies, deluding yourself that things like alchemy are going to help you find what you are looking for.
> 
> Also LMAO @ acetone charges, that would be brilliantly ironic - cheers sekio



No one is making any points about chemistry, everyone is just saying I personally don't know anything... So, I really don't think that this could be going any other way.


----------



## pharmakos

we didn't say you don't know anything.  we said you don't know nearly enough to be playing around with dangerous chemicals.

shaggy, i really think the best thing you can do to improve your life right now is take care of that warrant.  you seem to be in a hurry to get stuff done in your life, and waiting three years for that to go away is going to drive you batty.  the stress its causing already seems to be making you neurotic.

just a guess, though, of course i have no way of knowing that for sure.  but from my vantage point it seems that warrant looming over your head is probably a big source of strife for you.


----------



## ShaggyFin

thenightwatch said:


> i really think the best thing you can do to improve your life right now is take care of that warrant.  you seem to be in a hurry to get stuff done in your life, and waiting three years for that to go away is going to drive you batty.  the stress its causing already seems to be making you neurotic.



I really think I didn't come to discuss 100% legal fragrance strains to get advice for my legal situation. Anything that seems neurotic is because we are having 2 different discussions.


----------



## Solipsis

Oh thanks a lot dude, you already forgot things people explained about beta-ketones etc? It just happens to be so that you are out of your league and a lot you are trying to discuss doesn't make any sense. There is nowhere to go from there, except you realizing the truth about basic understanding of chemistry being absolutely necessary to participate in discussions like these. Sorry that you don't have any money to fix that, but the answer lies in getting chemistry eBooks and ones for other science subjects.

Then it requires years of studying, not playing around on a forum. If we could just skip all the studying we would all do it. You are not a genius that can just do without it. And if you are not willing to first do the hard work (let alone if you have the competencies to understand these matters) it just won't work.


----------



## ShaggyFin

Solipsis said:


> Oh thanks a lot dude, you already forgot things people explained about beta-ketones etc?



You seem to have forgotten that that was when this was it's own independent thread. I am now talking about the discussion HERE. I understand it was merged, but it is a new thread. And it seems people are just coming here for sport.


----------



## pharmakos

ShaggyFin said:


> I really think I didn't come to discuss 100% legal fragrance strains to get advice for my legal situation. Anything that seems neurotic is because we are having 2 different discussions.



fragrance strains aren't even how this conversation started, but okay.  feel free to post your ideas in this thread, but if what you are saying is incorrect don't get offended and accuse people of "trying to tear you a new asshole" when they simply are attempting to correct you.

love and peace.


----------



## ShaggyFin

thenightwatch said:


> fragrance strains aren't even how this conversation started, but okay.  feel free to post your ideas in this thread, but if what you are saying is incorrect don't get offended and accuse people of "trying to tear you a new asshole" when they simply are attempting to correct you.
> 
> love and peace.



The thread started with a discussion about creating aromatic compounds via what I was calling "Beta Ketoning" and everyone keeps harping on me on for not ever correcting myself and saying "Adding a Ketone in the Beta position". I get it. I have been corrected. 

Now, does anyone here ACTUALLY like to draw pictures of random molecules?


----------



## Solipsis

Regardless of which thread we are in, we tried to help you but you keep rejecting the judgement of several people (some of whom do have experience and knowledge in the field) that you are not ready to discuss the things you want to discuss. Yes we understand you don't like that, but that doesn't make it any less true. Otherwise you are being a child hearing only what he wants to hear.

Do you see me walking into a hospital barging into an operating room, looking at a swollen leg and saying random medical-sounding terms, making an completely inappropriate diagnosis and saying that I would like to cut the patient's leg off as treatment? No, they would be staggeringly confused, horrified and they would certainly hope I would never try to "cure" anyone again until I would finish medical training, if that.

@random molecules: maybe later


----------



## ShaggyFin

Solipsis said:


> Regardless of which thread we are in, we tried to help you but you keep rejecting the judgement of several people (some of whom do have experience and knowledge in the field)



No, I apologized various times and accepted correction (I didn't correct my pronunciation but I admitted when I was wrong) when we were talking about chemistry, you guys just wouldn't accept it and continued to harp on me.

The only thing I can't explain is the thing I read about moving things to their bk form with acetone. I can not find where I read that.


----------



## Solipsis

Is that the only thing? Alright fine, I dare you to produce the reaction mechanism to theoretically add chloroform to damascone. Use MS Paint for all I care.


----------



## sekio

Hint: it's not just _one _product, damascone is an a,B-unsaturated carbonyl, which will also undergo 1,4-addition reactions and maybe even a retro-aldol  ... double points if you can explain how to make the addition favour 1,2 over 1,4 addition.


----------



## ShaggyFin

Solipsis said:


> Is that the only thing? Alright fine, I dare you to produce the reaction mechanism to theoretically add chloroform to damascone. Use MS Paint for all I care.



I can't do it the way you want, but I can do it.

Damascone plays the role of Acetone, Chloroform plays the role of Chloroform. I don't know what the procedure is called, but there is a rule that when two (I think Alkyl Alcohols, I really wanted to wait till I had a book to do this) Aldehydes, or Alchols, etc are in the presence of each other and sodium, there is a reaction with the Sodium that causes the Hydrogen on the Chloroform and the Oxygen on the other one to react in a way that forms a new molecule with the two combined. In the case of Acetone and Chloroform, Chlorobutanol is formed. In the case of Damascone, Chloroscone would be formed.


----------



## pharmakos

inspired by ShaggyFin.... "beta-keto"-DMAA


----------



## ShaggyFin

thenightwatch said:


> inspired by ShaggyFin.... "beta-keto"-DMAA



See, this is more than I ever wanted. A molecule inspired by me. Lol. Usually it's the other way around.


----------



## sekio

2-aminoheptane is actually a stimulant, strangely, so that may not be too far off.


----------



## ShaggyFin

sekio said:


> 2-aminoheptane is actually a stimulant, strangely, so that may not be too far off.



And it doesn't seem too large, so it's possible it could be attached to an aromatic compound and not effect the sublimity.


----------



## ebola?

ShaggyFin said:
			
		

> The thread started with a discussion about creating aromatic compounds via what I was calling "Beta Ketoning" and everyone keeps harping on me on for not ever correcting myself and saying "Adding a Ketone in the Beta position". I get it. I have been corrected.



Sekio made several specific points about the chemistry you were discussing that you haven't engaged; I'd consider rereading his posts in this thread.  Also, I think that the decision to fold in your topic (which was essentially a repost of a prior closed thread) with this thread made a great deal of sense: this thread is for discussion of random molecular structures posed with little rationale, which is essentially what you were doing.

ebola


----------



## pharmakos

"sublimity" made me lol heh.  it definitely got your point across.    but the word you were looking for is "volatility" i believe.


----------



## Solipsis

Indeed DMAA is found in geraniums, so I can see the geraniol link.

The DMAA structure basically contains carbons linked in the same sort of pattern as amphetamine so it has a carbon that would match the beta position in amphetamine. So that is where TNW put a keto and nowhere else.

Neat man 

@SF: why and where would you want to attach an aromatic compound to it - please explain...


----------



## ShaggyFin

ebola? said:


> Sekio made several specific points about the chemistry you were discussing that you haven't engaged; I'd consider rereading his posts in this thread.  Also, I think that the decision to fold in your topic (which was essentially a repost of a prior closed thread) with this thread made a great deal of sense: this thread is for discussion of random molecular structures posed with little rationale, which is essentially what you were doing.
> 
> ebola



I will go back and read.

And I am not saying it was a bad decision to merge, I actually like the idea of people inventing their own things based on what I thought maybe could happen. Once I get my books and start theoretically playing with the Damascone and Myrcene Molecules, I hope that other people will find opportunities to play with structures from foods and plants they like. And we can have a future where drugs and alluring perfumes are one in the same.



thenightwatch said:


> "sublimity" made me lol heh.  it definitely got your point across.    but the word you were looking for is "volatility" i believe.



I understand that people talk a certain way in labs, but that scares people that hear about things made in labs. I understand this is pretentious but I want to make chemistry something that people are more comfortable with.



Solipsis said:


> Indeed DMAA is found in geraniums, so I can see the geraniol link.
> 
> The DMAA structure basically contains carbons linked in the same sort of pattern as amphetamine so it has a carbon that would match the beta position in amphetamine. So that is where TNW put a keto and nowhere else.
> 
> Neat man
> 
> @SF: why and where would you want to attach an aromatic compound to it - please explain...



That is awesome. So 2 natural compounds could end up working together if DMMA is natural. 

Attaching it to an aromatic compound would make it where the user could just have a small vial and take "wafts" of the substance. That way we can have a culture surrounding it that is not too "junky-ish". They won't be tieing off and doing rails. They will just be taking a few little sniffs for some pep, like coffee.


----------



## sekio

> I understand that people talk a certain way in labs, but that scares people that hear about things made in labs. I understand this is pretentious but I want to make chemistry something that people are more comfortable with.



You're not going to do that by making it impossible for anyone to understand you and talking like ye olde alchemysts. The jargon of chemistry exists for a reason, there are some complex concepts that are touched on.


----------



## pharmakos

they're not going to allow much more on the market in the way of inhalant stimulants.  i'm surprised Benzedrex hasn't already been pulled from the market.


----------



## ShaggyFin

sekio said:


> You're not going to do that by making it impossible for anyone to understand you and talking like ye olde alchemysts. The jargon of chemistry exists for a reason, there are some complex concepts that are touched on.



I understand there are certain names for certain things that make it where you can instantly understand what is happening. And when I get the books, I will all the sudden start using correct terms for different reactions, and talking about moles and all that bullshit. 

I really don't want to stop using the word "Sublimity" though because having a class of "Sublime Drugs" is what I am aiming for over the next 20 or so years.

Also, adding the DMMA to an aromatic compound could give it better reach across the Blood Brain Barrier.



thenightwatch said:


> they're not going to allow much more on the market in the way of inhalant stimulants.  i'm surprised Benzedrex hasn't already been pulled from the market.



Again, I understand the pretentiousness of what I am saying. But I hope to create a middle ground between the fragrance and drug markets. Women want to make people feel things with the way they smell, and we can do that now.


----------



## pharmakos

^ the structured i posted was based on DMAA, not DMMA btw.

re: women making people feel the way they smell.... i wonder if there are Oxytocin perfumes on the market.

----------------

my molecule from earlier, now cyclized for added toxicity:


----------



## ShaggyFin

thenightwatch said:


> ^ the structured i posted was based on DMAA, not DMMA btw.
> 
> re: women making people feel the way they smell.... i wonder if there are Oxytocin perfumes on the market.
> 
> ----------------
> 
> my molecule from earlier, now cyclized for added toxicity:



I totally know they have Oxytocin, and Mavicine or something like that, and others. Even Damascone is supposed to be an extremely potent ingredient. 

But let's put Oxytocin on Myrcene, then see what happens.


----------



## Solipsis

ShaggyFin: what do you think aromatic compounds are?

Can you give an example of an aromatic compound in the sense you meant?

By that I mean: why are you talking about taking wafts etc:



ShaggyFin said:


> Attaching it to an aromatic compound would make it where the user could just have a small vial and take "wafts" of the substance. That way we can have a culture surrounding it that is not too "junky-ish". They won't be tieing off and doing rails. They will just be taking a few little sniffs for some pep, like coffee.


----------



## ShaggyFin

Solipsis said:


> ShaggyFin: what do you think aromatic compounds are?



They are basically what we are talking about, minus the part where I said we should toy with the idea of adding things like 5-HTP to their extra spots, hence "Sublime Drugs".



Solipsis said:


> By that I mean: why are you talking about taking wafts etc:



I have been potentiating my Marijuana with Myrcene, so I was thinking "What if we slap THC and Myrcene together?" and that is what led me to the thoughts. THC is huge, and would probably be solid, but it would still have great ability to cross the BBB.

Then from there I thought about things like Opiod Peptide sniffers for addicts, instead of Methadone to get them high for a week.


----------



## pharmakos

ShaggyFin said:


> They are basically what we are talking about



that's not actually an answer


----------



## ShaggyFin

thenightwatch said:


> that's not actually an answer



They are Sublime materials, or liquid that vaporizes at room temperature or already gases. "Volatile" you guys would say.


----------



## Solipsis

Let me just lay it out anyway. It seems you are under the impression that aromatic compounds are chemicals that evaporate easily so that you can inhale them in wafts.

This is incorrect. Aromatic compounds are what they call chemicals that have a benzene-ring (also called phenyl ring) in their structure. Look up benzene ring.
The word you are looking for is ethereal or volatile.

Also will you finally abandon the idea of joining known active substance molecules together to create some sort of hybrid / siamese twins Frankenstein style? By now it has been explained countless times that is not how chemistry works.
Unless we are still doing things at random or just to have a laugh of course.

If you bind one chemical A with properties A to chemical B with properties B we do not get a chemical AB that has the properties of A and B added together. It forms a totally new chemical with - you can expect hardly related - properties C.
If you want to have the properties of A and B you just need to mix chemicals A and B together, this does not involve binding or any chemical reactions, just mixing like stirring.


----------



## pharmakos

^ indeed.

perhaps in simpler terms, shaggy -- whether or not a compound is "aromatic" in the chemical sense has nothing to do with whether or not it has a smell.  "aromatic" as a chemistry term is different than "aromatic" in its other day-to-day usage.

there are aromatic chemicals that have no smell, and there are non-aromatic chemicals that reek.


----------



## ShaggyFin

Solipsis said:


> Let me just lay it out anyway. It seems you are under the impression that aromatic compounds are chemicals that evaporate easily so that you can inhale them in wafts.
> 
> This is incorrect. Aromatic compounds are what they call chemicals that have a benzene-ring (also called phenyl ring) in their structure. Look up benzene ring.
> The word you are looking for is ethereal or volatile.
> 
> Also will you finally abandon the idea of joining known active substance molecules together to create some sort of hybrid / siamese twins Frankenstein style? By now it has been explained countless times that is not how chemistry works.
> Unless we are still doing things at random or just to have a laugh of course.



I understand that we can not expect to put a 5-HTP molecule on a Damascone, and suddenly have liquid that smells like roses and makes you happy. But we can see what happens, and we can create designer smells. So I am down for it.


----------



## ShaggyFin

thenightwatch said:


> ^ indeed.
> 
> perhaps in simpler terms, shaggy -- whether or not a compound is "aromatic" in the chemical sense has nothing to do with whether or not it has a smell.  "aromatic" as a chemistry term is different than "aromatic" in its other day-to-day usage.
> 
> there are aromatic chemicals that have no smell, and there are non-aromatic chemicals that reek.



When I say "Aromatic Compounds" I just mean the materials listed as "Backbones" here.
http://theresearchplanet.blogspot.com/2014/03/aromatic-compounds.html


----------



## Solipsis

ShaggyFin said:


> When I say "Aromatic Compounds" I just mean the materials listed as "Backbones" here.
> http://theresearchplanet.blogspot.com/2014/03/aromatic-compounds.html



That's not right, sorry. Many of those do not have phenyl rings (= benzene rings), so they are just not aromatic.


----------



## ShaggyFin

Solipsis said:


> That's not right, sorry. Many of those do not have phenyl rings (= benzene rings), so they are just not aromatic.



Which is my point. You are not understanding that I have over and over admitted I am not a chemist. And over and over said that I won't know any of this shit until I get books. I am talking about making FRAGRANCES that potentially have the ability to effect people.

This is the harping I am talking about.

I get it. I say shit wrong. But I am just saying "Compounds, that are Aromatic" or "Molecules that can get to your nose through the air with no heat needed to activate them"

And what if we just slap some Cinnemaldehyde on there, would that work for you? I have no idea if it's benzene, I'm NOT a chemist. And I won't know shit till the books come in.


----------



## pharmakos

ShaggyFin said:


> When I say "Aromatic Compounds" I just mean the materials listed as "Backbones" here.
> http://theresearchplanet.blogspot.com/2014/03/aromatic-compounds.html



this is what i meant earlier about your backpedaling.... "oh, i was actually right, i just said it wrong"... not gonna fool us =p

tbh shaggy i probably don't know a whole lot more about chemistry than you do... i just make few assumptions about the blank spots in my understanding.

as abraham lincoln supposedly said: "it is better to remain quiet and be thought a fool than it is to speak aloud and remove all doubt."

not that i think you're any less of a fool than i am   we're all together in this learning experience called life...



ShaggyFin said:


> Which is my point. You are not understanding that I have over and over admitted I am not a chemist. And over and over said that I won't know any of this shit until I get books. I am talking about making FRAGRANCES that potentially have the ability to effect people.
> 
> This is the harping I am talking about.
> 
> I get it. I say shit wrong. But I am just saying "Compounds, that are Aromatic" or "Molecules that can get to your nose through the air with no heat needed to activate them"



whoa, no need to get so defensive.  he wasn't harping, he was just correcting.  there's a difference.


----------



## Solipsis

It's not really a convenient combination to not be able to tolerate a politely worded correction and to also be wrong all the livelong day on the subject of chemistry.

The reality is that you will have to ask thousands of questions before being able to get anywhere near that goal, or alternatively presume that you know something and be corrected that many times. Sure you will also be right about things using your intuition and logic.

I am getting you to clarify yourself so that we can actually follow and understand what you are saying, suggesting, claiming and try to achieve.

About psychoactive fragrances: unfortunately it doesn't bode well that most known drugs do not taste or smell pleasant. DMT can have a flower-y attractive fragrance but that kind of chemical can also very easily start smelling like manure to a person, it's a fine line there.
I have seen methylone being sold in smartshops in my country with added vanilla scent to sell it under false pretenses. I suppose mixing a drug and a smell would be cheating to you?

Maybe some classical cannabinoids would be more along the lines of what you are looking for. The class THC etc are in?

Other than that myrcene sounds like the only one fitting the profile. You should research how it works pharmacologically, it is necessary to understand that so that you can infer how it may be modified and improved.


----------



## ebola?

Let's try to keep discussion on topic, guys.  Cluttering posts have been unapproved.
...


			
				ShaggyFin said:
			
		

> When I say "Aromatic Compounds" I just mean the materials listed as "Backbones" here.
> http://theresearchplanet.blogspot.co...compounds.html



But I still fail to understand what these molecular backbones share in common.  They're certainly not all volatile, nor are all of them even 'smelly'

ebola


----------



## ShaggyFin

ebola? said:


> Let's try to keep discussion on topic, guys.  Cluttering posts have been unapproved.
> ...
> 
> 
> But I still fail to understand what these molecular backbones share in common.  They're certainly not all volatile, nor are all of them even 'smelly'
> 
> ebola



They are used in perfume creation or flavoring, and to me they look like they all have a backbone similar to Myrcene. But again, I am not a chemist.


----------



## ebola?

> they look like they all have a backbone similar to Myrcene



But many of them do not.

ebola


----------



## ShaggyFin

ebola? said:


> But many of them do not.
> 
> ebola



They all look long and strong though and have points of attachment. So when I say I am creating a "new family" I am not referring to some "old family" that I am turning into new things. I am referring to a new family of compounds that will be made from those backbones. They will break apart, they will meet in new arrangements, they will break apart again, and they will meet again in again new arrangements.

I am not suggesting we create novel bullshit like Chlorobutanol every time, like that is just what I feel comfortable saying "I know I can do" right now. When I get the hang of reading these "Heiroglyphs" I will be proposing some WAY cooler stuff.


----------



## ebola?

> They will break apart, they will meet in new arrangements, they will break apart again, and they will meet again in again new arrangements.



A chemical family is not analogous to a literal family in this way though: unless they share some key structural similarity, they are in no meaningful sense in a family, regardless of their origins in particular chemical reactions or the conceptual genealogy that inspired them.

ebola


----------



## ShaggyFin

ebola? said:


> A chemical family is not analogous to a literal family in this way though: unless they share some key structural similarity, they are in no meaningful sense in a family, regardless of their origins in particular chemical reactions or the conceptual genealogy that inspired them.
> 
> ebola



I understand that, and I may end up having to reclassify it as MANY families once I actually start trying to figure out more than just Damascone. But I want to try to break down Myrcene and Damascone and put them together, then use that as the main backbone for everything.

I found a simpler route to getting started here, cheaper and easier to get than Damascone, and can be made into Damascone. In fact, Damascone is in this chemical family. lol.
http://en.wikipedia.org/wiki/Ionone





Myrcene is also cheap. So this looks like it's going to be moving forward soon.


----------



## sekio

Please, learn some practical chemistry before you start getting too excited.

That's all I have to say on that matter. If you're confident you're going to come back in two weeks and be a trained organic chemist, do that, don't waste our fucking time by just spinning your wheels and masturbating. You've produced nothing of note and only managed to argue that you know enough to play with the big boys but without any training or similar knowledge base.


----------



## ShaggyFin

sekio said:


> Please, learn some practical chemistry before you start getting too excited.
> 
> That's all I have to say on that matter. If you're confident you're going to come back in two weeks and be a trained organic chemist, do that, don't waste our fucking time by just spinning your wheels and masturbating. You've produced nothing of note and only managed to argue that you know enough to play with the big boys but without any training or similar knowledge base.



You guys take everything to the extreme.
I am not saying that in 2 weeks I will be a trained organic chemist, I am saying that in 2 weeks I will understand enough to start drawing new stable structures.

Just thought I would add this, I am making a collection here of all the (not too hard to find) molecules that can be used.
http://en.wikipedia.org/wiki/Ammonia


----------



## pharmakos

finn, play around with this http://www.webqc.org/moleculareditor2.php

it can even check your structure to see if you drew the molecule right, and spit out an IUPAC name for whatever you draw


----------



## ShaggyFin

thenightwatch said:


> finn, play around with this http://www.webqc.org/moleculareditor2.php
> 
> it can even check your structure to see if you drew the molecule right, and spit out an IUPAC name for whatever you draw



Thank you, I did not know things like that even existed.

My God, I just looked up Oxytocin and it's wild


----------



## Transform

ShaggyFin said:


> You guys take everything to the extreme.
> I am not saying that in 2 weeks I will be a trained organic chemist, I am saying that in 2 weeks I will understand enough to start drawing new stable structures.
> 
> Just thought I would add this, I am making a collection here of all the (not too hard to find) molecules that can be used.
> http://en.wikipedia.org/wiki/Ammonia



I can't wait to see what fine aromas your generate from ammonia.

Please can you adjust wikipedia image URLs so that they are shrunk to around 300-400 pixels. just change the  the [xxx]px in the url.

I recommend you take a coursera course on chemistry. I can also assure you that there are some very talented chemists even in community colleges. Regardless of whether they have failed at DOW (like Shulgin did, in a way) they will be able to teach you a LOT.


----------



## ShaggyFin

Transform said:


> I can't wait to see what fine aromas your generate from ammonia.
> 
> Please can you adjust wikipedia image URLs so that they are shrunk to around 300-400 pixels. just change the  the [xxx]px in the url.
> 
> I recommend you take a coursera course on chemistry. I can also assure you that there are some very talented chemists even in community colleges. Regardless of whether they have failed at DOW (like Shulgin did, in a way) they will be able to teach you a LOT.



Ammonia will not be a main structure, it will be a catalyst for other structures.

I don't have money for school. And I'm not going into debt because some people online think I need to learn fundamentals from a teacher.

I looked it all up, less than $1000 and we could be doing this shit, if ya'll were down to fund a company we could all even do it like next month and this wouldn't even just be a discussion. But I'm gonna go it alone, plus just get bitched at the whole time I guess.


----------



## sekio

> Regardless of whether they have failed at DOW (like Shulgin did, in a way)



Shulgin didn't "fail" at Dow Chemical, he invented a pesticide that made them money and then they continued to pay him until he got too heavily into drug synthesis. Sounds like a winner to me.


----------



## ShaggyFin

sekio said:


> Shulgin didn't "fail" at Dow Chemical, he invented a pesticide that made them money and then they continued to pay him until he got too heavily into drug synthesis. Sounds like a winner to me.



I was going to say something but thought it would just lead to more flaming, Shulgin definitely was not a "failed DOW chemist". He made medicine as we know it, he just doesn't get the recognition.


----------



## SeenSoFar

I'm sorry. I've held my tongue as long as I can. I can no longer. Forgive me in advance for my first loss of temper on this forum, if you would be so gracious.



ShaggyFin said:


> I was going to say something but thought it would just lead to more flaming, Shulgin definitely was not a "failed DOW chemist". He made medicine as we know it, he just doesn't get the recognition.



NO. NO. Just... NO. He did not make medicine as we know it. Not. Even. Close. You do realize he eschews SAR(that's structure-activity relationship)-based predictions on the activity of any given compound- which is the foundation of modern drug discovery- for a "make 'em and taste 'em" approach- which is the antithesis of how things are done in the labs of "big pharma"- right? You also realize that the pharmaceutical industry was already quite robust long before he ever produced a compound for human consumption?  Yes, he did discover lots of fantastic compounds that target 5-HT2A, but he did NOT INVENT MODERN MEDICINE. Saying that Shulgin invented medicine as we know it is like saying Colonel Sanders invented cuisine as we know it. So NO. Just... No.

Furthermore, you realize that I- as well as many of the geniuses you have belittled in your incoherient ramblings, I'm sure- was reduced to tears of laughter by your nonsensical gibberings, and then stoked to more anger than I believed I could feel from something as inconsequential as this by your total lack of respect for people who command it! Do you realize that, in my opinion, have poluted 7 FUCKING PAGES of what used to be a thread full of the light-hearted exchange of ideas between those who wanted to learn and those who had something of value to teach. Give you a hint: you're definitely not the latter, and although you've claimed otherwise, neither are you the former, since you consistently shit all over the very people who are trying to help you and have shown more patience with you than I believed was left in this world.

The very concept that you think throwing random-ass organic compounds into a pot is going to achieve anything other than making a mess, especially when you've admitted yourself that you know jack-shit about chemistry, including not being able to read a skeletal formula, repeatedly misusing and/or bandying around miscellaneous jargon (lmao at "decarboxylizing" in the context you applied it in), and then subsequently claiming you WILL be setting up a perfume company/supplement company IN THE NEXT FEW WEEKS. Somehow you will equip your "ghetto lab," despite the fact you can't afford much beyond food (your own statement). I look forward to seeing pictures on the news of the dumbass who got arrested for possession of controlled precursors in a lab that I'm sure would horrify even a bathtub crank chemist. Here's another hint for you: a range hood is not a fume hood, no matter how similar in form and function they appear to be.

To sum it all up: You're a fucking moron. You don't know shit about what you're talking about, and you're oblivious to that fact no matter how many times its painted in 500m high letters directly in front of you. You know what though, all of that is forgivable. You know what isn't? Mouthing off people who come to try and help you achieve your goals, no matter how half-baked said goals may be.

In conclusion, there's a phrase I heard from an old AA'er that applies FLAWLESSLY to this situation: Take the cotton out of your ears and put it in your mouth. It will do you far more service there. QED.


----------



## ShaggyFin

SeenSoFar said:


> I'm sorry. I've held my tongue as long as I can. I can no longer. Forgive me in advance for my first loss of temper on this forum, if you would be so gracious.
> 
> 
> 
> NO. NO. Just... NO. He did not make medicine as we know it. Not. Even. Close. You do realize he eschews SAR(that's structure-activity relationship)-based predictions on the activity of any given compound- which is the foundation of modern drug discovery- for a "make 'em and taste 'em" approach- which is the antithesis of how things are done in the labs of "big pharma"- right?



You realize that synthesis and testing are not the main parts of Pharma, right? Look at the families they use Piperazines (Abilify), etc. And before Shulgin "Mood Stabilizers" were called Sedatives or Euphoriants, because he brought ideas like "Psychedelic" and "Entactogen" to the forefront of human thought and they took it from there. 

Sure all the main stuff he was playing with is illegal now, but that is not at all because of him. If you look at medicine it is OBVIOUS they have carried Shulgin's wisdom. We would not know HALF of what we know about receptors without him. Chopra's (and his group's) discoveries of "Chemical Emotions" would have been impossible without Shulgin as a "precursor".


----------



## sekio

> You realize that synthesis and testing are not the main parts of Pharma, right?



Well, yeah, it's 2/3 of pharma's job to do drug discovery, the rest is marketing. Someone still had to make and screen a fuckload of compounds to come up with drugs like Abilify etc. Just because a compound is a piperazine doesn't mean it's intrinsically easy to make. Viagra is a piperazine and that's hardly a trivial synthesis...



> And before Shulgin "Mood Stabilizers" were called Sedatives or Euphoriants, because he brought ideas like "Psychedelic" and "Entactogen" to the forefront of human thought and they took it from there.



The term "psychedelic" was coined by Humprey Osmond 1n 1957, before Shulgin's work on mescaline analogs. You credit the man too much. He hardly brought anything to the "forefront" of society, that was people like Hunter Thompson,the Beatles, Ken Kesey and R. Gordon Wasson etc.



> If you look at medicine it is OBVIOUS they have carried Shulgin's wisdom. We would not know HALF of what we know about receptors without him.



He discovered a bunch of novel psychedelics, ate them, distributed them, and that's pretty much where it stopped... AFICT Dave Nichols was the guy who actually did receptor binding studies. And there's really a larger cast of characters in the GPCR family. 



> In conclusion, there's a phrase I heard from an old AA'er that applies FLAWLESSLY to this situation: Take the cotton out of your ears and put it in your mouth. It will do you far more service there. QED.


please


----------



## Transform

I should have clarified that more. Certainly I regard shulgin as a success but I am not sure that DOW feel the same and I didn't know how you were defining that. 

But yes; less talk of ammonia "catalysing" fragrance structures and more listening, please.


----------



## SeenSoFar

ShaggyFin said:


> You realize that synthesis and testing are not the main parts of Pharma, right? Look at the families they use Piperazines (Abilify), etc. And before Shulgin "Mood Stabilizers" were called Sedatives or Euphoriants, because he brought ideas like "Psychedelic" and "Entactogen" to the forefront of human thought and they took it from there.
> 
> Sure all the main stuff he was playing with is illegal now, but that is not at all because of him. If you look at medicine it is OBVIOUS they have carried Shulgin's wisdom. We would not know HALF of what we know about receptors without him. Chopra's (and his group's) discoveries of "Chemical Emotions" would have been impossible without Shulgin as a "precursor".



First off, props on totally ignoring everything that you feel you don't have an adequate rebuttal for, you would do fabulously as a half-baked independent political candidate. Second of all, major props for COMPLETELY MISUNDERSTANDING the most basic of concepts in the field you insist you are entering commercially imminently. Although I'm not sure why I'm bothering; since you're just going to flip-flop and say my explanation is exactly what you meant all along and we're all just too plebeian to understand you; but let me break it down for you:

1. Mood stabilizers and sedatives/euphoriants are NOT the same thing. Just because some compounds have been reclassified or additionally classified between said categories does not mean anything intrinsically.

2. Psychedelics and empathogen/entactogens have nothing to do with mood stabilizers or sedatives. Mood stabilizers often exert their effects through voltage-gated sodium channels and/or the GABAergic system. Psychedelics and empathogen/entactogens have literally the opposite effect of the compounds you have compared them to and act on the monoaminergic system.

Furthermore, as Sekio said, there is absolutely no correlation between Shulgin and any of what you just said. You say everything you have stated is so OBVIOUS and self-evident, and yet I have seen no sources presented or arguements made other than its just so obvious that Shulgin is the one true god of pharmacology and modern medicine. Don't get me wrong, I have lots of respect for the man, and I consider him a genius, but he did not do what you are stating. I have a feeling that if he were to read what you have stated here, he would be none-too-happy, since people like him have a strong sense of "credit where credit is due." I'm sure he would tell you to do some more research before speaking on a subject you clearly know less than nothing about. Yes, your knowledge is actually negative in this field, since you have about a hundred thousand misunderstood, ill-conceived, and downright WRONG ideas on this subject and you refuse to be educated by those who know more than you.

One more thing: what, pray-tell, is the main parts of the pharmaceutical industry if not SAR-based rational drug design, synthesis, and bioassay? Again, you don't bother to read the arguements you are trying to rebut, since you mention that synthesis is not the main part of the pharmaceutical industry, when I clearly said that SAR-based drug discovery is an important facet. I feel like I'm talking to a child here... Your arguements are refuted over and over, and yet you keep drumming on them ad nauseam. 

By the way, I think its so hilarious that you commented that you believe you're on a government watch-list for making a plaintext list of random-ass compounds...


----------



## MrPorter

Shaggy, you talk of these volatile compounds that you huff for a quick trip and yet you're set on whacking carbonyls everywhere. I'll give you some examples. 
Amphetamine: 11.3C mp, 203C bp
Methamphetamine: 3C mp, 212C bp

Ephedrine (beta-hydroxy methamphetamine): 188C mp
Noradrenaline (beta-hydroxy phenethylamine with some more hydroxyls): 217C mp, 442C bp

Admittedly these are hydroxyls and not C=O s but just chucking on Oxygens increase intermolecular forces, increases boiling point, decreases volatility. 

Now, Nitrous Oxide and Xenon are both gases at room temperature and both have a fairly short lasting high. I think I read Xenon can last up to 30 minutes but can't confirm it.

Fragrances tend to smell nice, so amines are out along with thios. This automatically means we aren't looking for alkaloids. THC, CBD, alcohols (GHB/GBL/EtOH) and Salvia don't have Nitrogens. They're the only ones I can think of right now. Salvias pretty short lasting, weed gets you stoned for a couple hours tops when smoked, yet hours on end when eaten. Maybe this is a way forward?

But wait! Alas, your beloved Myrecene almost matches up with LSD's semi-backbone. With just an extra Carbon in that Myrecene, it would fall perfectly on top (ignoring the amide's N)








I don't think closed ring bk-DMAA is closed enough, maybe we need this




My only worry with this is that it closely resembles LEGO, and I wouldn't like to swallow those sharp pointy edges.


Offtopic here but why do cokes esters not just hydrolyse in acidic conditions, or is that why coke is shit orally and not any other route?


----------



## pharmakos

MrPorter said:


> I wouldn't like to swallow those sharp pointy edges.



and those corners would probably be especially hard on the nasal cavity :D


----------



## SwampFox56

@ShaggyFin

You may now a bit of chemistry, but you utterly lack ANY knowledge of pharmacology. Just because a chemical is stable, doesn't mean it will be pharmacologically active. You also have no idea what this chemical is going to do in the body. It may have the desired psychoactive effects, but it's pharmacokinetics could be fucked beyond belief (like PMA) which just just results in the drug being poison rather than a psychoactive. 

You have totally left one huge, important factor out of all of your rambling, incoherient responses. The chemistry doesn't matter, THE BODY is what matters. You have to synthesize chemicals that will play nice in the body. Then you have to tweak that so it can be polar/non-polar enough to cross the BBB. Then you have to make sure it doesn't have neurotoxic effects. Etc. 

Most everything you've said, is quite possibly some of the dumbest things I have ever heard. At no point in any of your rambling, incoherient responses did I hear anything that could be considered a rational thought. Everyone in this thread is now dumber having read it. I award you no points, and may god have mercy on your soul.


----------



## Bagseed

not sure, if he is trolling or not....

either way, BoBL imo.


----------



## sekio

> Offtopic here but why do cokes esters not just hydrolyse in acidic conditions, or is that why coke is shit orally and not any other route?



They do hydrolise, that's why cocaine needs to be kept dry, has a short half life, and is best not taken orally.


----------



## ShaggyFin

Alright, so I have been doing some reading on fragrances today, and since there are a few things that can be extracted straight from plants at 80%+ purity (some as high as 95% even with other substances present) I am going to start with full spectrum steam distillation extracts, and all directly natural compounds except for the solvents. 

Benzoin Gum has Benzoic acid as the main ingredient, so I will use that to Benzylate things and make them "Aromatic" (I'm pretty sure that fits your definition), or just to see what happens. So, now I can talk about something besides the Chloroscone model.

But I have a question.

I was just reading online (citation for anyone that needs one http://www.rollitup.org/cooking-cannabis/286271-acetone-denatonium-benzoate-hash.html) that when someone made their hash with Acetone/Denatonium Benzoate and it made the hash bitter (I assume they tried it because they give an example), they commented that Denatonium Benzoate is used to Denature alcohol, and maybe "Denatured" the THC. But I am pretty sure that this is a wrong use of "Denatured", because the Alcohol is not effected molecularly it is just made nasty and maybe poisonous because they added a poisonous substance in with the alcohol.

I have a theory that Benzoic Acid would have similar effects to whatever the Denatonium Benzoate would do, but not so extreme as far as bad smell, etc. Creating a "THC Benzoate" Molecule. My theory is that this would be a much more Aromatic Molecule than plain THC, and could be used for Fragrance in states where Cannabinoids are legal.



MrPorter said:


> Shaggy, you talk of these volatile compounds that you huff for a quick trip and yet you're set on whacking carbonyls everywhere. I'll give you some examples.
> Amphetamine: 11.3C mp, 203C bp
> Methamphetamine: 3C mp, 212C bp
> 
> Ephedrine (beta-hydroxy methamphetamine): 188C mp
> Noradrenaline (beta-hydroxy phenethylamine with some more hydroxyls): 217C mp, 442C bp
> 
> Admittedly these are hydroxyls and not C=O s but just chucking on Oxygens increase intermolecular forces, increases boiling point, decreases volatility.
> 
> Now, Nitrous Oxide and Xenon are both gases at room temperature and both have a fairly short lasting high. I think I read Xenon can last up to 30 minutes but can't confirm it.
> 
> Fragrances tend to smell nice, so amines are out along with thios. This automatically means we aren't looking for alkaloids. THC, CBD, alcohols (GHB/GBL/EtOH) and Salvia don't have Nitrogens. They're the only ones I can think of right now. Salvias pretty short lasting, weed gets you stoned for a couple hours tops when smoked, yet hours on end when eaten. Maybe this is a way forward?
> 
> But wait! Alas, your beloved Myrecene almost matches up with LSD's semi-backbone. With just an extra Carbon in that Myrecene, it would fall perfectly on top (ignoring the amide's N)
> 
> 
> 
> 
> 
> 
> 
> 
> I don't think closed ring bk-DMAA is closed enough, maybe we need this
> 
> 
> 
> 
> My only worry with this is that it closely resembles LEGO, and I wouldn't like to swallow those sharp pointy edges.
> 
> 
> Offtopic here but why do cokes esters not just hydrolyse in acidic conditions, or is that why coke is shit orally and not any other route?



I like you.

Not sure about the coke thing, but thank you for bringing up all the other things. I'm not sure how to reply (because I am pretty sure most of what you said is a joke), but if the things about Amphetamine and Ephedrine changes are true, then this could be something more than just new smells.



SwampFox56 said:


> @ShaggyFin
> 
> You may now a bit of chemistry, but you utterly lack ANY knowledge of pharmacology. Just because a chemical is stable, doesn't mean it will be pharmacologically active. You also have no idea what this chemical is going to do in the body.



I'd say you have it backwards, I have NO understanding of chemistry but have a FAIR understanding of Pharmacology. And I already said that I can't guess at what the compounds will do and I said most of the things I make won't be active. And I said that I can only guess that _something_ will happen when 5-HTP or something is added, but I can not guess what that _something _is.

But thank you for reiterating.


----------



## sekio

> Creating a "THC Benzoate" Molecule. My theory is that this would be a much more Aromatic Molecule than plain THC, and could be used for Fragrance in states where Cannabinoids are legal.



THC is already an aromatic compound. You'll have a hard time making the benzoate ester with just benzoic acid as phenols are too acidic to be used in a Fischer esterification. More importantly, adding a relatively large benzoic acid group to a basically non-volatile compound isn't going to make it smellier. Fragrances have to be volatile, and starting with a heavy nonvolatile molecule and adding molecular weight won't make it *more* volatile.

Less essential oils chemistry and more drugs pls. Seriously Shaggy.





Sila-tramadol, inspired by that "silicon replacing carbon" thread.


----------



## ShaggyFin

sekio said:


> Less essential oils chemistry and more drugs pls
> 
> 
> 
> 
> 
> Sila-tramadol, inspired by that "silicon replacing carbon" thread.
> 
> 
> 
> THC is already an aromatic compound. You'll have a hard time making the benzoate ester with just benzoic acid as phenols are too acidic to be used in a Fischer esterification. More importantly, adding a relatively large benzoic acid group to a basically non-volatile compound isn't going to make it smellier. Fragrances have to be volatile, and starting with a heavy nonvolatile molecule and adding molecular weight won't make it *more* volatile.



THC alone is fairly non Aromatic as far as human senses, so I just meant that it could make it easier to smell. Which was demonstrated by the guy that says it makes hash "stinky", it might just be unlocking the air diffusion capability.

And I didn't mean just stick THC in Benzoic acid, but once I get the Chemistry books I will be able to speak on how Oxygen can be made to react (using some kind of solvent or something as a catalyst) with Hydroxide, or Hydrogen with Oxygen, or Hydroxide with Hydroxide, or Hydroxide with Hydrogen, or what H3C is on a molecule as far as react-ability because it doesn't exist as a lone structure. I understand that to you guys it is probably extremely like blatant, but I am not a chemist.


----------



## pharmakos

_something_ is likely to happen when you "slap together" two active molecules.... but that something is likely that you will make the two chemicals pharmacologically inactive.


----------



## ShaggyFin

thenightwatch said:


> _something_ is likely to happen when you "slap together" two active molecules.... but that something is likely that you will make the two chemicals pharmacologically inactive.



Ok, you have guessed further than me at this point. And again, I said I would be happy if I just invented a few new smells.


----------



## ebola?

> THC alone is fairly non Aromatic as far as human senses, so I just meant that it could make it easier to smell.



Aromaticity does not reliably confer an aroma to substances.  This is why everyone finds your chosen terminology problematic.



> I understand that to you guys it is probably extremely like blatant, but I am not a chemist.



Why not read up on some of the basics and get back to us?  I mean, I'm just a sociologist, so you clearly don't need some set of specific credentials to post in here, but conversation proves more fruitful if everyone involved has some idea of whether their ideas are plausible.

ebola


----------



## ShaggyFin

ebola? said:


> Aromaticity does not reliably confer an aroma to substances.  This is why everyone finds your chosen terminology problematic.


I understand that it sounds like I am saying that adding an aromatic compound will make it more aromatic, but THC is so large that I would not make this assumption without having read someone's opinion that THC Benzoate is "Stinky".

*EDIT*
I misread he said it made it "bitter" not "stinky". So I am probably wrong on that.



ebola? said:


> Why not read up on some of the basics and get back to us?
> ebola



I will get back to you when I read some basics, but I will share my progress up until then as well. I am sorry, someone else merged this thread with a more popular one. It was just meant to be a discussion about the idea, and the progress towards it and the eventually testing.


----------



## pharmakos

^ i think the bitterness was likely due to an impurity he introduced, not due to an actual chemical change to the THC itself.


----------



## ShaggyFin

thenightwatch said:


> ^ i think the bitterness was likely due to an impurity he introduced, not due to an actual chemical change to the THC itself.



Maybe, but I still feel like there is something in a Cannabinod/Benzoic Acid reaction, some kind of change, if the right catalyst is there. And THC NEEDS to be explored more.


----------



## sekio

> And THC NEEDS to be explored more.



Check the literature before you make such claims: there have been hundreds of analogs and derivatives of THC made and characterised ever since Mechoulam's initial work. Even THC benzoate has been already done.

You can often search compounds by their IUPAC names on PubMed.



> ^ i think the bitterness was likely due to an impurity he introduced, not due to an actual chemical change to the THC itself.



Correct, the bitterness is due to the presence of the fairly stable denatonium benzoate, which is sold commercially as Bitrex, and is the most bitter compound known to man (percieved at even a few parts per million). It's nontoxic but tastes awful because denatonium selectively activates the bitter taste receptors on your tongue. It is regularly used to make denatured alcohol because it won't kill people who consume large amounts, just make them sick.


----------



## ShaggyFin

I just found an interesting acid, could be helpful in catalyzing some interesting things, it's a basically Benzoic acid structure with extra Hydroxides for extra fun (meaning possibilities).
http://en.wikipedia.org/wiki/Gallic_acid







sekio said:


> Check the literature before you make such claims: there have been hundreds of analogs and derivatives of THC made and characterised ever since Mechoulam's initial work. Even THC benzoate has been already done.
> 
> You can often search compounds by their IUPAC names on PubMed.



I'm saying it needs to be done on a larger scale. Soon I will be teaching people in the Cannabis section that they can use their Extraction "Contaminates" to possibly make Designer forms of THC. Then from their, it's a whole new ball game, everyone will be playing with THC's (and other Cannabinoids) structure(s).


----------



## pharmakos

i wouldn't consider wild, misinformed speculation to be "teaching"... perhaps you should stick to just learning for now, bud.


----------



## ShaggyFin

thenightwatch said:


> i wouldn't consider wild, misinformed speculation to be "teaching"... perhaps you should stick to just learning for now, bud.



I am sticking to learning for now, until I can start drawing random molecules and sharing the concept with others.


----------



## ShaggyFin

I was just thinking about THC Benzoate while listening to 2 Chainz "Hit it with the fork" which is about cooking crack.





So I decided to look up what "Crack" actually is, because there has to be a difference between Cocaine and Crack. So I looked up the two molecules.
Cocaine






Baking Soda (Sodium Bicarbonate)





And it looks like Bicarbonate (Baking soda) is actually an acid or alcohol type structure with lots of reactable oxygens/hydrogens, but it has a magnetic change because a Sodium is polarized to it (not sure if that is the right word), so in essence when you use baking soda you are hitting it with Oxygen, and something that Catalyzes change (Sodium in the presence of certain things makes them change), basically making Cocaine Bicarbonate.

And this reminded me of some stuff I read about Toad Venom (Bufotenine) which when smoked in its natural acidic form (5-Hydroxy-DMT) it has too many react-able oxygens, but when you mix it with edible lime it becomes safe to use (basically the same as DMT) because the Hydroxy is neutralized by being attached to parts of the edible lime.

Now, my question is... With those 2 loose Hydrogens waving around (15 in total actually, I just don't understand what H3C is and how it reacts, because it is not an independent structure), and a Hydroxide (OH) sticking out like a sore thumb, and that oxygen hiding underneath... 





Has anyone ever tried THC in its base form?


----------



## sekio

> And it looks like Bicarbonate (Baking soda) is actually an acid or alcohol type structure with lots of reactable oxygens/hydrogens, but it has a magnetic change because a Sodium is polarized to it (not sure if that is the right word), so in essence when you use baking soda you are hitting it with Oxygen, and something that Catalyzes change (Sodium in the presence of certain things makes them change), basically making Cocaine Bicarbonate.



No. Wrong, wrong wrong and wrong again. Bicarbonate is not an alcohol, there's no magnetic charge on bicarbonate, cocaine bicarbonate isn't a stable compound,* it's not even sodium that is catalysing the change*, etc. 



> And this reminded me of some stuff I read about Toad Venom (Bufotenine) which when smoked in its natural acidic form (5-Hydroxy-DMT) it has too many react-able oxygens, but when you mix it with edible lime it becomes safe to use (basically the same as DMT) because the Hydroxy is neutralized by being attached to parts of the edible lime.



Bufotenine is quite smokeable as a freebase, it's only for snuff/nasal use you have to make it into a salt.



> Has anyone ever tried THC in its base form?



That's how it usually is. (It's not an alkaloid.)

Seriously Shaggy, *stop posting here*, and go take a chemistry course. Your rambling serves only to derail an otherwise fine thread. *This is a formal warning.* This thread is meant to be random drug structure doodles, not people trying their best to learn chemistry by continually posting incorrect shit over and over.


----------



## ShaggyFin

sekio said:


> No. Wrong, wrong wrong and wrong again. Bicarbonate is not an alcohol, there's no magnetic charge on bicarbonate, cocaine bicarbonate isn't a stable compound, etc.
> 
> 
> 
> Bufotenine is quite smokeable as a freebase, it's only for snuff/nasal use you have to make it into a salt.
> 
> 
> 
> That's how it usually is. (It's not an alkaloid.)
> 
> Seriously Shaggy, *stop posting here*, and go take a chemistry course. Your rambling serves only to derail an otherwise fine thread. *This is a formal warning.* This thread is meant to be random drug structure doodles, not people trying their best to learn chemistry by continually posting incorrect shit over and over.



As I have said before, I know I word things wrong. (and if you want to correct me, do so, don't just say "wrong wrong wrong")

But you are acting as if crack does not exist.

And I didn't come to this thread, I was merged here. Sorry for whatever inconvenience I have cause by being in your doodle thread. I will be doodling myself soon. I can go make my own thread, but I am sure I would be just sent back here for posting about molecules that don't exist.


----------



## SkyblueMolly

Here's a picture for flodafinil, a hypothetical experimental nootropic.





Here's a picture of what would happen if S-18,986 and amphetamine had a baby.





The next to last one is 2C-D-racetam, a hyperthical supernootropic based on 2C-D's nootropic effects at sub-psychedelic doses and the racetams having general nootropic effect. It might cause hallucinations at higher doses.





And the last one is a modified tametraline molecule. It might be a triple reuptake inhibiter, sort of like indanylaminopropane and MDxA.


----------



## SwampFox56

ShaggyFin said:


> As I have said before, I know I word things wrong. (and if you want to correct me, do so, don't just say "wrong wrong wrong")
> 
> But you are acting as if crack does not exist.
> 
> And I didn't come to this thread, I was merged here. Sorry for whatever inconvenience I have cause by being in your doodle thread. I will be doodling myself soon. I can go make my own thread, but I am sure I would be just sent back here for posting about molecules that don't exist.



You don't understand. A chemical HAS TO BE volatile in order to be smoked. Otherwise, the combustion will just destroy the molecule.


----------



## SeenSoFar

Thank you Sekio, I for one really appreciate you issuing a warning to that guy. He was really getting under my skin with his total inability to accept being corrected. I really just LOL'ed like crazy here in the Ikea cafeteria when I read his accusation that you were claiming crack doesn't exist. The SIMPLEST of searches into crack would have rectified his misunderstandings, but it seems his M.O. is to make up an explanation for things and then defend said explanations to the death whenever he encounters a concept he is unfamiliar with. Thanks again Sekio, we're all lucky to have you!

Anyway, with that lunacy out of the way, I have some new skeletal formulae to post when I get home in a little while. Some are hilarious, some are frightening, others are intriguing! Stay tuned for another mind-expanding episode of "SeenSoFar high and playing with ChemDraw!"

On Fognl


----------



## sekio

> As I have said before, I know I word things wrong. (and if you want to correct me, do so, don't just say "wrong wrong wrong")
> 
> But you are acting as if crack does not exist.



You are not "wording things wrong". You don't actually understand what is happening and you are bullshitting.

Crack is not cocaine bicarbonate. That would make it a salt (positively charged nitrogen and negatively charged counterion). The process of making crack starts with cocaine hydrochloride (aka "powder cocaine"), which technically speaking is a mixture bound at a molecular level of 1 part hydrogen chloride and 1 part cocaine, with the H of the hydrogen chloride being transferred to the N of the cocaine, making a charged compound. Because it's charged, the forces holding individual molecules together are stronger (explaining the higher melting point and why it just decomposes before it boils), and it has a large dipole which allows it to dissolve in polar solvents like water. 

The hydrogen transferred to the nitrogen on cocaine can be "removed" by reacting it with a base of some sort - any compound that has an affinity for "free" positively charged hydrogen atoms. This does not have to be bicarbonate, it's just the cheapest and most available base for most people. Other bases like calcium carbonate (chalk), calcium hydroxide (slaked lime, what Peruvians chew along with their coca leaf), sodium hydroxide, even ammonia will work too. The hydrogen chloride is "unbound" from the cocaine when it encounters a compound which would bind it tighter (is a stronger base). This reverts cocaine hydrochloride to "free base" cocaine and, if bicarbonate is used, sodium chloride, water, and carbon dioxide. 

See also, acid/base reactions and acid base extractions.

Free base cocaine has a much smaller dipole (is less polar) than cocaine salts are, and can't hydrogen bond very well (hydrogens attached to carbons are too tightly bound), so it prefers to dissolve in organic solvents rather than water, and if there's no organic solvents it will crystallize out. (or layer out as an oil, if the temperature is high enough). Its melting point and boiling point are lower and it can actually be "boiled" with minimal decomposition, because the intermolecular attractions are much weaker (as the free base is not electrically charged).

The base doesn't have to be sodium - sodium does not catalyse anything. You could use lithium hydroxide, potassium carbonate, ammonia, DBU, etc. and you'd still get crack. The base need not contain any oxygen at all. If you want to get risky you could also use sodium metal...

Nowhere does magnetism come into play. Sodium bicarbonate isn't magnetic, nor is cocaine. Nothing is "polarized to" anything else either. In fact, the ions in a dissolved salt can move freely amongst each other. It's only when they become a solid that it takes on a defined lattice.



> And this reminded me of some stuff I read about Toad Venom (Bufotenine) which when smoked in its natural acidic form (5-Hydroxy-DMT) it has too many react-able oxygens, but when you mix it with edible lime it becomes safe to use (basically the same as DMT) because the Hydroxy is neutralized by being attached to parts of the edible lime.



Bufotenin doesn't dissolve in water and is poorly absorbed, so people make it into a calcium salt (the OH on an aromatic ring can sometimes lose its proton - hydrogen atom-  and become a negatively charged O- atom). This principle is used to purify morphine, which has the same sort of "phenol" (benzene ring plus OH) group on it.



> Now, my question is... With those 2 loose Hydrogens waving around (15 in total actually, I just don't understand what H3C is and how it reacts, because it is not an independent structure), and a Hydroxide (OH) sticking out like a sore thumb, and that oxygen hiding underneath...



THC has more than 15 hydrogens. It has 30, in fact. When chemists draw skeletal formulas they don't draw and label every single carbon and hydrogen atom all the time - just other atoms. This is called a skeletal formula. It's faster and cleaner than drawing all the atoms because usually organic chemists are only concerned about the relative arrangement of the groups on the skeleton. The hashed and filled wedge lines are indicating which way the bonds go in 3D space - chirality. Not "looseness".






THC could be made into a salt the same way as bufotenine and the others, but it's still not very water soluble and prefers to reside in an organic solvent than water. See also: polarity and solubility.

Now: go take a chemistry course from somebody other than me. Especially organic chemistry. If you don't understand the drawings you're supposed to be making there's not much hope. A better use of your time than looking up "cool Structures and Catalysts whither to Effect changes Alchemikal in all manner of Patent and Factitious Airs, Manas, Earths, and Spirits" is *actually learning chemistry formally.*


----------



## ebola?

Fin said:
			
		

> As I have said before, I know I word things wrong. (and if you want to correct me, do so, don't just say "wrong wrong wrong")



Sekio has been correcting your points rather specifically--I would again reread what he has said.  Why don't you try learning some chemistry basics and subsequently ask us questions _on the basis of what you have read_?




> But you are acting as if crack does not exist.



Not at all.  In fact, I have absolutely no idea how sekio's post implied such, or even what such a claim could mean.  This again is illustrative of how you need to do more back-reading to render your speculation informed.



> And I didn't come to this thread, I was merged here. Sorry for whatever inconvenience I have cause by being in your doodle thread.



We merged your prior posts into this thread because they lacked sufficient merit to stand on their own.




			
				swamp fox said:
			
		

> You don't understand. A chemical HAS TO BE volatile in order to be smoked. Otherwise, the combustion will just destroy the molecule.



This is true but in a sense trivial: the existence of any vapor will reflect a compound's volatility at given conditions of temperature and pressure; given a combination of sufficiently high temperature and low pressure, any compound can vaporize.  Whether this occurs at temperatures below combustion at atmospheric pressure in presence of oxygen at atmospheric proportions is a matter of the particular compound's volatility and propensity to oxidize.

ebola


----------



## pharmakos

ebola? said:


> given a combination of sufficiently high temperature and low pressure, any compound can vaporize.



someday i want to prove that this statement is incorrect :D  but it is definitely correct 99.9% of the time


----------



## ebola?

I can't think of a compound for which it would not undergo this phase change for all possible combinations of temperature and pressure, and assuming a relatively inert atmosphere; under such conditions, one wouldn't expect oxidization to be an issue.

ebola


----------



## adder

6-alpha-alkylmorphines should be long-acting and in some cases of extreme potency as well if you compare them to orvinols (look at the stereocenter at C19 in orvinols; besides the hydroxy group at C19 is unnecessary if there is a methoxy group at C6 already, compounds with the furan ring fused at C6-C7 were prepared [1]). Unfortunately, the research on 6-alkylmorphines is scarce. Maybe one day... 6-alpha-methylmorphine is doable (as presented in Casy & Parfitt's), it was synthesized in the past, and it's longer acting than morphine. I suppose it's for a similar reason why orvinols are long-acting and in some cases super-potent. And perhaps if there was no additional ring as in orvinols, the compounds would dissociate somewhat faster from the opioid receptors (Edit: well, this presumption may be one step too far at this moment, so let's say they'd be a bit less lipophilic, but still lipophilic enough). 6-alpha-butyl and 6-alpha-isopentyl would need some more work-up, but their potency should be high enough for the mixture of alpha and beta isomers to still be two magnitudes more potent than morphine, and that actually means without separation they could be done almost in the kitchen with the right knowledge. The fourth compound, 6-acetyl-6-alpha-alkylmorphine or some other ester, is a related compound, and it could be used if it turned out that the separation is cost-inefficient. Still, I think that it would be possible to get the right isomer with the methods currently known.

I've got a lot of ideas, but I've changed my mind on sharing such thoughts. RC vendors set on making money are waiting out there all the time for such ideas to show up, and most of them aren't chemists or pharmacologists, but entrepreneurs who don't care much about the quality of their products as long as their clients are happy high. I've learned it the hard way and I don't want to contribute to that.8)


----------



## Transform

I'm sorry shaggy. I kind of admire your persistence but you really, really need to take a step back and learn the fundamentals before diving in. It's gotten to the point where your persistence is now working against you and as usual, greatly frustrating those trying to help you.





These are my favourite quotes:



> when someone made their hash with Acetone/Denatonium Benzoate and it made the hash bitter (I assume they tried it because they give an example), they commented that Denatonium Benzoate is used to Denature alcohol, and maybe "Denatured" the THC.


 As seiko pointed out, the bitterness is simply because of denatonium benzoate contamination.





> I just found an interesting acid, could be helpful in catalyzing some interesting things, it's a basically Benzoic acid structure with extra Hydroxides for extra fun (meaning possibilities).
> http://en.wikipedia.org/wiki/Gallic_acid


Chemistry - now with added fun.




> it looks like Bicarbonate (Baking soda) is actually an acid or alcohol type structure with lots of reactable oxygens/hydrogens, but it has a magnetic change because a Sodium is polarized to it (not sure if that is the right word)






And of course, any mention of aromaticity.


----------



## pharmakos

ebola? said:


> I can't think of a compound for which it would not undergo this phase change for all possible combinations of temperature and pressure, and assuming a relatively inert atmosphere; under such conditions, one wouldn't expect oxidization to be an issue.
> 
> ebola



such a compound has not been invented yet, but i think it might be possible for there to be a substance that is a non-volatile solid at all temperatures.

neutron star material maybe =p


----------



## sekio

Polymers like polyethylene, silicones, PEG etc be essentially nonvolatile at essentially all pressures if they're big enough; if you try to "distill" them they will thermally crack to smaller molecules even without oxygen.


----------



## SkyblueMolly

Here's another molecule. It's 3,4-DiMethyleneAmphetamine. Like a stronger form of IAP.


----------



## MrPorter

I think that would be 3,4-EthyleneAmphetamine, like the desmethoxy sister of 2C-G-2 (just G2?). I imagine synth would be pretty difficult because of the ring strain


----------



## Soulfake

1: AKB-48 with a fluorophenyl instead of a fluoropentyl side chain
2: AKB-48 with a cylcolhexyl instead of a pentyl chain (like BB22)
3: JWH250 Indazole-analogue 
4: JWH250 with phenyl-pyrrole instead of indole

I´d love to see more JWH-250 analogues, imo it´s one of the best Cannabinoids with almost no side effects.


----------



## SkyblueMolly

This might be a cooler, more potent nootropic than CX-546. I call it PP-028 (or Piperonyl Piperidine, Piperonylic Piperidine).




Here's 2C-D-Nifiram.




The last molecule is just for fun. It probably doesn't do anything. 4-Cyclohexyl-2m2bOH(4-Cyclohexyl-2-methyl-2-butanol)





I don't have chemdraw, so I use paint.


----------



## Incunabula

SkyblueMolly said:


> I don't have chemdraw, so I use paint.


Don't 

http://www.emolecules.com/

http://web.chemdoodle.com/


----------



## MagickalKat777

wow ILTDPoRM sure went to hell...

Would a 2C-D nootropic even work? I would probably just take 2C-D... The molecules look cool though.


----------



## Solipsis

Don't want to dismiss the entire concept right off the bat, but trying to pull off a hybrid pharmacophore often doesn't really work out. It's like trying to achieve both things at the same time but failing at both because the requirements are not met because of the 'concessions'.

Of course a given neurotransmitter system will be more akin to some than others, as we know for example there isn't such a huge difference between the catecholamines DA and NE so there is much more pharmacophore overlap so to speak. 

Hybridizing 2C-D and (s)unifiram is much much more of a stretch. The SAR foundation of AMPAkines seems a lot more obscure to me and the 2C-D group is bound pretty randomly to the unifiram group - there is probably not a much better way since there just isn't that much 'kinship'.

I think that it would only pass if from the 2C-D point of view the additional group is acceptable as far as binding dynamics go, so basically a ball and chain - and/or the other way around. It seems extremely likely that putting it on that 4-position is absolutely not acceptable in that sense, if anything it would have to dangle like an NBOMe on the amine function.

Funny question actually MagickalKat, since 2C-D is considered to be somewhat of a nootropic on its own. That may not be a coincidence, perhaps that was already SkyblueMolly's association.

FYI: the reason I said I didn't want to dismiss it right off the bat is for example bk-2C-B, which is a pretty rogue hybrid of empathogen drug design strategy applied to a psychedelic structure.


----------



## sekio

Let us not forget the abomination that was 2C-B-BZP. 





2C compound? Piperazine? (un)Fortunately, it was a failure as both.


----------



## MagickalKat777

^ you know that feeling you get when something is so insanely scary of an idea to you that you simultaneously get shivers and paralysis at the same time? That's what just looking at that molecule did to me...

And Soli, that was my point. I would rather take 2C-D for its known nootropic properties than take a mixture of 2C-D and another nootropic... sounds like a recipe for disaster. Considering that 2C-D is one of the lightest materials I've ever had at high doses, its safety at nootropic doses is undoubtedly good, why mess with it?


----------



## pr0d1gy

Guys please don't discourage shaggy from posting. His posts have literally been the highlights of my reading bluelight for some time.


----------



## SkyblueMolly

Thanks! I'll give it a try and see how it goes. It seems very technical though. How do I export from emolecule?
Nevermind. I found marvin online from chemaxon. It's not the ideal chemical drawing place, but it's very tech challenged friendly.
I drew fluorenol. %)




It's not letting me import more pictures, but that's probably the computer. I'll try on another computer and find out.
Nevermond again. It was the computer that acted up for a while. Now it's working.
Here's a picture of fluorenamphetamine.




The last one is a pure monstrosity. Since 2C-I is a stimulant at low doses and 2C-D is a nootropic at low doses, and since fluorenol is a non toxic wakefulness enhancer, this "Fluorene-Di-2C-I-D" monstrosity would reek havoc assuming it's biologically active.




Another even worse monstrosity! Fluorene-Di-2C-I-D-PhenylPiracetam.




It would be ironic and funny if S-18,986 would leave the rest of these molecules in the dust.
Molecules are fun! :D Braino!


----------



## pharmakos

>



^ could use a methylenedioxy or two imho


----------



## SkyblueMolly

thenightwatch said:


> ^ could use a methylenedioxy or two imho



Coming right up. But first, the fictional molecule 2C-U.




Now there's the molecule, DiMethyleneDioxyAmFluoreneAmine.




Or was it molecule 2Y?




Or molecule 2Z?




Here's a pretty cool molecule. PhenylNefiracetam.




2C-3D




2C-3D-I




IodoFairy




2C-TAG.




Acceleron.




Ignoritol.




Ignoritol jr




Ignoritalynn.




SBF-1, or SBF-H.




SBF-D




2C-NAP-I




2C-NH2




ZUH? I don't even know.




MegaSpike!




2C-AMT, or CAMT.




The cool molecule, STM-18986, or STIM-22.




The molecule, Memorimax. Based on ISRIB.




Stimvector. Based on Cyprodenate.


----------



## Incunabula

SkyblueMolly said:


> How do I export from emolecule?


Take a screenshot? 



SkyblueMolly said:


> 2C-TAG.



That would be 2C-CP. This one would probably be active, I reckon. And an interesting one to booth. I'd hit it for sure 

2,5-dimethoxy-cyclopropyl-4-dimethoxy-phenethylamine 

or the IUPAC 2-(4-Cyclopropyl-2,5-diethylphenyl)ethylamine.

Also 2C-CPM would be an interesting one. 

2,5-dimethoxy-cyclopropylmethyl-4-dimethoxy-phenethylamine 

(2-[4-(Cyclopropylmethyl)-2,5-diethylphenyl]ethylamine) I'll ad a drawing later when I have time.


----------



## black53

it's pretty too


----------



## SwampFox56

Pomzazed said:


> Wee! Great!
> So now the random molecule wont spread around all over the topics!
> 
> Let me start this (supposedly fun?) topic by this one:
> (Please vote a name for it!)



I always see this one on the front page, and it always intrigues me. Synthesis and BBB aside, what would this chemical do? Wouldn't it just destroy everything and anything it formed a complex with?


----------



## Katuskoti

I call it Taaracetam


----------



## SkyblueMolly

I just came up with some cooler molecules.
This one is 2C-TP(2C-Triangular Pyramid).




This one is D(MDP)2P, or 1,3-Di(Methylenedioxyphenyl)-2-Propanone.
Or D(Sm)2P, 1,3-Di(Sesamyl)-2-Propanone.




Here's piperecoline. It's sort of a combination of piperic acid and arecoline.




Here's bm-MDA.




WTH-2901(what the hint-2901). :D




What if the WTH-2901 would cause the brain to grow uncontrollably and get smarter too fast?
Better stick with hollow-2C-E, hahaha! Funny.







Katuskoti said:


> I call it Taaracetam




The taaracetam looks cool.


----------



## Katuskoti

SkyblueMolly said:


> The taaracetam looks cool.


I drew it wrong so its not exactly a racetam but it might possibly be a TAAR1 agonist like RO5166017

I like your drawings!! Haha Triangular Pyramid... It takes you back to ancient egypt.


----------



## pharmakos

_____O
_____||
_O\/\/\/N\
<__||
_O/\/

ascii molecules ftw


----------



## Katuskoti

thenightwatch said:


> _____O
> _____||
> _O\/\/\/N\
> <__||
> _O/\/
> 
> ascii molecules ftw



Looks like methylenedeoxypropylhexedrine, I heard that one is a bitch  (as in, impossible)


----------



## Incunabula

Nah, that's gotta be bk-mdma


----------



## Katuskoti

Fagott said:


> Nah, that's gotta be bk-mdma



Derp, sorry meant bk-MD-propylhexedrine. That's no phenyl! haha


----------



## pharmakos

drawing the double bonds of a phenyl would mess up the spacing in a monowidth font heh

and i was going for alpha-desmethyl-bk-mdma


----------



## Incunabula

thenightwatch said:


> drawing the double bonds of a phenyl would mess up the spacing in a monowidth font heh
> 
> and i was going for alpha-desmethyl-bk-mdma


LOL :D 

Give us one more, this is fun


----------



## pharmakos

______O
_____||
_/\/\/\OH
_|
/
|
\____/\/\
_|___|
_\/\/

might be a toughie

four undrawn double bonds


----------



## ebola?

This looks vaguely like anandamide.

ebola


----------



## pharmakos

close

same metabolic pathway iirc


----------



## ebola?

arachidonic acid?

ebola


----------



## pharmakos

^ indeed

here's an easy one:

______O
_____||
HO\/\/\OH


----------



## Katuskoti

^not GABA!!

1 billion points to the first poster that can get this one (hint: very closely related to GABA)
_______O
H2N/\/\//
.____|_|
____/\_OH
.___|_|
____\/

edit: I have no life
_________O
H2N/.\./.\.//
.___._|__.|
.___./_\\_OH
.___|l_._|
.___.\,.//


----------



## SkyblueMolly

Yup!



thenightwatch said:


> ^ indeed
> 
> here's an easy one:
> 
> ______O
> _____||
> HO\/\/\OH



GHB (Gamma-Hydroxy-Butyric acid)



Katuskoti said:


> ^ GABA!!
> 
> 1 billion points to the first poster that can get this one (hint: very closely related to GABA)
> _______O
> H2N/\/\//
> .____|_|
> ____/\_OH
> .___|_|
> ____\/
> 
> edit: I have no life
> _________O
> H2N/.\./.\.//
> .___._|__.|
> .___./_\\_OH
> .___|l_._|
> .___.\,.//



Me neither! YAY! That one is phenibut.
Cool. (┌●_●)

Here's another molecule I drew. NZX-18986 (NZX-18,986).





Here's another one. It's 2C-PH-I.




Here's 2C-Ph.




Here's 2C-NAP-I


----------



## Katuskoti

^ Ding ding ding! You win! Jesus though. I can't brain today I have the  dumb. Amide and hydroxy are totally the same guys. The only difference  is one is aromatic and one isn't. So only one is the future of 'smells'  that get you high. (jk :D)

Skyblue you should just write Pihkal 2 already! Those are awesome though.

O^i^

<O^i^ 

_┐
.,O^^
_└


----------



## Black

what about this one? has it been synth'ed? is it active or doesn't that position take any kind of substituents? since, according to recent literature, the metabolites like HHMA and HMMA are most likely to be the cause of neurotoxicity at high(er) dosis, we could make the molecule a bit less susceptible to attack from those pesky enzymes. if it doesn't work, just replace the methyl by a t-butyl, but i don't think we'd have any chance of seeing activity then


----------



## black53

this one is a bit similar and suspected to be active


----------



## sekio

MDA itself is more active than the fluorinated/methylated compounds. There's not much room for fiddling with the MDO bridge.


----------



## black53

I didn't mean to say it would be very active/good just that it may have at least some activity.


----------



## ShaggyFin

I came home today and it says that the books were delivered, so I get them Monday. Later than expected (I thought they would come before I left), so about another week until I start drawing molecules.


----------



## MrPorter

I cannot wait


----------



## SkyblueMolly

The 2C-Ph-x series might carry high nootropic potential. Based on the activity of 2C-x at sub-psychedelic doses.
2C-Ph-D. Get it? 2C-"PhD"?




2C-Ph-I




2C-Ph. This molecule alone may carry stimulant effects.




Here's Super E, or Super MDA. Let's call it Jenny-X. %) The theory is that if the 2 oxygens are closer together, it'll become more active and enpathogenic.




Here's 2C-Ph-C.




Here's 2C-Ph-T-4.




Here's 2C-Ph-Se-4.




This one is 2C-Se-4.




2C-Fluorenol.




Here's AcBZP, or Acetic-Benzylpiperazine. It looks similar to sunifiram, and ione of it's metabolites might be BZP. Other nootropics have a BZP metabolite. Hopefully, the AcBZP has some nootropic potential. I think that if such a molecule were to exist, doses must never exceed 25mg. 




There's also more molecules. Stay tuned!
Here's 2C-Sm. The longer name is 2,5-Dimethoxy-4-Sesamylphenethylamine.




Here's 2C-6MO-I. The longer name is 2,5-Dimethoxy-6-Methoxy-4-Iodophenethylamine.




Here's 2C-3MO-I.




Here's 2C-3Mo-6MO-I




Here's 2C-2MD-I. The longer name is 5-Methoxy-2,3-MethyleneDioxy-4-Iodophenethylamine.




Here's 2C-5MD-I. The longer name is 2-Methoxy-5,6-MethyleneDioxy-4-Iodophenethylamine.




Here's 2Z-I. The longer name is 2,3-MethyleneDioxy-5,6-MethyleneDioxy-4-Iodophenethylamine.




The last one, 4Z-I.


----------



## MrKhazar

ShaggyFin said:


> I came home today and it says that the books were delivered, so I get them Monday. Later than expected (I thought they would come before I left), so about another week until I start drawing molecules.



Love your videos dude! You're gonna be a well-loved and popular member on this forum! Keep it up!


----------



## sekio

Shaggyfin I hate to diappoint but it looks like myrcene is a Prop 65 carcinogen now because it turns out mice don't work right when you fill them full of turpentine.

throw all your mangos, lemon grass, hops in the fuckin garbage man


----------



## Solipsis

Hold on, aside from the fact that he has no business doing research experiments or anything related... aren't hops supposed to have a sedative effect? I do wonder what is actually known about the (albeit mild) psychoactivity.

Likewise I'm curious about theanine and how other alkylamide homologues besides the ethyl compare. Unfortunately the MOA seems to remain obscure.


----------



## ShaggyFin

sekio said:


> Shaggyfin I hate to diappoint but it looks like myrcene is a Prop 65 carcinogen now because it turns out mice don't work right when you fill them full of turpentine.
> 
> throw all your mangos, lemon grass, hops in the fuckin garbage man



Myrcene is in like everything. And everything causes cancer. 
So I really don't see the point of throwing anything away.


----------



## perpetualdawn

Is this something that has been made?


----------



## sekio

It's known as a 5ht1a/d agonist.


----------



## perpetualdawn

Does it have a name?


----------



## :DNA

perpetualdawn said:


> Does it have a name?



Yeah, I guess you could call it a name: RU-28306


----------



## perpetualdawn

Thanks!

Anyone able to explain how these receptor binding affinity studies are conducted? Tissue cultures?

edit: nevermind, just checking out this Nichols lecture: https://www.youtube.com/watch?v=2tN_L1bRq7Y
he explained it really well.


----------



## Black

sekio said:


> It's known as a 5ht1a/d agonist.



also a 5-ht2 agonist. but the only data on that is older than the discovery of distinct subtypes of 5-ht2 receptors.


----------



## Soulfake

(1R,2R)-2-[(dimethylamino)methyl]-1-(3-hydroxyphenyl)cyclohexyl propanoate

Would this act as a pro-drug for desmethyl-Tramadol?


----------



## MrKhazar

Soulfake said:


> (1R,2R)-2-[(dimethylamino)methyl]-1-(3-hydroxyphenyl)cyclohexyl propanoate
> 
> Would this act as a pro-drug for desmethyl-Tramadol?



Yes, esterases present in the blood plasma will catalyze the ester hydrolysis reaction to form O-desmethyltramadol and propanoic acid.


----------



## sekio

The tertiary ester would probably eliminate to form some sort of MPTP analog, though.


----------



## Solipsis

Yikes! (MPTP = indirect neurotoxin FYI - though you probably all know)

Oh no wait in this case it wouldn't be neurotoxic right? Since the cyclohexene can't be metabolized into a methylpyridinium containing MPP+ analogue since it is not a tetrahydropyridine, correct?

Soo esterifying the phenol moiety ("phenolyl" ??) instead would be the way to go for yielding in vivo M1 and possibly circumventing the iffy profile of tramadol itself?


----------



## sekio

> Oh no wait in this case it wouldn't be neurotoxic right? Since the cyclohexene can't be metabolized into a methylpyridinium containing MPP+ analogue since it is not a tetrahydropyridine, correct?



It looks that way, yes. It still doesn't bode well for thermal stability of the compound.

I think desmethyl tramadol is already pretty good as a drug wrt pharmacokinetics.


----------



## SkyblueMolly

Here's a picture of ToluenylPiperazine, or TNP.




Here's a picture of Neo-2C-D.




The molecules will get ridiculous!
Here's WTH-19.




Here's WTH-20.




Here's WTH-MD21.




Here's ZXS-BZ-14.




Here's ZXT-BZ-14.




Here's Super Fluorenol. This is just in case regular fluorenol causes sleepiness instead of wakefullness.


----------



## Solipsis

The Neo-2C-D may be an interesting idea, I don't know if hooking up a beta oxy to the amine in PEAs works - maybe we should look at the efficacy of RMDMA (Thread here) to get an indication of that, especially if the N-desmethyl version of that would exist.

The ZXT's look potentially carcinogenic / teratogenic / mutagenic to me - polycyclic aromatics like that may intercalate between DNA grooves...

Some eugeroics like modafinil may indeed have paradoxical effects and cause sleepiness. Apparently consistently in rare individuals and incidentally in others (I've felt it at least once), not sure how that happens and how it can be avoided by modding structure and activity. 

I'm interested in heterocyclic simply substituted PEA-like stimulants like the concept behind MPA. I also wonder about cycloheptatriene amph analogues for example. The cyclobutadienes like WTH-20, that is not stable is it? Antiaromatic..

Here's some phantasies of my own (#1-#5), I must admit I really wonder about the MET-type azetidine (#5)!! Never mind the chloro, bromo or if there are alkyl antlers, do you think it makes sense? Is it protected from MAO while potentially losing little of the specific DMT / MET character?
_edit: _Although the constitutional isomer pyrollidine tryptamine (Pyr-T) is apparently unpleasant if you refer to TiHKAL.


----------



## SeenSoFar

I'd be really interested in bioassaying the azetidide MET homologue. That could really hold some promise I think. I would also be interested in sampling mescaline-piperidine, but I am inclined to believe that activity may be lost, given the comparison with 2C-B-BZP. Still, it is different enough to at least warrant exploration, although perhaps with a more potent substitution than the 3,4,5-trimethoxy pattern.  GOOD ONES SOLIPSIS!!

For those interested in messing with the fluorene derivatives, you might want to have a look at these:

http://en.m.wikipedia.org/wiki/2-Acetylaminofluorene

http://www.ncbi.nlm.nih.gov/m/pubmed/8397005/

It seems that with very simple substitutions to the base fluorene moiety, it is possible to produce powerfully mutagenic compounds. This is not to say that such things will occur with other substitutions, and it seems to be related to substitutions at the 2- position, but still, it would be VERY wise to tread lightly indeed...


----------



## Solipsis

Oops, yikes apparently this has been thought of before:

Read in this thread here... http://www.bluelight.org/vb/threads/298517-Indolethyl-dimethylazetidine

Still, I wonder if the constrained DPT analogue (indolethyl '2,4-diethylazetidine) or the DET analogue (indolethyl '2,4-dimethylazetidine) could help elucidate which way the N-alkyl substitution antlers point best for binding - as was the whole point of designing LSZ...
Or even the trialkyl (vicinal)?

And yeah those look nasty, Seensofar!


----------



## Famous

nj754 said:


> Methylenedioxymichaeljackson (mdmj):
> 
> 
> 
> 
> 
> 
> (methylenedioxypropofol)
> 
> I like the md-buckyball. That would have quite a bit of ring strain, though.



I agree with all of this, although I would be curious to see how the methylenedioxy group would affect such a GABA agonist...atypical...almost reminiscent of the 'mdAi' meets propofol.  Now, what if there were an amine were the phenolic hydroxyl group goes??


----------



## Famous

What about phenmetrazine analogues, I mean, Jesus, morpholine @ benzyl position...I think phenmetrazine is the preferrable phenethylamine-like structure from which to do analogues...


----------



## ebola?

We don't yet know much about their activity or what SAR suggests.

ebola


----------



## Solipsis

Famous said:


> What about phenmetrazine analogues, I mean, Jesus, morpholine @ benzyl position...I think phenmetrazine is the preferrable phenethylamine-like structure from which to do analogues...



This is a recent thread though:  http://www.bluelight.org/vb/threads/716648-Methylenedioxyphendimetrazine-(MDPDM-RMDMA)


----------



## angiebeard74

What step is taken away or added to the equation that gives you that cocaine feeling from  meth when ivd


----------



## SkyblueMolly

Cool molecules solipsis. Very MAO resistant it looks like.
In reply to the greenlighter with the m-eth question. the answer is probably DMAA.
Here's a list of fictional fluorenol prodrugs.
Fluorenol Modified D.




Fluorenol Modified DO, or Stiminsomfinil.




Here's Fluorenol Modified DO2.




Fladrafinil, based on Adrafinil.




Last one, Flodafinil. based on Modafinil.


----------



## sekio

Skybluemolly, the second-to-last is already known: 
http://en.wikipedia.org/wiki/CRL-40,941


----------



## Solipsis

Oh goody, after flephedrone, now fladrafinil - I was just thinking the other day: we need more drugs that sound like Daffy Duck came up with em.

SBM, any reason you didn't include the more obvious one?:


----------



## pharmakos

Solipsis said:


> Oh goody, after flephedrone, now fladrafinil - I was just thinking the other day: we need more drugs that sound like Daffy Duck came up with em.



I always wanted to hear daffy say "fluoroethylthiophenethylamine" :D


----------



## SkyblueMolly

Solipsis said:


> Oh goody, after flephedrone, now fladrafinil - I was just thinking the other day: we need more drugs that sound like Daffy Duck came up with em.
> 
> SBM, any reason you didn't include the more obvious one?:



Which obvious one? That molecule looks like N-methyl-insomfinil.

This molecule is Ecstatrion.




This molecule is EGHQE-D, or 4-Methoxy-(Ethyleneglycolyl-hydroquinone-ether)-1-Ethylamine.




The eugerioc(wakefulness enhancer), 2C-G-N. 2C-NAP, 2C-NAP-H, or 2,5-dimethoxy-naphthylethylamine. It exist already. It's only posted so you can see where the next molecule came from.




This molecule is 2C-Naplock. What if you can stay up for over 80 hours with this. Or the longest anyone has ever stayed up, which is i don't know. Could it make you stay up for 30 to over 110 hours?!




3C-Naplock.




4TC-Naplock. Maybe it'll cause someone to stay up from 35 to over 200 hours. 200HOURS!!! They'll DIE INSTANTLY!   :D XD




Maybe the 4TC-x series of compounds may carry most of the nootropic effects of the 2C-x series, but almost none of the psychedelic effects. The series might be more empathogenic/entactogenic and euphoric at higer doses though. Who knows?




Here's Nortametraline. Nor means it doesn't have the N-methyl substituent like tametraline does. Since it's likely a norepinephrine/dopamine reuptake inhibitor, and not just a dopamine reuptake inhibitor, it's likely to retain it's stimulant strength while being less addictive. Like a safer, cleaner version of ritalin with less dependance and less damage.




Megalert is like tametraline on steroids. It might cause so much stimultion, you'll stim to another dimention. Hahaha!




This is ultericrash!. Ultericrash! would be crazy. /!\Warning: Extreme stimilation! The exclamation point is totally nessesary. Ultericrash!




This might be the cooler series. 2C-x-N1C-x serieses. Cooler than N-bomes! Starting with 2C-x-N1C-D series.
this is 2C-I-N1C-D.




This is 2C-Ph-N1C-D.




Here's 2C-Ph-N1C-NAP.




There are hundreds of possibilities with the 2C-x-N1C-x serieses.


----------



## Dresden

3,4,5-trifluoroamphetamine


----------



## Hammilton

I find the names annoying.  Were I someone who was doing actual research and actually tested one of these compounds, I'd want to have naming rights, but instead someone's gonna go online and be like, haha douche, some guy on Bluelight beat you to it!


----------



## kingbuyer

What do you all think of this.


----------



## Black

^ what's it gonna do? make the physical side effects even more pronouned than the non-beta-keto version?


since we're talking about fluorinated things:




those fluorine atoms should fit nicely into serotonin releaser SAR (after all fenfluoramine also does with that 3-trifluoromethyl group). cardiac fibrosis shouldn't be a problem with sporadic use (at least not more than with the APBs). there's also a lot of room for variation in the number or flourine atoms (from one to all four positions indicated) and also with the stereochemistry. i'd definitely be interested in receptor binding studies and would imagine some of those variants to be fun.


----------



## Solipsis

Ebola, I noticed you killed a bunch of people in Guinea... what's up with that man?


----------



## ebola?

I have the drive to reproduce, like anyone else. 

ebola


----------



## sekio

Just some doodles.






I also recently saw this paper detailing some CNS active carboranes (and other funny shapes.)





So, why not carborane-JWH? (actually, carborane-AM2201) It should be promising given what we know about SAR at the cannabinoid receptors.


----------



## iamthesuck

DISCLAIMER: i know didly about chemistry past a college 100 level

http://tinypic.com/r/1puxx0/8

edit: trying to post an image, link works


----------



## iamthesuck

Another between classes. someone PM me w/ help to get the images up?
http://tinypic.com/r/xgfnkh/8


----------



## pharmakos

iamthesuck said:


> DISCLAIMER: i know didly about chemistry past a college 100 level
> 
> http://tinypic.com/r/1puxx0/8
> 
> edit: trying to post an image, link works





iamthesuck said:


> Another between classes. someone PM me w/ help to get the images up?
> http://tinypic.com/r/xgfnkh/8



just copy the "IMG code for forums and message boards" field from the bottom left of the tinypic page, like so:











you can also click "quote" on my post to see the code.



sekio said:


> So, why not carborane-JWH? (actually, carborane-AM2201) It should be promising given what we know about SAR at the cannabinoid receptors.



dammit sekio, i hope the synthesis for this is pretty difficult, otherwise we're going to see it available from china in about a week


----------



## iamthesuck

Ergoloids, I think they might be active. I have no clue, but 5/6 of the ones I posted I would actually expect something from.

Now, I picked phosphorus to change it up, but theoretically nitrogen could be used there as well


----------



## iamthesuck

final contribution for today


----------



## pharmakos

some good possibilities there ^




here's one because i'm feeling silly and i kind of miss shaggyfin's hybrid molecules idea =p






i'm almost certain i messed up some of the bonds.


----------



## blueberries

I call it hormonal-girlfriendamine.

EDIT: I tried to make the amine Nitrogen Oxide but Marvin said 'N-OH'


----------



## pr0d1gy

I was recently wondering if the thianapthene derivative of 5-APB might be of any interest. From a synthetic perspective, thianapthene is a very different animal than benzofuran. However, I don't have nearly enough biochemistry/related experience to even guess to how this would carry over in terms of pharmacology.


----------



## SeenSoFar

So, here is another big batch of randomness from me. The motivations for these are all relatively straightforward. Compounds 1-4 are all variations on applying the phenmetrazine SAR to tryptamines, God only knows how well that will work. Compounds 5-10 are all different ring constraints applied to the tryptamine backbone, a-la aminoindane and aminotetralin compounds. In addition, compounds 9 and 10 are an attempt to make a tryptamine homologue of lorcaserin. The basic tryptamine ring and N- substituents could be applied to any of these, and they have been labeled as such where applicable.

I would be interested in sampling any of these compounds, as I am sure that most would have some level of interesting pharmacological activity. It would be interesting to know if the aminoindane/aminotetralin-esque compounds would end up being SSRAs like their phenethylamine counterparts, or if something totally unexpected would happen. I'm sure eventually we'll find out for many of these, since most are not too far out and are at least VAGUELY grounded in some sort of SAR.

Comments?


----------



## LordJewington

Dissociative psychedelics?


----------



## SkyblueMolly

Cool new made-up molecule. Hypnofluorenol!




This one is 2C-TAC.




Here's BZR, or BenzylRacetam.




Here's 2C-T-2m2b.




Here's 3-MTA, or 3-MethylThioAmphetamine




Here's WTS-989.




WTS-5CXA.




Here's NZTX-542.




Here's 2C-CM, or 2C-MC.




This one is indanetraline.


----------



## Jesusgreen

sekio said:


> So, why not carborane-JWH? (actually, carborane-AM2201) It should be promising given what we know about SAR at the cannabinoid receptors.



Won't bring anyone's mother back but you'll be too stoned to care.

I like it.

















_*there's a reference in there for those that didn't get it_


----------



## Pomzazed

"WTS 5CXA"

ZOMG, No no no with that aziridine in the PEA-like structure!, Its even more reactive than an epoxide!
(Eg... It reacts and covalently bound with any unselective tissue!)


----------



## Solipsis

Would it polymerize in a chaotic way? Can't that kind of reactive chemical react with parts of itself?


----------



## Pomzazed

It should polymerize to a black gum... But not insomuch chaotic way

A nucleophile will kick-start the ring opening polymerization... Getting more NH2 "opened" and becoming a nucleophile.
Other parts of the molecule shouldnt affect this, thioether should be stable enough until runaway heating occurs.

And yes the leftover will attach to the body 

Btw, i do like the carborane one of sekios above! It isnt too far from what is required (bulk, somewhat hydrophobic). Idk if its stable in vivo tho!


----------



## SkyblueMolly

Here comes another wave of made up molecules. This time, it's mainly stimulants.
Here's AX Jr. It's based on aminorex.




Here's B-PhenylAmphetamine, Beta-PhenylAmphetamine, or "super speed".




Here's B-PhenylHydroxyAmphetamine




Here's B-PhenylSelegiline.




Here's MDMPG, or Mindormeprag. It's an experimental treatment taken daily for Parkinson's.




Here's EA, or EthylAmphetamine.




Here's 2-methyl-2-butylphenidate, or 2m2bPhND.




Here's Methylcyclopentanidate.




Here's NRG-64, based on desoxypipradrol.


----------



## Solipsis

Nice ones :D
Pretty sure some of them like the beta-phenyl amphetamine seem very familiar, like I'm pretty sure it is a known compound. But I don't mean that as criticism, more like: you got a point coming up with it. Actually hoping for a regular to point out existing info on some of them cause I can't really find it.

I am curious about how ethylamphetamine (crystal eth? lol) would differ pharmacologically, if it is mostly less potent or if there is a shift in which monoamines are mostly affected. I gotta say that ethcathinone is kind of shitty (it emphasizes on NE release IIRC?) but not sure how it compares analytically to methcathinone...

Does anyone have a link for some good stim SAR discussion? I think alpha-alkyl chain makes something increasingly dopaminergic for example, what about N-substitution, etc? And 4-substitutions can have effect on serotonergic qualities while 2-substitutions are more for dopaminergic qualities? etc I may be off but it would be cool to get some clarification...

The aminorex one would have to be aromatic I think (so cyclopentadiene) to be more accurate..


----------



## ebola?

> I am curious about how ethylamphetamine (crystal eth? lol) would differ pharmacologically



IIRC, it's less selective for NE over DA than meth, and slightly more serotonergic.  Nice stuff, but less potent than meth, similar potency to perhaps amp itself, maybe less.



> I gotta say that ethcathinone is kind of shitty (it emphasizes on NE release IIRC?) but not sure how it compares analytically to methcathinone...



It's entirely selective for NE, except for some direct adrenergic affinity and metabolism to cathinone.



> I think alpha-alkyl chain makes something increasingly dopaminergic for example, what about N-substitution, etc? And 4-substitutions can have effect on serotonergic qualities while 2-substitutions are more for dopaminergic qualities? etc I may be off but it would be cool to get some clarification...



It's a bit tricky to come up with a good theory in aggregate, particularly as the effects of some substitutions depend on the configuration of other substitutions, especially with the beta-ketone substitution.  SAR becomes pretty different moving from releasers to reuptake inhibitors.

ebola


----------



## SeenSoFar

SkyblueMolly said:


> Here comes another wave of made up molecules. This time, it's mainly stimulants.
> ...



Awesome! Keep up the good work dude!

Something to keep in mind when designing something like a stim, if you replace the main aromatic ring (benzene, thiophene, etc) with something non-aromatic, you will almost certainly lose affinity for the DAT and SERT, leading it to have mainly (nor)adrenergic effects. It is possible to have indirect DA and 5-HT releasing properties a-la propylhexedrine, but its just as likely to be something akin to methylhexanamine. Far be it from me to tell you what to draw, but I think AX Jr. and methylcyclopentanidate with a thiophene ring, or even possibly a furan or pyrrole ring, would be VERY interesting!


----------



## Dresden

N-ethylamphetamine is also a Schedule I drug, which makes getting ahold of any more difficult.


----------



## SkyblueMolly

Cool!
Here's a couple of more molecules.
Z-17 (hypothetical molecule stronger than methylphenidate).




Here's thioscaline.




Here's PhenylMethylPiracetam.




This one's a bit dodgy. Cotiracetam.




This one's DMPMP-I.




Too much free time!


----------



## golden1

btw methylphenylpiracetam is a sigma1 modulatr:

http://onlinelibrary.wiley.com/doi/10.1111/bph.12506/abstract


----------



## Dresden

(1) Alexander Shulgin has already made and bioassayed thiomescaline.

(2) Does anyone else think that N-(2-MeO)benzyl-MDA would make a great 'legal' research chemical?


----------



## pharmakos

4-thiomescaline looks like a total winner, idk why its never made the rounds


----------



## SeenSoFar

thenightwatch said:


> 4-thiomescaline looks like a total winner, idk why its never made the rounds



I completely agree. I've wanted to sample it for some time now. A few years back someone I know was going to synth it, but nothing ever came of it in the end, his excuse was that some intermediate was too impure to work with and too difficult to purify  I think he just couldn't be arsed to bother and made up some bullshit.


----------



## MrPorter

Dresden said:


> (1) Alexander Shulgin has already made and bioassayed thiomescaline.
> 
> (2) Does anyone else think that N-(2-MeO)benzyl-MDA would make a great 'legal' research chemical?



I think someone made it, tested it, and decided it was crap/inactive
http://www.bluelight.org/vb/threads/589711-MDMA-NBOMe

As mentioned in the last post a-alkylation is a no no for NBOMes, so you'd assume MDPEA-NBOMe would be quality. I think I remember reading this was also bioassayed and decided goddamn awful, but i can't find a link to back that up.


----------



## Dresden

That may well be true, but I know that baseball players in the 1960s and 70s used to take little green prescription pills called 'Greenie Meanies' before big games.  The active ingredient was N-(2-chloro)benzyl-amphetamine, a molecule with an N,alpha carbon.


----------



## MrPorter

pills would suggest they ate them, right? We don't know for sure, but assume that there's cleavage at the N which in that case would leave just plain old amphetamine. Unless they're snorting them or something, it's not the N-(2-Cl)Bn- part that makes the effects.


----------



## sekio

That's clobenzorex, an amphetamine prodrug, sort of similar to benzphetamine. Both are long lasting "extended release" prodrugs for amphetamine. The liver cleaves it to amphetamine.

People have investigated NBOMe-amphetamines, but they're far less potent than NBOMe-phenethylamines. So NBOME-MDA is probably a loser.


----------



## pharmakos

^ "far less potent" isn't necessarily a bad thing, considering that the NBOMe-phenethylamines are active in the sub-milligram range


----------



## SeenSoFar

thenightwatch said:


> ^ "far less potent" isn't necessarily a bad thing, considering that the NBOMe-phenethylamines are active in the sub-milligram range



I believe that alpha-alkylation of psychedelic N-benzyl-PEAs causes them to act as antagonists/weak partial agonists at 5-HT2A/C, so potency is kind of a moot point. They might be a starting point for selective 5-HT2A/C development a-la ketanserin, but recreational compounds they do not make. I have a feeling that they are probably too bulky to act at the SERT/DAT/NET as well, at least as releasing agents, so N-benzylation of MRAs is probably a non-starter as well...


----------



## adder

I think that we could have methadone analogues that wouldn't bind to NMDA receptors as I'm sure that NMDA antagonism is responsible for the zombifying effect of methadone. Either substitute the phenyl ring(s) to lower affinity for NMDAR or lengthen the alkyl chain attached to the carbonyl. I'm wondering why this is not researched. The quality of people's life could be so much better. Even if it was less potent than methadone, it'd be a good thing, perhaps an analogue with more substitutions that would boost the potency.


----------



## SkyblueMolly

Here's the next wave of molecules. Most of them are fictional stimulants. Some novel fictional psychedelics will be next.
Here's AX-1




Here's AX-2




Here's STM-200




Here's STM-200-M




Here's STM-201




Here's STM-201-M




This is Z-238




This one's XTVA and it should have similar effects to MDA




Here's ZXQ-STM




Here's ZXQ-21




Here's ZXQ-22




Here's ZXQ-22b




Here's STM-202




Here's ZXQSTM-238




Here's XTZ-101





Here's 3,4-MethyleneDioxyHydroxyEthylAmphetamine, or MDHEA. I wonder if this one's even active though. I hope so.





More molecules coming soon.


----------



## Jabberwocky

before asking this, i'm well-aware this doesn't vibe w/ this thread's purpose... but i figure th eminds here could elaborate and help me to understand.


I read about non-commercial, non-distributed, highly  dopaminergic drugs (the RT series, ie rt55, to be precise), and am just wondering why such compounds haven't jumped into the marked, either as cuts to coca product, bath salts products, or any combo thereof.  The pharmacological data from the rti series of dopiminergics is 'promising', w/ respects to DAT hijacking / minipulation, so why on earth are they now available* drugs right now (*I'd note that, based on a rudimentary understnading, they're probably more dangerous than based coca or mdpv, but, let's be real, that won't give a pause to an RC vendor, so why haven't we seen a lot of the RTi series set for the rc  market?


----------



## sekio

Because nobody has a quick easy stereoselective synthesis for anhydroecgonine.


----------



## Transform

adder said:


> I think that we could have methadone analogues that wouldn't bind to NMDA receptors as I'm sure that NMDA antagonism is responsible for the zombifying effect of methadone. Either substitute the phenyl ring(s) to lower affinity for NMDAR or lengthen the alkyl chain attached to the carbonyl. I'm wondering why this is not researched. The quality of people's life could be so much better. Even if it was less potent than methadone, it'd be a good thing, perhaps an analogue with more substitutions that would boost the potency.



Isn't methadone's NMDA antagonism valued though, as a way to mitigate tolerance build?


----------



## ebola?

Does it really work out in vivo though?  It seems to me that the main value of the nmda-antagonism is synergistic analgesia.

ebola


----------



## SkyblueMolly

*Fake NZT molecules from the movie limitless.*

In the end, Eddie Morra creates NZT-49 (nootropic), leaving NZT-48 (fake nootropic) obsolete. NZT-49 permanently boosts cognition to a four digit IQ and is non-toxic. Continual use may even lead to a 5 digit IQ. Such a hightend intelligence would effectively lead to the cure for certain cancers and even the creation of new elements. Such elements would be in the "island of sability" and allow the person to become nearly indestructable.
The alternate ending is scarier. There's no NZT-49 in the alternate ending, only NZT-48. NZT-48 only temporarily boosts cognition to a four digit IQ. The toxicity is speculated to come from the thallanyl (thallium based) molecule. Such an error leads to fatal toxicity and permanent brain and body damage. Thallium also causes extreme sickness and death. Death! Thallium is HIGHLY toxic!

Here's NZT-48, or thallanylzirconio-methyl-tetrahydro-triazatriphenylene.





Here's NZT-49, or phosphanylzirconio-methyl-tetrahydro-triazatriphenylene.





Here's the ending of Limitless where he makes NZT-49 in the end.






Here's the ending of Limitless where he's stuck on NZT-48 and didn't create NZT-49.






Hypranootropics(super nootropics)
Nootropics(permanent cognitive enhancement)
Quasinootropics(temporary cognitive increase, little or no brain damage)
Pseudonootropics(fake nootropics. The effect is temporary and there's extensive damage, toxicity, and a host of side effects including high addiction potential, blackouts and brain damage)

I wonder if near indestructability and NZT-49 would ever become real possibilities. That would be so cool! :D %)


----------



## sekio

why do we need to post fictitious compounds in a forum discussing real drugs. 

good luck making a thallium (III) hydride under any earthly conditions. or even any organometallic compound with a Zr-Tl bond. 



> Thallium is HIGHLY toxic!



thallium(I) is, thallium(III) is much less so. i would be more concerned about the phosphine that would be released from hydrolysis. or the fact these are triazines and will probably decompose releasing nitrogen or ammonia or some other nastiness. or the fact they're polyaromatic aromatic hydrocarbons. or that transition metal organometallic compounds have a tendency to explode into flames in the air. or on contact with water. 

so yeah, fictitious compounds are fictitious. some of the stuff you draw in the random molecules thread are more plasuaible as a drug than this ever would be.

and i'm not sure i follow how having a superior intelligence means you can create new elements. we know damn well how to do that, we smash elements into each other. the problem is: atoms are fucking small, and particle colliders are comparatively expensive and kind of require their own power generating stations dedicated to them. we're not limited because we're not smart enough, we're limited because physics always makes us look like a bitch. 

i know i'm just a big bundle of fun wet blanket but ... i'm also a chemist? and again this is supposed to be a forum about real drugs. otherwise this devolves into a wonderful discussion of the pharmacology of redeye (c.f. cowboy bebop).


----------



## SkyblueMolly

I don't know what forum this belongs in. Is there a forum for fake molecules? Maybe I want NZT-like compounds to exist and to obtain them _too_ badly.


----------



## phuckingnutz

SkyblueMolly said:


> I don't know what forum this belongs in. Is there a forum for fake molecules? Maybe I want NZT-like compounds to exist and to obtain them _too_ badly.



You should be glad that shit doesn't exist.
If you had a few people that had 4 or 5 digit IQ's you'd end up with a singularity and then all bets are off...
So if that shit ever gets invented you better hope to hell you are on the short list for a dose.


----------



## SkyblueMolly

Here's Methylenedioxycarbon Nanotube. %)





Here's some cool music to go along with the molecule.






Here's 2C-IM.


----------



## DL-ark

Originally i wanted to design a morphine based psychedelic - but settled on phenanthrene instead. The one on the bottom is a double 2cb connected at the N position. The one next to the phenanthrene one is based off ethylphenidate/amphetamine/mdma but with a lot of amide groups. I know the double 2-cb wouldnt be active, Im not even sure that amide group could be reached by a receptor if the giant chemical passed the BBB. I honestly wonder about the other 2.

I call the phenanthrene one BTOMPA - Bromo -TriOxyMethylPhenanthrenamide
and the weird amphetamine Beta, 4 oxy phenethylamine methyledioxyamideamphetamine

Edit: I actually really wonder if the phenanthrene based compound would be active?


----------



## Nevermore89

Anbybody got any thoughts on whether this would be active?  Sorry if someone else has posted this before.


----------



## pharmakos

probably won't be -- psychedelic phenethylamines typically don't retain activity when N-methylated or N,N-dimethylated.

these all have an alpha-methyl as well. but here are some examples:

https://www.erowid.org/library/books_online/pihkal/pihkal090.shtml
https://www.erowid.org/library/books_online/pihkal/pihkal105.shtml
https://www.erowid.org/library/books_online/pihkal/pihkal127.shtml


----------



## atara

SkyblueMolly said:


> Here's 3,4-MethyleneDioxyHydroxyEthylAmphetamine, or MDHEA. I wonder if this one's even active though. I hope so.
> 
> 
> 
> 
> 
> More molecules coming soon.



Ha, what a brilliantly simple idea. Hasn't ever been tried, either. The methyl homologue, FLEA, is active, if you're wondering.


----------



## SkyblueMolly

Here's more molecules.

Here's furanylpropamine, or 1-(furan-2-yl)propan-2-amine.




Here's 5-iodo-MDEA, or 5-iodo-3,4-methylenedioxyethylamphetamine.




This molecule is called "mega awake death!". It's a hypothetical wakefulness enhancer witch will keep you awake for OVER 9,000! hours even after you die(you'll literally be dead and yet have your eyes awake).




Here's bipyrene. It's a hypothetical stimulant that is a hybrid of 2-amino-indane and Z-17.




This one is a hybrid of desoxypipradrol and fluorenol. Professor scweak, or squeek. It's a combination eugeroic and stimulant.


----------



## black53

Not sure if this has already been posted:





2-methoxy-4-ethyl-5-methylthio-phenethylamine

Were this or related compounds ever tested? I know that replacing one methoxy with an ethoxy works.
Would seem like an obvious way around various drug laws..


----------



## pharmakos

^ the amphetamine version was created and tested by shulgin: http://www.erowid.org/library/books_online/pihkal/pihkal170.shtml


----------



## black53

Great find, thanks.


----------



## pharmakos

he also made the 4-methyl version of that, as well as the 2-thio-4-methyl/ethyl versions.... the   5-thio-4-ethyl one looks like the most interesting of the four, so good call there.


----------



## black53

And now I wonder how the fly versions of these would be 






2c-e-thio-fly for example

or an unrelated tryptamine (could have already been posted:






or slight variation of lsz:






or

6-tfm-6-nor-lsd (tfm lad?):


----------



## SeenSoFar

black53 said:


> And now I wonder how the fly versions of these would be
> 
> 
> 
> 
> 
> 
> 2c-e-thio-fly for example
> 
> or an unrelated tryptamine (could have already been posted:
> 
> 
> 
> 
> 
> 
> or slight variation of lsz:
> 
> 
> 
> 
> 
> 
> or
> 
> 6-tfm-6-nor-lsd (tfm lad?):



Cool! Keep up the good work! I would bet my stash that the first two would be incredibly interesting to sample!

As for the second two, I think the lysergic acid 2,3-dimethylaziridide would probably not be stable, if you even managed to successfully synthesise it at all. I seem to recall that David E. Nichols tried to synthesise it but the ring kept opening, which is what prompted him to look at the 2,4-dimethylazetidide homologue instead, but don't hold me to that, I could be wrong. I'll bet that if you could synthesise it successfully and keep it together long enough to bioassay it, it would be awesome, but getting there is the real problem. 

As for the 7-trifluoromethyl homologue, messing with the 7-position is tricky. I'm not aware of anything other than alkyl and alkenyl groups being substituted there successfully. Furthermore, I've never heard of an n-trifluoroalkyl substituted tryptamine before either, so this is totally unknown territory. I have no idea what effects such a substituent would have on activity, pharmacokinetics, or toxicity. I could imagine that such a thing might make n-dealkylation more difficult, but that's as much speculation as I'm comfortable with... Anyone else have any comments?


----------



## DL-ark

Got another one - 1,N,N methylenedioxy diethyl ethylamide barbituric acid

Active? I think this would be adequatley lipophilic, although it is a bit large and I would be worried about it breaking down in stomach.

EDIT:

Just made a couple more - these are some GABA/Tapentadol analogues - including one that is supposed to be a mix of the two.


----------



## black53

@ SeenSoFar

I agree, the first two should work.

Your right about the third, it's the lsd analoge Nichols never managed to make. But chemistry is advancing every year, who knows what will happen in 50 years. If I wrote a post in 2010 that LSZ and AL-LAD would soon become available, most ppl would think I'm lying. It should work if it is made.

The fourth one I have no idea. Depends on what properties of the methyl are important.

How about this:





al-lad, lsz, ald-52 in one.. should be active but hard to make imo





the indole replaced by a benzofuran, works for tryptamines.... would also probably be a bitch to make


----------



## Jabberwocky

SkyblueMolly said:


> In the end, Eddie Morra creates NZT-49 (nootropic), leaving NZT-48 (fake nootropic) obsolete. NZT-49 permanently boosts cognition to a four digit IQ and is non-toxic. Continual use may even lead to a 5 digit IQ. Such a hightend intelligence would effectively lead to the cure for certain cancers and even the creation of new elements. Such elements would be in the "island of sability" and allow the person to become nearly indestructable.
> The alternate ending is scarier. There's no NZT-49 in the alternate ending, only NZT-48. NZT-48 only temporarily boosts cognition to a four digit IQ. The toxicity is speculated to come from the thallanyl (thallium based) molecule. Such an error leads to fatal toxicity and permanent brain and body damage. Thallium also causes extreme sickness and death. Death! Thallium is HIGHLY toxic!
> 
> Here's NZT-48, or thallanylzirconio-methyl-tetrahydro-triazatriphenylene.
> 
> 
> 
> 
> 
> Here's NZT-49, or phosphanylzirconio-methyl-tetrahydro-triazatriphenylene.
> 
> 
> 
> 
> 
> Here's the ending of Limitless where he makes NZT-49 in the end.
> 
> 
> 
> 
> 
> 
> Here's the ending of Limitless where he's stuck on NZT-48 and didn't create NZT-49.
> 
> 
> 
> 
> 
> 
> Hypranootropics(super nootropics)
> Nootropics(permanent cognitive enhancement)
> Quasinootropics(temporary cognitive increase, little or no brain damage)
> Pseudonootropics(fake nootropics. The effect is temporary and there's extensive damage, toxicity, and a host of side effects including high addiction potential, blackouts and brain damage)
> 
> I wonder if near indestructability and NZT-49 would ever become real possibilities. That would be so cool! :D %)


fun post, thnx.  Could you writeup "fluid karma", or "substance D' nxt?
//am not even joking lol, your post made me watch/enjoy limitless which i hadn't seen 

[edit: 'fluid karma' is from Southland Tales, 'substance D' is from A Scanner Darkly; both are epic in their own right, but imagine most in this sub have seen these


----------



## Jesusgreen

Given that Benzodiazepines, Apigenin and the Qualones are all somewhat structurally similar and all GABAergic drugs I wonder if carrying over structural modifications that work for say the Qualones to Benzodiazepines or vice versa would result in some interesting changes in effects.

Like: 1-methyl-5-(2-methylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one "Methazepam" (?)





Or: 7-chloro-2-methyl-3-phenyl-3,4-dihydroquinazolin-4-one "Clodesmethaqualone" (?)





Or the one I'd be most skeptical about (Apigenin based) but felt like drawing anyway:
3-methyl-2-(2-methylphenyl)-4H-chromen-4-one "Methachromone"





Just thoughts. Pretty certain the last one would be a silly idea but maybe a little tweaking could make something active.


----------



## blueberries

Some ketamine analogues that I've thought up. I realised that balance (between the amine and the 2 position) in the molecule was essential for holes to occur as such (2-MeO-Ket and N-ethyl-Ket had no holes whatsoever and they were unbalanced as hell (2-MeO-Ket after the methyl is cleaved, so you'd need a halogen there to secure it), though still as potent) so each is balanced by atomic numbers (I have a feeling that the mass would be different though), the only problem is some may be too bulky to succeed. I'd love to hear your thoughts.






EDIT: After calculating their atomic masses, I've found great differences between them, so it's back to the drawing board. However, do you think this would matter? Also the significance of the double bonded oxygen, would this count into the effects profile for holes to occur or is it just there for extra opioid content?

In fact, is there a solid reasoning why and how holes occur on some substances but not others? I'm very interested in this subject as after trying the Ketamine analogues (and ACHs in general), it seems the hole is a rare occurrence. MXE has a hole but it's Methoxy bond is at the 3 position (9/15 after cleavage, N-25/44), possibly making it more balanced than at 2, even though it lacks the atomic mass balance, whereas 3-Br-PCP holds absolutely no activity whatsoever (35/80 at 3, 37/74 at N). This _should_ be an excellent candidate for activity _and_ a hole, however nothing, indicating the need for a balanced compound at 3 is much less than at 2.

This tells me that at the 3 position roughly a third of the overall balanced molecule is needed for a hole to occur, making it more potent but much longer in duration and without the satisfactory hole that Ketamine provides.

Anyway, please let me know if what I am saying is correct or not, I'm still learning!


----------



## black53

@: Jesusgreen:
Methazepam may well have been tested by some pharm company back when benzos were the next big thing 
I mean all the current rc benzos are from old pharm research.

@: blueberries:
Lots of ketamine/pcp/pce/.. related chemicals were tested by UK rc vendors before all of them were banned. I know one offered some very unusual ones for it's advanced customers.


Anyway, what are the important properties of the two methyl groups on the nitrogen in DMT? -CF3 has some similarity to -CH3, so would n,n-ditrifluoromethyltryptamine work?


----------



## blueberries

@black53

Which ones exactly are we talking? Ketamine, 2-MeO-K, NEK, Tiletamine, MXE, 3-MeO-PCP and 4-MeO-PCP, I have tried and only found holes on MXE and Ketamine (and a minor hole on 3-MeO-PCP, containing stark ego-loss with not much else).

As I re-edited, I explained the importance of balance on the N side so making N, N-ditrifluoromethyl-des-N,methyl-ketamine would be a horrific failure if what I am saying is correct, as the atomic number/mass at N would be 73/152, while the 2-position would remain at 17/35. So an increase of 118 in atomic mass. However trifluoromethyls when added to PEA's usually increase potency by a fair amount but the same is true of increasing Halogens at 4 (i.e: 2C-C = 20-40mg, 2C-B = 15-25mg, 2C-I = 10-25mg etc, etc.) which is not the case with Arylcyclohexylamines.


----------



## black53

The ones I know of are:
3-meo-PCP
3-meo-PCE
3-meo-PCPr
3-meo-PCPy


----------



## blueberries

Huh, I didn't realise these were available at some point. Goddamn, I'd have loved to have tried them.


----------



## blueberries

DL-ark said:


>



I'd love to know more about the 2-ketone-2C-B analogue. I had a theory over whether double bonded oxygens would be batter or worse than their methoxy counterparts in 2C's. I'm not sure how that oxygen would work at 3 as every PEA I know has a complete phenyl ring. Does anyone else have speculation as to whether this would work or not? Also the methoxy bond would work better at 6 than at 5, nevertheless you've given me some great ideas, so thanks!

The 6-APB analogue scares me a little though, a double nitrogen? Would this give it opioid content as an analogue of Tapentadol + serotonergic amplification via the MDA pathway? To me it seems like the joining of the two wouldn't work out as expected and would turn into some form of anti-depressant/MAOI but I don't know nearly enough to put my full weight behind this theory. If someone does please, please chime in as I _love_ these innovative compounds!



SkyblueMolly said:


> Here's 5-iodo-MDEA, or 5-iodo-3,4-methylenedioxyethylamphetamine.



I'm interested in this, although I faintly remember that halogenated subbed MDA analogues (save for fluorine) are inactive as halogens would make it too heavy for activity. Also working with the 5 position usually makes quite high dosage compounds like MMDA and 5-Methyl-MDA so utilising the 2 position would be a much better idea IMO.


----------



## DL-ark

^ Thanks, didnt even realize the  implications on the ketone being there, otherwise I would have removed the stupid oxygen. I was just playing around with GABA. Anyway, the apb analogue is going to be difficult to make have properties of an opioid along with keeping the amphetamine. Thinking about it now I realize there is a low likely hood of those nitrogens contributing to activity without being amino groups. Are there any instances of such a compound? I definitely see the potential for some sort of maoi. I wonder if it would then keep its opioid affinity. Id imagine this chemical woul either be wildly   nonselective or very selective for MAO or SERT. Does anyone hsve a QSAR for these?


----------



## sekio

You can't in general dearomatize phenyl rings and expect the compounds to be the same pharmacologically.



> I'd love to know more about the 2-ketone-2C-B analogue. I had a theory over whether double bonded oxygens would be batter or worse than their methoxy counterparts in 2C's. I'm not sure how that oxygen would work at 3 as every PEA I know has a complete phenyl ring. Does anyone else have speculation as to whether this would work or not? Also the methoxy bond would work better at 6 than at 5, nevertheless you've given me some great ideas, so thanks!



It's a cis-diene so it'll Diels-Alder on you. Water could also open the lactone, and the bromine and methoxy at the bottom could likely also get hydrolysed. It's also very unlikely to behave like a methoxybenzene.

Related compounds with 2-pyrone groups are stuff like the kavalactones.



> The 6-APB analogue scares me a little though, a double nitrogen? Would this give it opioid content as an analogue of Tapentadol + serotonergic amplification via the MDA pathway?



Hydrazides are generally a little too reactive for people to use them as drugs. The only ones I know of are things like irreversible enzyme inhibitors... MAOIs.


----------



## DL-ark

^ the oxygenated phenyl was just playing around with the structure of GABA. How would the 2 ketone effect its activity compared to the methoxy? That is without that silly oxygen in the 3 position.


----------



## sekio

It would tautomerize to a phenol.


----------



## DL-ark

^ interesting, thanks for the info, sekio.

I thought that the keto isomer is usually the more stable one, guess I was wrong.

50th post! does this mean I am finally a bluelighter?


----------



## DL-ark

Ok, updated models of the 2 chemicals blueberry commented on. I am curious as to the activity of this diethyl cathinone I have made here. In addition I did the best I could in keeping the ketone, as sekio said it would tautomerize, so I hooked it on to an extra carbon. Although I think I should have gone with an aldehyde group.


----------



## SkyblueMolly

More molecules!
Here's 2C-Zr-I5




Here's PP-028, Piperonyl Piperidine, or Piperonylic Piperidine. PP-028 is a drug based on CX-546.




Here's 3-MTA or 3-MethylThioAmphetamine. It's like a stronger version of 3-Methoxyamphetamine.




Here's 2C-Zr.




Here's 2C-Y.


----------



## blueberries

sekio said:


> It would tautomerize to a phenol.



What if it were already a phenyl? Like this:


----------



## sekio

That's a Texas carbon you've got there. Carbon won't accept 5 bonds.


----------



## DL-ark

blueberries said:


> What if it were already a phenyl? Like this:




As sekio said, carbon wont accept 5 bonds. I think an aldehyde group is best for using the double bond.


----------



## Jabberwocky

he said 5 bonds


----------



## black53

constrained tryptamines, based on http://en.wikipedia.org/wiki/RU-28306 aka constrained dmt:

constrained dmt:





constrained det:





constrained dpt:





constrained met:





constrained mipt:





constrained dipt:





constrained amt:





constrained mpmi:





constrained whatever this would be called:


----------



## blueberries

Someone sent me a Hydrocodone analogue with some phenyl ring hanging off the end so I altered it and made this:






I'm expecting an opioid PCE metabolite with a PPOM-esque main structure. IMO it's a complete clusterfuck but make of it what you will!

PS: The fluorine is for style


----------



## blueberries

black53 said:


> constrained dpt:



I saw a bug that looked like this the other day. It was menacing. I imagine the same for the compound!


----------



## blueberries

DL-ark said:


> As sekio said, carbon wont accept 3 bonds. I think an aldehyde group is best for using the double bond.



Shit, yeah, I kinda forgot about that!


----------



## black53

2c-c analogues:

2c-c:





tcc-2:





2c-c-5eto:





2c-c-5thio:





2c-c-fly:





2c-c-thiofly:





bk-2c-c:





bh-2c-c:





bm-2c-c:





bk-2c-c-fly:





bh-2c-c-fly:





bm-2c-c-fly:


----------



## black53

5-methyl-mda analogues:

5-methyl-5-apb:





5-methyl-5-apdb:





5-methyl-5-mapb:





5-methyl-5-mapdb:





5-methyl-6-apb:





5-methyl-6-apdb:





5-methyl-6-mapb:





5-methyl-6-mapdb:





5-methyl-mdma:





MMDA-2 analogues:

2-methoxy-5-apb:





2-methoxy-5-apdb:





2-methoxy-5-mapb:





2-methoxy-6-apb:





2-methoxy-6-apdb:





2-methoxy-6-mapb:





2-methoxy-6-mapdb:






@blueberries:
lol :D


----------



## sekio

What is this, combinatoric chemistry month?


----------



## black53

something like that


----------



## blueberries

black53 said:


> 5-methyl-mda analogues


  Vs. 





black53 said:


> MMDA-2 analogues



5-sub-MDA analogues are much lower potency than their MMDA-2 and MMDA-3a counterparts, so go for those instead. In fact all the hype surrounding 5-MMDA was in fact caused by either 2 or 3a-MMDA, as what tends to happen with the 5 positions is they greatly reduce potency (See MMDA & practically all 5-Me-MDA reports). They wane to act towards a mescaline type compound rather than a 2C type compound (also just looking but where is Shulgin's final TMA? At 6, 5, 4, opposite the a-Methyl). 

Also looking at METHYL-MMDA-2, adding an N-methyl bond would eliminate most of it's activity, it truly is a wonder how MDMA worked out so well, I'd have thought it would be much stimmy-er to be honest!

DMMDA & DMMA-2, too, would wok fairly well. Another thing to look at is Ethyl, Isopropyl, Vinyl, Ethenyl, Ethynyl, 2-Methyl-Ethynyl, Methyl-trideutero, Nitroxide, Thioxy and possibly Fluorine bonds at these points (but only at 3a (and, hesitantly, at 5), as that Methoxy at 2 is fairly essential and cannot be tweaked with too much, due to stearic hinderance). Basically anything that isn't too bulky and can be able to be broken fairly easy in vivo (so not really halogens, although I'm still unsure over fluorine (that thing can go anywhere!)).

There's just so many analogues in the MDA pile it's ridiculess, and I'm willing to bet each of them would be amazing.


----------



## black53

:D

I'd like to see those constrained tryptamines, 2c-c-fly and tcc-2 too 

And some more:

2c-al





2c-mal





3c-al





3c-mal





dom dragonfly





6-tfm-6-nor-lsd





6-mal-6-nor-lsd





various fluorinated mpa versions for example:





various difluoroamphetamines/methamphetamines, for example:





d-threo-iph:





lisdexfluoroamphetamies, for example lisdex2fa:





eph reverse ester:





iph reverse ester:





all variations on http://imgur.com/a/vYJrY


----------



## blueberries

Ok, I'm not going to draw out each one but you can see where I'm coming from, hopefully!

These are my notes on Tryptamines & Phenethylamines:

TRYPTAMINES


N, N, xx-Trypamines :

DMT 
MET 
MiPT 
MPT
MBT 
MALT 
DET 
EiPT 
EPT 
EBT 
EALT 
DiPT
iPALT 
DPT 
PET 
PiPT 
PBT 
PALT 
DBT 
MBT 
EBT 
iPBT 
PBT 

More xxT's include:

Ethenyl (V)
Ethynyl (Y) 
2-Methyl-Ethenyl (MV)
2-Fluoro-Ethenyl (FV)
2-Chloro-Ethenyl (CV)
Ethyl-Dimethy (IB)

Therefore:

MVT 
EVT 
iPVT 
PVT 
BVT 
ALVT 
MYT 
EYT 
iPYT 
PYT 
BYT 
ALYT 
MMVT 
EMVT 
iPMVT 
PMVT 
ALMVT 
MFVT 
EFVT 
iPFVT 
PFVT 
BFVT 
ALFVT 
MCVT 
ECVT 
iPCVT
PCVT 
ALCVT 
DiBT 
MiBT 
EiBT 
iPiBT 
PiBT 
ALiBT 


Halogens:

DFT 
MFT 
EFT 
iPFT 
PFT 
BFT 
ALFT 

Then all substitutions inbetween using V, Y, MV, FV, CV, iB:

VYT 
VMVT 
VFVT 
VCVT 
ViBT 
YMVT 
YFVT 
YCVT 
YiBT
MVFVT 
MVCVT 
MViBT 
FVCVT 
FViBT 
CViBT 

Substituted Tryptamines (using same N, N substitutaions as previous):

4-HO-xxT

4-AcO-xxT

4-Propioniyl-xxT  

5-MeO-xxT

4-HO-MPMI - alpha-pyrrole n, methylT, 

4-HO-xPMI with N-Substituted attachments.

4-Fluoro-xxt??

4-HO,5-MeO-DMT-5-HemiFLY: furan ring from 5-Meo to 6 position

4/5 benzofuran-xxT - like 4,5 MDO but ABPish. 4=potent, 5=psychedelic

6-HO-xxT - Metabolised from 4-HO-xxT

4, 7 DiMeO 5-Fl/Cl/Pr/etc xxT **

4,5,6 - Halogen - xxT - Halogenated T

5-Ethoxy-xxT

5-Ethyl-xxT

4-HO-xEFT N - 2, fluroethyl-

4-HO-DTFMT - ditrifluoromethyltryptamine

DTFMT - Ditrifluoromethyltryptamine

7-TMT - 7 position could be 'magical' position along with 5

4, 5 MDO-xxT - MDMA Tryptamine

5, 6 MDO-xxT - MDMA Tryptamine

7-MeO/HO/Fl/Cl/Br/I/MeS-xxT - 4 position in phens

2-Me-xxT - weak tryptamines

Mexamine - Endogenous dream compound - 5-Me-T

5-CT - Nonselective, high affinity full agonist at HT1A, B, D, 5A and 7 receptors, as well as at HT2, 3 and 6 with lower affinity. Negligible affinity for HT1E & 1F. It binds strongest to HT1A however.

PHENETHYLAMINES

4-SUBSTITUTIONS:

Methyl
Ethyl
Propyl
isoPropyl
Butyl
Methenyl
Ethynyl (YN)
Propynyl (PYN)
Ethenyl (IV)
Propenyl (PIV)
isoButyl
Carboxy (COOH)
Cyanide
Amine
Ethylamine
Propylamine
Cyclopropylmethyl
Pyrrole
Phosphorous
Benzyl
Napthyl
Morpholine
Allyl
Methallyl
Ethallyl
Propallyl
Thio-Alkyl
Di-Alkyl
Thiodialkyl
Oxo-isopropyl

Fluorine
Chlorine
Bromine
Iodine
Selenium
Tellerium
Fluoromethyl
Fluoroethyl
Fluoropropyl
Chloromethyl
Chloroethyl
Chloropropyl
Bromomethyl
Bromoethyl
Bromopropyl
Iodomethyl
Iodoethyl
Iodopropyl
Difluoromethyl
Difluoroethyl
Difluoropropyl
Dichloromethyl
Dichloroethyl
Dichloropropyl
Dibromomethyl
Dibromoethyl
Dibromopropyl
Diiodomethyl
Diiodoethyl
Trifluoromethyl
Trifluoroethyl

3,4/4,5 DiAlkyl
3,4/4,5-Bnb,
3,4/4,5-Methylenedioxy
4/5/6-Benzofuran


I hope everyone can make sense of this and apply it to various Tryptamines and PEA's

This is the big list and can be tinkered with in anyway possible.

This is but the beginning, we can use these alkyls and halogens to produce multitudes of compounds.

The structure soon turns into art and the greatest compounds can be made from all of these suffixes.

Have Fun!


Oh! And by the way the total number of psychedelic compounds utilising such substitutions are over 50,000. The key is to find that *one* chem that could be a game changer!


----------



## black53

Some of these were already made actually  and are even available for sale..


----------



## blueberries

black53 said:


> Some of these were already made actually  and are even available for sale..



Yep. This is the full line-up of all substitutions. These can be applied anywhere, in the right places of course. On the whole though this is the entire list of substitutions that can be made at appropriate positions. Shulgin (RIP) made but a few of these. T & P structures are now turned into an artform, do what you will with the suffiixes and have fun.

For drawing random chems this is the database. You can go anywhere and add what you will to everything, Indole and PEA combined. So what's next?

Somewhere in the thousands of possible structures, there are golden ones. Find them, test them, distribute them. 

The world is _your_ oyster.


----------



## black53

>So what's next?
Target other signaling systems? Other modes of action ( activity enhancers for example )? Skip the receptors/neurotransmitters entirely and target the upstream effects they produce?


----------



## blueberries

Or directly implant nanobots to agonise/antagonise the receptors to a specified affinity so we can make our own cocktail of drugs to our own personal needs.

Whichever first, I guess, and at the rate that technology is evolving, it certainly could be the nanobots!


----------



## blueberries

I tried to combine the structure of Delorazepam with Ketamine, simply because I wanted it to be named DeLoramine; the closest thing I could think of to DeLorean.

So this is DeLoramine: 
	

	
	
		
		

		
		
	


	



I chose Ketamine because hopefully you'd go back to the future with it!

___________

For good measure: 3C-PO - 
	

	
	
		
		

		
		
	


	



___________

And of course, Ar2-D2: 
	

	
	
		
		

		
		
	


	




___________

I'm in a weird mood tonight..

___________

THIS MUST STOP!


----------



## DL-ark

Ar 2 D2 wont work, argon of course being a noble gas, and will not easily bond with anything at all. Otherwise, 3CPO looks like an actually promising molecule... although since you added the alpha methyl it isnt really 3cpo.


But I am just being a real party pooper, I guess its all fun anyway, although it would be nice if some of those were active too!


----------



## DL-ark

Just made my take on an efavirenz analogue - Although, I just realized it really resembles a psychedelic phenethylamine, analogue'd or not.


----------



## pharmakos

DL-ark said:


> although since you added the alpha methyl it isnt really 3cpo.



naw he had it right... in shulgin's nomenclature, "3C" denotes a molecule with the 3,4,5 substitution pattern and an alpha carbon.  3C-E, for example, is 3,5-dimethoxy-4-ethylamphetamine


----------



## DL-ark

thenightwatch said:


> naw he had it right... in shulgin's nomenclature, "3C" denotes a molecule with the 3,4,5 substitution pattern and an alpha carbon.  3C-E, for example, is 3,5-dimethoxy-4-ethylamphetamine



Aw ok, I always thought using the C was meaning that it wasnt an amphetamine, but I haven't read a whole lot of shulgin's work (although I plan to.)


----------



## pharmakos

its because of the order he came up with everything in... he did the 3,4,5-subbed phenethylamines first (a la Mescaline), then moved his way to  the 2,4,5-substituted amphetamines (DOx).  it wasn't until after he played around with those two classes that he started making the 3,4,5-amphetamines and the 2,4,5-phenethylamines.  so, "2C" stands for the alpha-desmethyl version of its DOx cousin, and "3C" stands for the alpha-methyl version of its Mescaline-analogue cousin. 

so 2C-E is the phenethylamine version of DOET, and 3C-E is the amphetamine version of Escaline (3,5-methoxy-4-ethoxyphenethylamine).


----------



## blueberries

thenightwatch said:


> its because of the order he came up with everything in... he did the 3,4,5-subbed phenethylamines first (a la Mescaline), then moved his way to  the 2,4,5-substituted amphetamines (DOx).  it wasn't until after he played around with those two classes that he started making the 3,4,5-amphetamines and the 2,4,5-phenethylamines.  so, "2C" stands for the alpha-desmethyl version of its DOx cousin, and "3C" stands for the alpha-methyl version of its Mescaline-analogue cousin.
> 
> so 2C-E is the phenethylamine version of DOET, and 3C-E is the amphetamine version of Escaline (3,5-methoxy-4-ethoxyphenethylamine).



Yeah, Shulgin's nomenclature wasn't exactly on point (in some parts(F-22? It sounds like a plane!)) but it did give us the basics for future chems. I don't know how I'd have named it (3C-E) though, maybe MA-4-EO? Doesn't have the same ring to it, in all fairness. Props to Shulgin then!


----------



## N0 W4RN1NG

Posted this on a different forum but didn't receive much feedback. Was wondering what you lot thought.





1-[4-(3-METHYL[1,1-DIPHENYL])-1-methyl-4-piperidyl]AMINOETHANE

DiPhenMethylPipEtAmine; DPMPEA, DPPE

A PCE + Ketobemidone + Desoxypipradrol hybrid which should retain affinity at both NMDA receptors, Mu receptors, and the DAT - for simultaneous, POTENT, DARI + NMDA antagonism + Opioidergic activity in situ.

I realize it might be TOO long lasting...a solution to that which might also enhance mu-affinity would be to add a hydroxyl group at the 1- diphenyl carbon.

This may lower NMDA antagonism though. Shouldn't affect DAT blockade. The keto-piperidine derivative should work as well, ala *etamines.


----------



## DL-ark

N0 W4RN1NG said:


> Posted this on a different forum but didn't receive much feedback. Was wondering what you lot thought.
> 
> 
> 
> 
> 
> 1-[4-(3-METHYL[1,1-DIPHENYL])-1-methyl-4-piperidyl]AMINOETHANE
> 
> DiPhenMethylPipEtAmine; DPMPEA, DPPE
> 
> A PCE + Ketobemidone + Desoxypipradrol hybrid which should retain affinity at both NMDA receptors, Mu receptors, and the DAT - for simultaneous, POTENT, DARI + NMDA antagonism + Opioidergic activity in situ.
> 
> I realize it might be TOO long lasting...a solution to that which might also enhance mu-affinity would be to add a hydroxyl group at the 1- diphenyl carbon.
> 
> This may lower NMDA antagonism though. Shouldn't affect DAT blockade. The keto-piperidine derivative should work as well, ala *etamines.



Wouldn't the DARI action also mean that it would have some action on Norepinephrine reuptake? I don't know how I feel about an adrenergic dissociative.


----------



## N0 W4RN1NG

Not necessarily, although I see your concern. PCP has quite a bit of DARI action IIRC, but lacks any appreciable NET obstruction.


----------



## DL-ark

N0 W4RN1NG said:


> Not necessarily, although I see your concern. PCP has quite a bit of DARI action IIRC, but lacks any appreciable NET obstruction.


Hmm, that is interesting! I haven't seen many compounds that do that.


----------



## blueberries

N0 W4RN1NG said:


> Posted this on a different forum but didn't receive much feedback. Was wondering what you lot thought.
> 
> 
> 
> 
> 
> 1-[4-(3-METHYL[1,1-DIPHENYL])-1-methyl-4-piperidyl]AMINOETHANE



I like this. However, I think it would wane towards the DRI side rather than being an NMDA antagonist/opioid, it could even step into the anti-histaminergic side. I know too little of this SAR to comment though. If someone does a synth, however, consider me a rather small rodent!


----------



## Incunabula

blueberries said:


> ___________
> 
> For good measure: 3C-PO -
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> ___________
> 
> 
> ]



I love that one! It's so cool. I do wonder what the body would do with that PO though?


----------



## N0 W4RN1NG

Fagott said:


> I love that one! It's so cool. I do wonder what the body would do with that PO though?



I can guarantee it would be quickly hydrolyzed into a -OH group, and 4 -OH PEAs are usually not great :/


----------



## black53

benzo analogue of etiz:





thienodiazepine versions of

alprazolam:





flunitrazepam:





few mxe analogues

pcpr mxe





pcpy mxe:





tcp mxe:





tcpy mxe:





tiletamine mxe:





thieno lsd:





think any of these would work?


----------



## blueberries

I was recently thinking of the thienobenzos to be honest! I went with isoprotizolam. I'm not sure how the sulphur would react with the chlorines though as someone had warned them off to me before, so I didn't go much further. Would they work?

That tiletamine MXE scares me though. I _do not like_ Tiletamine!!


----------



## blueberries

N0 W4RN1NG said:


> I can guarantee it would be quickly hydrolyzed into a -OH group, and 4 -OH PEAs are usually not great :/



What about 2C-N? Given, the bodyload and all that but it worked well as an amp and an nbome. Surely the same must be said for the Phosphorous?


----------



## black53

blueberries said:


> I was recently thinking of the thienobenzos to be honest! I went with isoprotizolam. I'm not sure how the sulphur would react with the chlorines though as someone had warned them off to me before, so I didn't go much further. Would they work?
> 
> That tiletamine MXE scares me though. I _do not like_ Tiletamine!!



I just posted a few examples of thio/benzo switches, if the chlorine would be the only problem, just use one without it.
Do you have a pic of isoprotizolam? Sounds interesting.


As for the MXE analogues, again, just posted a whole bunch of them. Some may end up good, right?  It's time for a good one... especially now that MXE is being banned EU wide...


----------



## blueberries

Sure here you go: 
	

	
	
		
		

		
		
	


	




MXE analogues, I think, are mostly dead in the water, although I wouldn't mind seeing a few with that amine in different substitutions. I've been playing around with the ACH's quite a bit but never drawn them properly (most are in my notebook). The few I have done are above in the "analogues that _should_ produce holes" picture. 

IMO ACH's are very fun to design, I mean there are so many ways you can alter them that have just not been tested ('adder', however gave us that backbone - he's definitely a Shulgin-esgue kind of guy!). I could go on all day with ACH analogues but without testing properly I can't find that golden combination. It may be that the golden one is, in fact, MXE and the rest are pure piss. I don't think so though. I mean MXPy looks great, I wonder if subs on that ring would do any good? For the moment there are hundreds that are active but adding subs on the amine ring would square that number.

I've been thinking about 3-Fl analogues a lot, also 4-propylbenzene analogues...I'm thinking a _huge_ change in potency there!


----------



## black53

Interesting, here is one for you:




notice to which it's similar? 

MXE analogues idk.. so many possible ones, some might be ok. On the other hand most other ketamine analogues were crap.

Perhaps we'll be able to simulate activity on our pcs one day... would take a lot of the guess work out of making new ones.
Imo 3-meo-2-oxo-pcp would be good, but that's just a feeling. 

The difluoroamphetamines/methamphetamines should be good too imo. 
Like:





Or fluorinated phenmetrazine analogues like:


----------



## N0 W4RN1NG

blueberries said:


> What about 2C-N? Given, the bodyload and all that but it worked well as an amp and an nbome. Surely the same must be said for the Phosphorous?



The difference is Nitrogen forms more stable bonds with oxygen and carbon then Phosphorus does - look at the rapid metabolism of psilocybin.


----------



## Solipsis

N0 W4RN1NG said:


> The difference is Nitrogen forms more stable bonds with oxygen and carbon then Phosphorus does - look at the rapid metabolism of psilocybin.



That is not really a fair comparison is it? In psilocybin it is a phosphoryl *ester*, and it is one in 3C-PO as well. In 2C-N there is no oxygen and certainly no ester.
The point is that other esters like acetoxies are also readily cleaved but it says nothing about the carbon that is there in the acetoxy, which would bind quite strongly to another carbon.

By the way that phosphate is missing an oxygen


----------



## DL-ark

How about this ether of 2-cb molecules? Am I correct in think that this should be metabolized into two 2-cb molecules?






And how about a giant thread of these hooked together as ethers (kind of)

http://i.imgur.com/cd02f5q.png

I'll let you click the link to see it, as it is pretty giant and ISN'T an ester as I thought.
We can weave this stuff into clothing, or make 2-cb blotter paper. Paper that is actual 2cb.


----------



## black53

if this actually gets split in to 2x 2c-b it would be legal here since it's not a classic ester


----------



## N0 W4RN1NG

Solipsis said:


> That is not really a fair comparison is it? In psilocybin it is a phosphoryl *ester*, and it is one in 3C-PO as well. In 2C-N there is no oxygen and certainly no ester.
> The point is that other esters like acetoxies are also readily cleaved but it says nothing about the carbon that is there in the acetoxy, which would bind quite strongly to another carbon.
> 
> By the way that phosphate is missing an oxygen



I think you misunderstand me - I was simply telling him that, like you said, 3C-PO would rapidly be cleaved into 3C-OH. I never questioned carbons' ability to bind to carbon, haha. 

Also, 2C-N *does* have two oxygens...it is a nitro group, not an amino group:





An amino group would be too hydrophobic to bind to 5HT2x, and therefore probably be inactive.

In addition, I believe in "3C-PO", it would be an* ETHER*, not Ester.

And technically his 3C-PO is ok without an additional oxygen, note the 2 double bonds, not single bonds - all orbitals are used correctly.

EDIT: @ DL- ark and black53, those are not esters actually, DL-ark yours is an ether, Black53 yours is a simple ketone(I know black, you didn't say yours WAS an ester), and both of them would have less-than-ideal conversion into 2C-B...and who knows what the parent compound would do inside the body.

THIS would be an ideal pro-drug into 2C-B, although you would have to be very careful to keep it out of the heat, etc:






Incidentally, that IS an ester, lol.

EDIT2: Actually, yours would not convert into 2C-B at all, you joined the structures at the alpha carbon instead of at the amine. If you wanted to bridge them that way, you could do this:






^Also an ETHER, not an ester...It would break down into 1 (2C-B) and 1 (alpha-hydroxy-2C-B), though.


----------



## DL-ark

N0 W4RN1NG said:


> I think you misunderstand me - I was simply telling him that, like you said, 3C-PO would rapidly be cleaved into 3C-OH. I never questioned carbons' ability to bind to carbon, haha.
> 
> Also, 2C-N *does* have two oxygens...it is a nitro group, not an amino group:
> 
> 
> 
> 
> 
> An amino group would be too hydrophobic to bind to 5HT2x, and therefore probably be inactive.
> 
> In addition, I believe in "3C-PO", it would be an* ETHER*, not Ester.
> 
> And technically his 3C-PO is ok without an additional oxygen, note the 2 double bonds, not single bonds - all orbitals are used correctly.
> 
> EDIT: @ DL- ark and black53, those are not esters actually, DL-ark yours is an ether, Black53 yours is a urea(I know black, you didn't say yours WAS an ester), and both of them would have less-than-ideal conversion into 2C-B...and who knows what the parent compound would do inside the body.
> 
> THIS would be an ideal pro-drug into 2C-B, although you would have to be very careful to keep it out of the heat, etc:
> 
> 
> 
> 
> 
> 
> Incidentally, that IS an ester, lol.



Woops, sorry.. Guess I got the oxygens confused with carbons.

Because 2cb is already relatively stable by itself, would this 2cb ester be more or less as stable as LSD?


----------



## N0 W4RN1NG

DL-ark said:


> ...would this 2cb ester be more or less as stable as LSD?



Less, I think. :/


----------



## DL-ark

N0 W4RN1NG said:


> Less, I think. :/


But then wouldn't it just break down to 2cb or would be it be something else like N-Hydroxy 2cb


----------



## N0 W4RN1NG

It would break down into N-Hydroxy-2C-B (HOB), which in turn would be quickly metabolized in the gut to regular 2C-B.

A fair portion of it would probably break down directly into 2C-B as well, actually.


----------



## DL-ark

N0 W4RN1NG said:


> It would break down into N-Hydroxy-2C-B (HOB), which in turn would be quickly metabolized in the gut to regular 2C-B.
> 
> A fair portion of it would probably break down directly into 2C-B as well, actually.




Sooo.... Problem solved? 

edit: also I wasn't completely wrong for once, hooray!


----------



## N0 W4RN1NG

^ Yeah, but the problem here could be that small amounts could degrade into 2C-B before you want them to, and that could get you in legal trouble.

I wonder if cyclizing the structure would gain more stability...*looks at sekio quizzically*

I.e:







...Shit, here's one that will metabolize into 2C-B *AND* GHB!





The dose of GHB you got would be pretty low, because you would only want to take so much 2C-B, but still...just a cool novelty haha.


----------



## DL-ark

N0 W4RN1NG said:


> ^ Yeah, but the problem here could be that small amounts could degrade into 2C-B before you want them to, and that could get you in legal trouble.
> 
> I wonder if cyclizing the structure would gain more stability...*looks at sekio quizzically*
> 
> I.e:
> 
> 
> 
> 
> 
> 
> 
> ...Shit, here's one that will metabolize into 2C-B *AND* GHB!
> 
> 
> 
> 
> 
> The dose of GHB you got would be pretty low, because you would only want to take so much 2C-B, but still...just a cool novelty haha.



Your first structure has a triple bond which will not work in that place (carbons cant accept 5 bonds) god damn I am dumb


----------



## N0 W4RN1NG

DL-ark said:


> Your first structure has a triple bond which will not work in that place (carbons cant accept 5 bonds)



I know carbon can't accept 5 bonds! (well, technically it can, but I'm not going to get into that)

It's only a quaternary carbon my friend, take a second look at the picture.


----------



## blueberries

N0 W4RN1NG said:


> ...Shit, here's one that will metabolize into 2C-B *AND* GHB!
> 
> 
> 
> 
> 
> The dose of GHB you got would be pretty low, because you would only want to take so much 2C-B, but still...just a cool novelty haha.



I was thinking of this earlier. I noticed throughout the world of compounds that adding a benzene group *somewhere* would create a much more potent version of that compound, as in the case of Bromadol, Etonitazene, NBOMe's, PPOM etc.

So, I give you this on the offchance of it being workable: 
	

	
	
		
		

		
		
	


	




That benzene ring could be modified in a way similar to the aforementioned potent compounds, depending on whether or not it would be workable or not. I tried to make it para, as is the custom but being a 7 sided ring, there are dual options. This is pure SAR theory based on what little I know, so be brutal, as this theory has plagued me for ages now and I want an answer!


----------



## adder

^ Where do you have an additional benzene ring in your modified 2C-B? Making a more potent analogue is not as simple as adding a benzene ring somewhere to a molecule. The reason why this works for various drugs (like bromadol or NBOMe's) is because that additional benzene ring is capable of interacting with another portion of receptors making binding stronger. The N-(2-methoxybenzyl) added to phenethylamines makes NBOMe's look more like LSD if you try to make them overlap like this.






Then we could modify NBOMe's substituting 2-methoxybenzyl with some bioisosteric functional groups and end up with analogues from the second row. I'll make an exception and share this.

---

It's no brainer here, but I've been wondering why we haven't seen 1-(thiophen-3-yl)propan-2-amine popping out and its N-methyl analogue.






It should resemble dopamine more than MPA does and perhaps its oxidized metabolites would be even more active.


----------



## N0 W4RN1NG

adder said:


> It should resemble dopamine more than MPA does and perhaps its oxidized metabolites would be even more active.



Adder, I believe that the a-propyl, N-pyrrolidine deriv of that is available, under the name "a-PVT-2" and it is indeed more potent than a-PVT (the 2-thiophene variant). Meaning you are probably right, and that homologue of MPA should be explored.

What do you think of my "N-dioxazole"(?) 2c-b 2 posts up? Would it be ridiculously unstable?


----------



## DL-ark

N0 W4RN1NG said:


> I know carbon can't accept 5 bonds! (well, technically it can, but I'm not going to get into that)
> 
> It's only a quaternary carbon my friend, take a second look at the picture.


Oh my god I am such a dumbass...


----------



## N0 W4RN1NG

All good, happens to the best of us


----------



## DL-ark

N0 W4RN1NG said:


> All good, happens to the best of us


Well, sorry for trying to call you out anyway.


----------



## DL-ark

Here is a chemical designed to be a psychedelic... It is based off of efavirenz, the FLY series of compounds and.... mescaline(kinda)!


----------



## adder

> What do you think of my "N-dioxazole"(?) 2c-b 2 posts up? Would it be ridiculously unstable?



First of all, 2C-X-NBOMe's doesn't seem to tolerate too many changes to their structure. DOX's drugs don't really benefit from adding NBOMe part as 2C-X's do. So you really need to be careful when you add bulk to a compound's structure.

Also, cyclohexane has completely different chemical properties from benzene. In benzene there is a lot going there, because you've got a delocalized pi system there, so its electrons are capable of creating interaction based on charges and partial charges, especially when it's also substituted. E.g. that's how dopamine interacts with DAT, its 3,4-dihydroxyphenyl part interacts with the same site as the ester part in cocaine and phenyltropanes. And that's also how, I think, the analogues of NBOMe's that I posted yesterday would substitute for LSD/LSZ and 2C-X-NBOMe's. Of course when you change one functional group to another, you have to remember that it may not have exactly the same properties even if it has the same size.

In your compound, you don't have a secondary amine there. You've got a dioxazepanone fused into the ethyl side-chain, too many oxygens there and that nitrogen won't be able to interact in the way amines in 2C-X's and 2C-X-NBOMe's interact with the 5-HT(2A) receptors. Perhaps it would be metabolised into some amount of 2C-B, but that's just about it. The 4-methylcyclohexyl part (the one that you mistook for phenyl, I guess) certainly won't substitute for 2-methoxybenzyl in NBOMe's. Generally I don't think that your original compound would be stable, also, I don't really think that it would pay off to synthesize it. But above all I think that your molecule is too big to fit in as NBOMe's fit into the receptor's cleft.


----------



## DL-ark

adder said:


> First of all, 2C-X-NBOMe's doesn't seem to tolerate too many changes to their structure. DOX's drugs don't really benefit from adding NBOMe part as 2C-X's do. So you really need to be careful when you add bulk to a compound's structure.
> 
> Also, cyclohexane has completely different chemical properties from benzene. In benzene there is a lot going there, because you've got a delocalized pi system there, so its electrons are capable of creating interaction based on charges and partial charges, especially when it's also substituted. E.g. that's how dopamine interacts with DAT, its 3,4-dihydroxyphenyl part interacts with the same site as the ester part in cocaine and phenyltropanes. And that's also how, I think, the analogues of NBOMe's that I posted yesterday would substitute for LSD/LSZ and 2C-X-NBOMe's. Of course when you change one functional group to another, you have to remember that it may not have exactly the same properties even if it has the same size.
> 
> In your compound, you don't have a secondary amine there. You've got a dioxazepanone fused into the ethyl side-chain, too many oxygens there and that nitrogen won't be able to interact in the way amines in 2C-X's and 2C-X-NBOMe's interact with the 5-HT(2A) receptors. Perhaps it would be metabolised into some amount of 2C-B, but that's just about it. The 4-methylcyclohexyl part (the one that you mistook for phenyl, I guess) certainly won't substitute for 2-methoxybenzyl in NBOMe's. Generally I don't think that your original compound would be stable, also, I don't really think that it would pay off to synthesize it. But above all I think that your molecule is too big to fit in as NBOMe's fit into the receptor's cleft.


Wow, you really know your stuff!


----------



## N0 W4RN1NG

Adder, thanks for your detailed response! But I think you analyzed blueberries' compound, which I knew wouldn't work, for reasons you have described well.

I was asking about the stability of these:










Not as active compounds in their own right, but as clever pro-drugs.


----------



## adder

Oh, I'm really sorry. I got set back with benzodiazepine withdrawal and I feel so dumb at times lost deep in thoughts.

With the second compound you'd probably get both 2C-B and GBL as metabolites, because these nitrogen-oxygen bonds should be fairly easy for human body to break. I'm not really sure whether you'd get appreciable amounts of these drugs, perhaps the compound or some other metabolite would be excreted very fast. But like I said, it would be a challenge to synthesize it first, you'd have a hard time finding an investor, I guess.  I think you need someone else more experienced to fully answer your question.

What's with the first compound? What would you really want to get as a second metabolite? Ethynol perhaps? With the triple bond there and the size of the ring your body would metabolize it into a straight chain alkenol that would be quickly hydroxylated and thus very short-lived. But that's a tricky one for me, I don't really have experience with such small molecules to be honest.


----------



## endotropic

N0 W4RN1NG said:


> I was asking about the stability of these:




That alkyne will probably be highly reactive with that much ring strain put on it (alkynes prefer 180* orientation), so not terribly stable I would imagine.


----------



## black53

> EDIT: @ DL- ark and black53, those are not esters actually, DL-ark yours is an ether, Black53 yours is a simple ketone(I know black, you didn't say yours WAS an ester), and both of them would have less-than-ideal conversion into 2C-B...and who knows what the parent compound would do inside the body.


I specifically said that it's not an ester. Our law is very clear regarding this - esters and ethers of illegal substances are illegal too. So if this would metabolize to 2c-b it would be 100% legal. Now would it metabolize to 2c-b and if yes how fast/how much I have no idea.


----------



## DL-ark

Another attempt at a tapentadol based/2c ish chemical. I just read that Tapentadol is already a NARI/SRI, so this may suggest that it already acts similarly to a subsituted phenethylamine (although its self not being a substituted phenethylamine. Of course, SERT/NE affinity is not often a characteristic for psychedelic phenethylamines, however this activity may suggest that Tapentadol's structure acts similarly to phenethylamines with receptors (at the  very least at NE/SERT).


The goal is a psychedelic with in vivo mu-opioid receptor agonism. 25i-Nbome has very high affinity for mu-opioid in vitro, but it is unknown whether it is an agonist/antagonist or simply has low affinity for mu-opioid in vivo.






And here I have a potential new NMDA antagonist similar, but still distinctive from ketamine or MXE. Also, it kinda looks like a robot dancing! Either it is dancing or shaking it's fist at someone.


----------



## adder

I don't think there's a chance that your tapentadol derivative would work as an opioid. Putting chlorine on the aromatic ring likely abolishes all the opioid activity, because it's hydrophobic and there must be a group capable of forming hydrogen bonds close to the aromatic ring for an opioid to work (this applies to almost all opioids known today if not all). Perhaps you could get away with a fluoro group or a trifluoromethyl group instead of chlorine as fluorine can form hydrogen bonds, but it's not a certain thing. Fluorine can only function as a proton acceptor (but that's still rare in organic compounds) and hydroxyls can be both acceptors and donors. For a very weak mu opioid agonist like tapentadol I don't think changing hydroxyl to fluoro or trifluoromethyl would work well anyway.

The ortho-methoxy group in your compound corresponds to C4 in morphinan and there are quite a few morphinans that have hydroxy or methoxy there instead of substitution at C3, so after demethylation the hydroxyl there might work if it wasn't for the chloro (and probably the other methoxy) that would mask it.

What's up with the additional primary amine at beta-carbon in the alkyl chain? This is what could kill both opioid and serotonergic activity. Without that amine, the N-demethylated and N,N-dimethylated metabolites could be SRIs.

The other compound doesn't really follow any SAR for dissociatives, at best it could interact with SERT (and perhaps NAT).


----------



## DL-ark

adder said:


> I don't think there's a chance that your tapentadol derivative would work as an opioid. Putting chlorine on the aromatic ring likely abolishes all the opioid activity, because it's hydrophobic and there must be a group capable of forming hydrogen bonds close to the aromatic ring for an opioid to work (this applies to almost all opioids known today if not all). Perhaps you could get away with a fluoro group or a trifluoromethyl group instead of chlorine as fluorine can form hydrogen bonds, but it's not a certain thing. Fluorine can only function as a proton acceptor (but that's still rare in organic compounds) and hydroxyls can be both acceptors and donors. For a very weak mu opioid agonist like tapentadol I don't think changing hydroxyl to fluoro or trifluoromethyl would work well anyway.
> 
> The ortho-methoxy group in your compound corresponds to C4 in morphinan and there are quite a few morphinans that have hydroxy or methoxy there instead of substitution at C3, so after demethylation the hydroxyl there might work if it wasn't for the chloro (and probably the other methoxy) that would mask it.
> 
> What's up with the additional primary amine at beta-carbon in the alkyl chain? This is what could kill both opioid and serotonergic activity. Without that amine, the N-demethylated and N,N-dimethylated metabolites could be SRIs.
> 
> The other compound doesn't really follow any SAR for dissociatives, at best it could interact with SERT (and perhaps NAT).



Eh, the amine is to make it more phenethylaminy, I put it in there and meant to remove it but forgot when I actually generated the image to do that.

What if it was the S- S- entiamer of tapentadol, which is more potent on mu-opioid, would that work better with a chlorine? Or better yet, what if I replaced the chlorine with an ethyl?


----------



## adder

Tapentadol mostly relies on its spatial configuration to fit into mu opioid receptors, so changing stereochemistry would be a bad idea.

If you replaced chlorine with an ethyl, that wouldn't do anything good for opioid activity. Ethyl (generally alkyl) and chloro are both hydrophobic groups, and you need a hydrophilic group on the aromatic ring. Classes of compounds capable of hydrophilic interaction are alcohols, carboxylic acids, amines, amides, also sulfonic acids, sulfonamides, etc. etc. Using a methoxy instead, perhaps you could end up with some psychedelic compound a la TMAs that could be metabolised into an active opioid. But honestly I think it's going to be much harder than that. The SARs for opioids and psychedelics differ so much that I guess you will need to work in 3D to design a compound that could be both an opioid and a 5-HT(2A) receptor agonist psychedelic. Additional methoxy groups as in phenethylamines may be too much to fit into MOP receptors. Just look at how complex ibogaine and its analogues are to bind at both 5-HT(2A) and opioid receptors and it only does it effectively at relatively high doses.

Of course depending on the rest of a compound's molecule you don't necessarily need a phenolic hydroxy group to have an opioid. Pethidine and methadone don't have a hydroxy on their aromatic rings and yet they're both quite potent compared with morphine. There's a nice article on the 3D model of a pharmacophore for mu opioid receptors. It also compares how various opioids overlap. It's called "Consensus 3D Model of μ-Opioid Receptor Ligand Efficacy based on a Quantitative Conformationally Sampled Pharmacophore". Also, try googling for an image showing beta-FNA binding to a mu opioid receptor, it gives a general idea where and what types of functional groups you need in a compound to make it an opioid, it should be somewhere on www.nature.com. I think it's a good start. Then you can look for some sites and articles on bioisosterism, it's used to design new compounds based on existing ones.

This is such a complex subject that a small message on a board isn't enough to fit in all the important stuff about it. At the beginning almost every time I searched for some little bit of information when something was wrong with my idea, there was a lot of things new to me and I'm still learning the ropes.:D


----------



## pharmakos

and even if you did come up with a compound that bound to both the mu opioid receptor and the 5ht-2a receptor, there's no telling whether the relative potency of the two effects would be balanced enough for the chemical to effectively fill both functions at doses that are both noticeable and safe.  if its potency as an opioid is 10x higher than its potency as a psychedelic then you would pass out or die before you started to trip.  conversely, if its potency as a psychedelic was 10x higher than its potency as an opioid then your ego would be pretty much shattered before you even felt so much as a numb opioid itch.


----------



## DL-ark

thenightwatch said:


> and even if you did come up with a compound that bound to both the mu opioid receptor and the 5ht-2a receptor, there's no telling whether the relative potency of the two effects would be balanced enough for the chemical to effectively fill both functions at doses that are both noticeable and safe.  if its potency as an opioid is 10x higher than its potency as a psychedelic then you would pass out or die before you started to trip.  conversely, if its potency as a psychedelic was 10x higher than its potency as an opioid then your ego would be pretty much shattered before you even felt so much as a numb opioid itch.




Thats why it is a challenge!

anyway @adder thanks for the suggestions on where to look for info, definitely going to check those out at some point.


----------



## black53

water soluble flubromazepam anyone?


----------



## black53

ok, so if:




is 2c-c-fly

and




is chlorodragonfly

what would these 2 be called:


----------



## Transform

They don't have names. The increased rigidity of the fourth one should increase potency compared to 2C-X fly but I don't believe that's ever been made, perhaps due to synthesis challenges.


----------



## black53

It was meant more as what would you call them if they were made or what would be a logical name for them.

I'd call the first DOC-fly and the second 2c-c-saturatedfly.


----------



## Transform

black53 said:


> It was meant more as what would you call them if they were made or what would be a logical name for them.
> 
> I'd call the first DOC-fly and the second 2c-c-saturatedfly.



That would be 2c-c-unsaturatedfly; bit of a mouthful.


----------



## black53

Yeah, I'm retarded today. Not only the saturated/unsaturated mistake, but I called DOC-fly DOB-fly on another board 

2c-c-fruitfly? (since fly, dragonfly and butterfly are already taken)


----------



## WSH

black53 said:


> 2c-c-fruitfly? (since fly, dragonfly and butterfly are already taken)



How about 2c-c-I-believe-I-can-fly?

It would be a very suitable name for a psychedelic


----------



## Transform

http://isomerdesign.com/PiHKAL/explore.php?domain=tk&id=2031&name=2C-B-DFLY

Who knew.

2C-B-DFLY is the name.


----------



## black53

Nice find


----------



## blueberries

The latter one would be 2C-C-Dragonfly I believe.

But in all honesty, who really cares what they're called, just get them in my belly!


----------



## black53

Think any of these would work as a mxe/ket replacement?


----------



## pharmakos

i would try them


----------



## black53

I have more 

MXE = 3-meo-2-oxo-pce
BXE and IXE got rid of the 3-meo and replaced it with 2-bromo or 2-iodo (ketamine has 2-chloro), but kept the 2-oxo-pce part, so bxe = 2-bromo-2-oxo-pce and ixe = 2-iodo-2-oxo-pce

another option would be to keep the 3-meo-2-oxo and replace pce with other possibilities:

3-meo-2-oxo-pcpr (MXR?)






3-meo-2-oxo-pcpy (MXY?)






3-meo-2-oxo-tcp (MXT?)






3-meo-2-oxo-pcp (MXPCP since MXP is already taken)






3-meo-2-oxo-tiletamine (MXTA?)






3-meo-2-oxo-TCPy (MXTY?)


----------



## DL-ark

Top molecule is originially intended to be an antihistamine/GABA agonist, used as a powerful anxiolytic/antiemetic etc.
The one to the left of that is kind of a silly cyclized GABA/Lactone, made to look a bit like 2cb.
Now here is a silly cyclobutadiene based 2-cb thingy, probably would not be very stable at all, unfortunately.
the methylone look alike I think may have some potential, does anyone know how stable and active this would be?

The rest are just kind of silly.


----------



## black53

The top left looks nice 

Idk about your version of bk-mdma, but I'd make bk-5 and 6-mapb.

And some more potential MXE replacements (yeah, I'm bored):
2-chloro-pce





2-chloro-2-oxo-pcp - CXP





2-chloro-2-oxo-pcpr - CXR





2-chloro-2-oxo-pce - CXE


----------



## DL-ark

black53 said:


> The top left looks nice
> 
> Idk about your version of bk-mdma, but I'd make bk-5 and 6-mapb.



Thanks, the bk-mdma one started out as trying to use propylhexedrine with a methylenedioxy on it, but I figured it would be too unstable with all the lack of bonds on the cyclohexane. However, in theory the bk, and the double bonds wouldn't be needed but it would probably not be very stable, but it might be fairly active, anyway, just kind of playing around.

Anyway, do you know how active the top left would be? Was I correct in saying it would have antihistamine/GABA activity. I think a compound with that sort of activity could be an amazing anxiolytic/sedative. I think it might be better if I put a N,N dimethyl on it, like how diphenhydramine has.

If it doesn't have that activity what do you think it may have?

By the way, I really like the look of CXP


----------



## black53

Sorry, can't say I know if your top left would work or not and I'd rather not guess because it might be totally wrong... it certainly looks like a real drug, if that helps 

Thanks for the CXP.... I think that if we start from MXE (3-meo-2-oxo-pce) and ketamine (2-chloro-2-oxo-pcm), the pcm/pce/pcp/... determines the basic duration/potency/binding, the 2-oxo lowers potency and duration to something more manageable and the 3-meo pushes the experience towards something more positive and affects binding to a certain degree. Not sure about the 2-chloro, but perhaps that is responsible for K-holes being easy to achieve?


Were beta fluorine 2c-xs ever considered? The C-F bond is similar to the C-H bond, you'd get rid of dimerization problems, .. Or is there some reason they are likely a bad idea:





What about bk-2c-x-nboh? Again, no dimerization, probably a dose between 10-20 mg, ...:


----------



## DL-ark

black53 said:


> Sorry, can't say I know if your top left would work or not and I'd rather not guess because it might be totally wrong... it certainly looks like a real drug, if that helps
> 
> Thanks for the CXP.... I think that if we start from MXE (3-meo-2-oxo-pce) and ketamine (2-chloro-2-oxo-pcm), the pcm/pce/pcp/... determines the basic duration/potency/binding, the 2-oxo lowers potency and duration to something more manageable and the 3-meo pushes the experience towards something more positive and affects binding to a certain degree. Not sure about the 2-chloro, but perhaps that is responsible for K-holes being easy to achieve?
> 
> 
> Were beta fluorine 2c-xs ever considered? The C-F bond is similar to the C-H bond, you'd get rid of dimerization problems, .. Or is there some reason they are likely a bad idea:
> 
> 
> 
> 
> 
> What about bk-2c-x-nboh? Again, no dimerization, probably a dose between 10-20 mg, ...:


I haven't personally seen any beta-fluorines, it definitely looks like an interesting concept as far as research chemical design goes. One concern is the stability of putting a halogen in a spot like that, although I am not quite versed well enough to give a proper prediction. 

For the bk-nbome, I think if the dose is lowered by that, it kind of defeats the purpose of NBOMes/NBOHs, one of the big appeals is that they are somewhat similar to LSD, and even come on blotter paper. The low dose also means that it can be mass produced very easily, meaning that they have that trademark NBOx inexpensiveness. If people are looking for a more expensive higher dose psychedelic, generally they would choose the 2Cx series or DOx. Regardless, it may serve as another legal replacement if NBOHs get scheduled.

Anyway, I dont mean to be nitpicky, but your version of your NBOH has an extra carbon inbetween the benzyl and the bk-2cb. What you have there is bk 2cb-NPOH (N-phenyl hydroxy).


----------



## black53

Idk about the synth, that may well be hard, but as far as I know the C-F bond is very strong and once attached the F tends to stay attached. Of course it might interfere with binding or make the duration too long or whatever... idk... but it looks like an obvious substitution to try.

The bk-2c-x-nboh... that's kinda the point it lowers the dose from the very high bk-2c-x dose to something smaller, but doesn't lower it enough to make it super potent and dangerous to handle. It also prevents dimerization. I picked NBOH over NBOMe because the NBOHs have a shorter duration and less unwanted bodyload. Perhaps the duration might even become lower than bk-2c-x, which is a bit long for some people. And if you want it to fit on a blotter... bk-2c-p-nbome might.... or bk-2c-tfm-nbome.

I think the drawing is correct because:
a) a benzyl is this - 
	

	
	
		
		

		
		
	


	



b) all other NBxx drawings I've ever seen have the carbon there.


----------



## DL-ark

black53 said:


> Idk about the synth, that may well be hard, but as far as I know the C-F bond is very strong and once attached the F tends to stay attached. Of course it might interfere with binding or make the duration too long or whatever... idk... but it looks like an obvious substitution to try.
> 
> The bk-2c-x-nboh... that's kinda the point it lowers the dose from the very high bk-2c-x dose to something smaller, but doesn't lower it enough to make it super potent and dangerous to handle. It also prevents dimerization. I picked NBOH over NBOMe because the NBOHs have a shorter duration and less unwanted bodyload. Perhaps the duration might even become lower than bk-2c-x, which is a bit long for some people. And if you want it to fit on a blotter... bk-2c-p-nbome might.... or bk-2c-tfm-nbome.
> 
> I think the drawing is correct because:
> a) a benzyl is this -
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> b) all other NBxx drawings I've ever seen have the carbon there.


Shit sorry, you are right, for some reason I always thought it was just a bond from the nitrogen to the ring. I was also a bit high I guess, in any case. Sorry, once again im calling out people and being wrong like an asshole.


----------



## black53

Haha, no problem man, everyone makes mistakes. Just look at my naming of the flys on the previous page :D


----------



## ebola?

black said:
			
		

> What about bk-2c-x-nboh? Again, no dimerization, probably a dose between 10-20 mg, ...:



We have no basis to expect this: the world of n-benzyl-phenethylamine SAR is topsy turvy, with surprises at every turn.  We don't even have firm evidence predicting an increase vs. a decrease in potency from the parent bk-2Cx.  Still, this compound seems like it's worth a try...the activity of bk-2cb is encouraging in this respect.




			
				DL-ark said:
			
		

> For the bk-nbome, I think if the dose is lowered by that, it kind of defeats the purpose of NBOMes/NBOHs, one of the big appeals is that they are somewhat similar to LSD, and even come on blotter paper. The low dose also means that it can be mass produced very easily, meaning that they have that trademark NBOx inexpensiveness. If people are looking for a more expensive higher dose psychedelic, generally they would choose the 2Cx series or DOx. Regardless, it may serve as another legal replacement if NBOHs get scheduled.



Eh...It's uncharted territory, and it might be qualitatively superior to or at least distinct from the 25x-n-benzyl-phens.  Dosage from 10 to 100 mg is way more wieldy for most end users.  I also disagree with you about the "purpose" of the nbomes...they are what we make of them, and I find the primary attraction simply that they are qualitatively distinct from other compounds.

ebola


----------



## black53

> We have no basis to expect this: the world of n-benzyl-phenethylamine SAR is topsy turvy, with surprises at every turn. We don't even have firm evidence predicting an increase vs. a decrease in potency from the parent bk-2Cx. Still, this compound seems like it's worth a try...the activity of bk-2cb is encouraging in this respect.


You're right, the bk might change the effect on potency a NBOH modification would have on bk-2c-b. But since they are putting this (ok NBOMe, but still) on everything to see what happens, I'd say bk-2c-b would be a good candidate. And since NBOHs usually don't last as long as NBOMes and have less side effects, I'd pick bk-2c-b-nboh over bk-2c-b-nbome if I was testing new compounds.


I guess a 10-20mg dose and a little shorter duration is the best case result.


----------



## DL-ark

This is an ester of GABA and Propofol that should make a pretty powerful sedative.


----------



## Transform

That is a cool suggestion! I would not expect it to be stable in that orientation though, I would bond the other end of gaba to give their carbamate.

On second thoughts it looks like you have just added an extra carboxyl group, I would stick with the regular ester.


----------



## DL-ark

Transform said:


> That is a cool suggestion! I would not expect it to be stable in that orientation though, I would bond the other end of gaba to give their carbamate.
> 
> On second thoughts it looks like you have just added an extra carboxyl group, I would stick with the regular ester.



Woops, I was playing around on where I wanted the oxygen for the ester and I guess I forgot to remove the other one. I agree, stick with the regular ester.

I made a revised version, with the gaba reversed to make it a carbamate, as to your suggestion.


----------



## blueberries

A friend came up with this:






So I decided to tinker with it a bit and came up with these two. Firstly I figured a TFM bond would increase potency but eliminating one to give it a broken ring capability:






Then I figured a propylcyclohexane ring would be better for potency and include that broken ring capability:






EDIT: Bugger, seems I didn't take adder's advice on the last page to heart with the 'no extra benzene bits'! disregard the last compound.

Also looking at a 2C-B/4-MAR analogue, I came up with this:


----------



## DL-ark

I made some alpha carboxylic acid analogues of MDA, MDPEA, and DMT. Hopefully aromatic amino acid decarboxylase breaks off the carboxyls. MDPEA is not a drug which has been used as it too closely resembles dopamine and is broken down in first pass metabolism. the carboxy MDA probably isn't too stable and one could end up with MDPEA or just some other inactive compound like phenyl propanoic acid. none of these should be taken with MDMA or any serotonin releaser as depletion of monoamines will make AADC more active, from what I understand.


I'd also bet if they do work, they would be pretty neurotoxic, as they would inhibit AADC from making serotonin from 5-htp and from making dopamine from levodopa. Talk about depletion! After the drug wears off ofcourse one could take their supplements and they would work as normal, in addition one would probably have a small excess of precursor amino acids which would be quickly metabolized into neurotransmitters by the recently upregulated AADC enzymes.


So, four possibilities based on my speculation: 
1. Ultra hangover with depression and all the works from an entactogen hangover.
2. Strong normal empathogenic effects followed by milder effects (depletion). Quick recovery from hangover as there is excess precursor amino acids and AADC is upregulated.
3. mild comeup (inhibition of AADC -> less serotonin/dopamine to begin with) as all of the drug is metabolized, AADC is upregulated and there is excess 5-htp and ldopa. These are metabolized to the now much needed dopamine/serotonin. excess + upregulation = more serotonin = longer lasting release. normal hangover (maybe quicker recovery because of upregulation?)
4. No activity at all...

Of course non of this applies to the dmt version.

this is all speculative, im not even sure if enzyme upregulation is a thing.


----------



## black53

anyone else think it would be great?


----------



## sekio

whats to say flunitrazolam wouldn't be soluble a la midazolam?


----------



## black53

could be, but the third one could be made as a salt and freely soluble at neutral ph


----------



## DL-ark

Should have put an extra methoxy on tp2c, the way its drawn up now its probably inactive as a psychedelic, perhaps it may be a histamine agonist or other psychostimulant.
Chlorophenbarbamide felt too obvious as an interesting idea. I doubt however it is useful or even safe for abuse. It may make more an excellent dual action anesthetic.
Next to that I've made a funny looking molecule. Look closely and you'll see the inspiration for it. I have no idea what sort of activity it might have, perhaps opioid, perhaps nmda, perhaps even 5-ht2a.
Next one is a compound which should be serotoninergic and could have opioid activity similar to ibogaine.


The rest im sure look silly to more versed members but I have made these with the intention of these being active in some way.

*oh also chlorophenbarbamide is missing the amide on that other side of the ketone to make it barbituric acid.*


----------



## Tim3

May I please ask, if you have no idea about chemistry, can you just make something and use it on yourself?


----------



## DL-ark

Tim3 said:


> May I please ask, if you have no idea about chemistry, can you just make something and use it on yourself?


To make it you would have some ideas about chemistry in the first place unless you are doing something simple and shady like heroin from morphine.


----------



## ebola?

> May I please ask, if you have no idea about chemistry, can you just make something and use it on yourself?



No, no you can't, depending on your definition of "make", eg, you could likely easily synthesize freebase cocaine from cocaine hcl. 

ebola


----------



## DL-ark

ebola? said:


> No, no you can't, depending on your definition of "make", eg, you could likely easily synthesize freebase cocaine from cocaine hcl.
> 
> ebola




Or freebase methylphenidate from methylphenidate hcl...



good ol' kitty crack


----------



## sekio

You can eat dirt from your front yard if you want, there's nothing stopping you but common sense and social mores. So yes, you can make whatever drug or chemical you want and eat it if you so choose. It's just that generally that's a mighty risk that could land you in the hospital at best and a grave at worst. Such is the reason Shulgin has his titration up from nanograms.

People generally stick to making closely related derivatives of chemicals that have known activity first, and then test them in cell culture or animal models to make sure they aren't acute toxins,l before human ingestion takes place. The lucky few make compounds (or close analogs_ that have already been tested in biological systems and usually have already been patented for some use (mephedrone, MXE, JWH analogs), so the hard work is done first by someone else and they reap the profit.

(either way - Tim is banned because he's not very creative as an alt account of a known spammer/shit poster. So sorry, Tim, but we don't need to put up with your shit. The mystery NDRI you take is not good for you.)


----------



## SeenSoFar

A nice, simple one for you all. A ring-opened morphinan analogue. Because of the ring-opening it should bypass the analogue clauses of many countries because they specifically refer to morphinan analogues, which, since the 4th ring is opened, this is not. It is merely a bizarre phenanthrene, which is outside the scope of the legislation, in my country and others. The morpholine ring was just the first thing that came to mind, that also helped to further distance it from its parent compound. It could just as easily be replaced by an n,n-dimethyl, n-methyl-n-phenethyl, or whatever else the mind desires. Thoughts?


----------



## blueberries

Any ideas if this could work?


----------



## DL-ark

SeenSoFar said:


> A nice, simple one for you all. A ring-opened morphinan analogue. Because of the ring-opening it should bypass the analogue clauses of many countries because they specifically refer to morphinan analogues, which, since the 4th ring is opened, this is not. It is merely a bizarre phenanthrene, which is outside the scope of the legislation, in my country and others. The morpholine ring was just the first thing that came to mind, that also helped to further distance it from its parent compound. It could just as easily be replaced by an n,n-dimethyl, n-methyl-n-phenethyl, or whatever else the mind desires. Thoughts?


That looks really good, and it gave me an idea for novel opioid:





The NBOME series has a very high affinity for mu-opioid, but since it has like 20x higher affinity for 5-ht2a, one doesn't feel it. It shows that a structure like this could be possible for mu opioid affinity.


----------



## black53

blueberries said:


> Any ideas if this could work?


Wouldn't the H3C be too big to fit? Perhaps an F....


----------



## blueberries

I love your thinking! I was toying around with putting one there as I do love the 'ol fluoros but I decided to stick with a methyl to set a baseline. Any idea what the effects or even just potency would be like? I've not seen anything like it before, but it must have been thought of, no?


----------



## black53

I'd put a F there, it's about the same size as a hydrogen, the methyl is imo too big.


----------



## SeenSoFar

Another quick one for you all. This one is for sure outside the scope of most every analogue clause it there, and almost sure to be a very powerful μ-opioid agonist. I would really like to take this one for a spin, I'd bet it would be fantastic! Any thoughts?


----------



## blueberries

black53 said:


> I'd put a F there, it's about the same size as a hydrogen, the methyl is imo too big.



You could always dideuterate it? Then again it wouldn't really do much in terms of effects. Hydroxy? Or even an amine?

How about 2 fluorines on the IAP skeleton?! Or actually the bottom one would be a fluorine then the top a methoxy to form the broken ring.


----------



## DL-ark

SeenSoFar said:


> Another quick one for you all. This one is for sure outside the scope of most every analogue clause it there, and almost sure to be a very powerful μ-opioid agonist. I would really like to take this one for a spin, I'd bet it would be fantastic! Any thoughts?


Maybe another hydroxy? Either on the phenyl or the piperidine?


----------



## DL-ark

blueberries said:


> You could always dideuterate it? Then again it wouldn't really do much in terms of effects. Hydroxy? Or even an amine?
> 
> How about 2 fluorines on the IAP skeleton?! Or actually the bottom one would be a fluorine then the top a methoxy to form the broken ring.



Hydroxy might hurt the BA I believe. But, maybe you could use an acetyl group, which will metabolize to hydroxy like 4-aco-dmt or heroin?

Like this:





What about something like this?


----------



## adder

SeenSoFar said:


> Another quick one for you all. This one is for sure outside the scope of most every analogue clause it there, and almost sure to be a very powerful μ-opioid agonist. I would really like to take this one for a spin, I'd bet it would be fantastic! Any thoughts?



Why do you think it would be an opioid? I bet it's not an opioid at all or a very very weak one at best, the nitrogen is differently orientated in relation to the aromatic ring than in morphinans and related opioids. No matter how you rotate it, the nitrogen seems to be too far away and the additional bulk doesn't bode well either. Keeping all that in mind, it wouldn't pay off to do the synthesis, which would be quite complicated.

Cheers!


----------



## SeenSoFar

adder said:


> Why do you think it would be an opioid? I bet it's not an opioid at all or a very very weak one at best, the nitrogen is differently orientated in relation to the aromatic ring than in morphinans and related opioids. No matter how you rotate it, the nitrogen seems to be too far away and the additional bulk doesn't bode well either. Keeping all that in mind, it wouldn't pay off to do the synthesis, which would be quite complicated.
> 
> Cheers!



Well, in 3D it actually overlays extremely closely with both morphian and phenylpiperidine opioids. As for extra bulk, the N-Phenethyl substitution actually works to increase potency quite well in most every opioid. I would venture a guess that it would be extremely potent.


----------



## black53

>You could always dideuterate it?
Isn't the point of your molecule to make a legal analogue? Deuterium counts as hydrogen. The properties may be a little different, but it's not very well researched.... now replacing the hydrogen wtih http://en.wikipedia.org/wiki/Kaonic_hydrogen would probably be a new substance, but unless you have a huge particle accelerator...


----------



## blueberries

DL-ark said:


> Hydroxy might hurt the BA I believe. But, maybe you could use an acetyl group, which will metabolize to hydroxy like 4-aco-dmt or heroin?
> 
> Like this:
> 
> 
> 
> 
> 
> What about something like this?



The first I love, think it'd be great. Second not so much, look at F2 & 22. Completely down in activity. Nothing, really unfortunate cos looking at them you'd think they'd be great. Also deuterating them wouldn't be to get around laws, I honestly don't give a fuck about drug laws anymore, the effects profile however is a different matter! Anyway I think deuterating them would only make them slightly smoother, similar to a hydroxy on the amine on PEA's ala HOT-7. I guess this is mostly at beta I'm thinking but still if you're having body-load issues then it's a golden charm, which this substitution may or may not cause.

EDIT: However with F2 & 22 it was with methyls, so perhaps an acetoxy there instead?


----------



## adder

SeenSoFar said:


> Well, in 3D it actually overlays extremely closely with both morphian and phenylpiperidine opioids. As for extra bulk, the N-Phenethyl substitution actually works to increase potency quite well in most every opioid. I would venture a guess that it would be extremely potent.



Even the isomer most resembling morphinan has the nitrogen farther away from the aromatic ring than morphine does (one C-C bond is 1.54 angstroms) and I don't know what function the cyclopentane ring may have. Morever, the hydroxy group is on the position that corresponds to C2 in morphinan, which seems to lower MOP activity in the SAR I know. If you rotate it by 180 degrees horizontally, the nitrogen is completely off its place.






If you're aiming to design a molecule resembling phenylpiperidines (like pethidine), then you need to know that the piperidine ring isn't flat when interacting with MOP receptors but is rather in a chair conformation. In your molecule additional cyclohexane ring between the aromatic ring and the piperidine constrains it so the nitrogen is "pushed away". Or am I not seeing something else?


----------



## SeenSoFar

adder said:


> Even the isomer most resembling morphinan has the nitrogen farther away from the aromatic ring than morphine does (one C-C bond is 1.54 angstroms) and I don't know what function the cyclopentane ring may have. Morever, the hydroxy group is on the position that corresponds to C2 in morphinan, which seems to lower MOP activity in the SAR I know. If you rotate it by 180 degrees horizontally, the nitrogen is completely off its place.
> 
> 
> 
> 
> 
> 
> If you're aiming to design a molecule resembling phenylpiperidines (like pethidine), then you need to know that the piperidine ring isn't flat when interacting with MOP receptors but is rather in a chair conformation. In your molecule additional cyclohexane ring between the aromatic ring and the piperidine constrains it so the nitrogen is "pushed away". Or am I not seeing something else?




I'm specifically looking at the 3D conformations of the morphinan and phenylpiperidine opioids, as well as the compound in question. I realised after that the hydroxyl group is in the wrong position, but you can still see from the 3D conformations what I'm talking about:

Meperidine: http://pubchem.ncbi.nlm.nih.gov/vw3d/vw3d.cgi?cmd=crtvw&reqid=1015007800769262441

Morphine: http://pubchem.ncbi.nlm.nih.gov/vw3d/vw3d.cgi?cmd=crtvw&reqid=705244037862120859

Compound in question minus n-phenethyl: http://pubchem.ncbi.nlm.nih.gov/vw3d/vw3d.cgi?cmd=crtvw&reqid=3248658153260012628

Now I could be missing something, but (other than the misplaced hydroxyl, which is just a brain fart) when I overlay these they overlap just about flawlessly. I'm forced to use pubchem right now because I'm on my cell, so I can't show the actual comparison, but it's pretty clear looking at it just individually and comparing. With the N-Phenethyl it fits quite closely with fentanyl and other N-Phenethyl opioids as well. Have I missed something?


----------



## SeenSoFar

Here is another one. This one I am positive of its opioid effects. The n-methylcyclopropyl homologue of this one has been assayed and shown to have good affinity for the opioid receptors[1]. The synthesis shouldn't be extremely complicated, and the rewards will most likely be quite bountiful. I would love to see the N-Phenethyl homologue too.






[1] - http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=167448#itabs-2d


----------



## crmt28

2C-B with a bridge in the 2,5 position. Could it work?


----------



## blueberries

crmt28 said:


> 2C-B with a bridge in the 2,5 position. Could it work?



Bugger! That's an interesting one! I don't think it's as simple as that though, you're missing the broken rings with that.


----------



## endotropic

^ yea I don't think that one will work, phenyl subsitutions are planar, there's way too much strain to connect those oxygens with only 2 carbons in between.


----------



## DL-ark

just mu? BZD +mu agonist?nothing?





Triple reuptake inhibitor.


----------



## SeenSoFar

Very nice, DL-ark! I'd be interested in seeing that one for sure!!

Here is one that has been tested in the literature with decent results and yet I've never seen it before anywhere, or really anything similar for that matter either. It is a ring-expanded fentanyl analogue, and has been shown to be active at .13 mg.kg in the tail flick test in mice[1]. Again, I believe this would bypass the analogue laws of most countries besides the US. What are we waiting for, let's see it get out there!






[1] - https://www.ebi.ac.uk/chembl/compound/inspect/CHEMBL3103259


----------



## FunctionalOlfactio

adder said:


> Making a more potent analogue is not as simple as adding a benzene ring somewhere to a molecule. The reason why this works for various drugs (like bromadol or NBOMe's) is because that additional benzene ring is capable of interacting with another portion of receptors making binding stronger. The N-(2-methoxybenzyl) added to phenethylamines makes NBOMe's look more like LSD if you try to make them overlap like this.
> 
> 
> 
> 
> 
> 
> Then we could modify NBOMe's substituting 2-methoxybenzyl with some bioisosteric functional groups and end up with analogues from the second row. I'll make an exception and share this.



This is interesting, don't you all think so?


----------



## DL-ark

FunctionalOlfactio said:


> This is interesting, don't you all think so?


Of course it is, all of adder's comments are really fascinating.


I'm glad that he is a member of the community, and I guess we dont give him enough credit.




methylphenidate analogues are fun.
the 2c-c analogue I actually drew up on paper a while ago, when adder posted his explanation of why NBOMEs work, I decided to post it.


----------



## adder

There's an article called "Molecular Interaction of Serotonin 5-HT2A Receptor Residues Phe339(6.51) and Phe340(6.52) with Superpotent N-Benzyl Phenethylamine Agonists" and the research they've done seems to be against my idea of NBOMe's overlapping with LSD. They checked the affinity of various tryptamines, phenethylamines, and LSD at mutated 5-HT2A receptors and while LSD still had a high affinity at the 5-HT2A receptor with the mutation at F339, NBOMe's did not. So the conclusion is the amide of LSD and the N-benzyl group of 2C-X-NBOMe's bind differently.

Perhaps if we placed an amidoethyl group on phenethylamines, it would bind to the same residue as the amide in LSD, but it's hard to say whether such compounds would have a high potency overall enough to make them interesting, it's possible though.


----------



## DL-ark

adder said:


> There's an article called "Molecular Interaction of Serotonin 5-HT2A Receptor Residues Phe339(6.51) and Phe340(6.52) with Superpotent N-Benzyl Phenethylamine Agonists" and the research they've done seems to be against my idea of NBOMe's overlapping with LSD. They checked the affinity of various tryptamines, phenethylamines, and LSD at mutated 5-HT2A receptors and while LSD still had a high affinity at the 5-HT2A receptor with the mutation at F339, NBOMe's did not. So the conclusion is the amide of LSD and the N-benzyl group of 2C-X-NBOMe's bind differently.
> 
> Perhaps if we placed an amidoethyl group on phenethylamines, it would bind to the same residue as the amide in LSD, but it's hard to say whether such compounds would have a high potency overall enough to make them interesting, it's possible though.


It would be interesting to test this using the 2-c-c analogue I drew in the post above. It would answer the question I have: can the 2,5 dimethoxy 4 X phenyl substitute for the indole.


----------



## SkyblueMolly

Here's a new molecule I drew.
It's bcpn-A, or beta-cyclopentyl-Amphetamine. It's a long lasting super-stimulant!


----------



## pharmakos

because i'm feeling silly in between classes.... Diphenidine-C-B






edit -- more silliness.... methylenedioxydiphenidine









i miss shaggyfin =p


----------



## adder

DL-ark said:


> It would be interesting to test this using the 2-c-c analogue I drew in the post above. It would answer the question I have: can the 2,5 dimethoxy 4 X phenyl substitute for the indole.








I think you drew it wrong. Or you mean the phenethylamine's phenyl substituting for the pyrrole part of the indole in tryptamine? I don't think it's possible, if you tried to make DOC overlap in the same way, the alpha-carbon would stick out to the other side.

I don't think it's that simple actually. Even if aromatic rings of phenethylamines and tryptamines interact with the same residue, I doubt that they perfectly overlay. There's a reason why tryptamines need tertiary amines for the best effect while phenethylamines tolerate only primary amines if they are to be psychedelics. And there's a reason why phenethylamines need to have their phenyl rings substituted to have affinity at 5-HT2A receptors and it doesn't seem to be only an electronic effect, these 2 methoxy groups actually seem to bind to two serine residues. But the electronic effect probably plays some important role as well. In both 4-substituted-2,5-DMPEAs and 4-substituted-3,5-DMPEAs the highest density of electrons is at C2, C4, and C6 of the phenyl ring (the summary effect of all substituents). In the study I mentioned in my last post 2C-I and mescaline affinities seem to decrease in a similar manner when there's a mutation at F340. Still mescaline may not be an ideal compound for the test, because it's a weak agonist itself, it's a shame they didn't test a longer alkoxy chain analogue like escaline or allylescaline. However, when you look at the most potent compounds from both groups, you can clearly see that 2,5-DMPEAs don't tolerate 4-alkoxy substituents as well as 3,5-DMPEAs do. Admittedly, there are two 4-alkoxy-alpha-methyl-2,5-DMPEAs in PIHKAL that are psychedelics - TMA-2 (4-methoxy) and MEM (4-ethoxy), but they're also amphetamines and their potency is far lower than their 4-halo analogues. Moreover, while in the mescaline analogues series allylescaline and proscaline are the most potent, the 4-propoxy-2,5-DMA (MPM) is definitely less potent than MEM. 2,5-DMPEAs and 3,5-DMPEAs are clearly different.

Anyway, there are various ways in which people tried to make phenethylamines and tryptamines overlap, but I think it's pointless to assume that certain atoms in 2C-X's have their exact equivalents in tryptamines because there are other factors at play. One theory was that C2 in 2C-X's corresponds to C5 in tryptamines and the 5-methoxy corresponds to the indolic nitrogen. If this worked 100% fine, 7-substituted-5-methoxy-DMT analogues would be as good as 2C-X's, but perhaps there is some steric problem. Perhaps it's actually C6 of the indole that corresponds to the para position in 2C-X's... But then there's some worry about 6-halotryptamines neurotoxicity.

In my opinion it's also possible that both the phenyl group of 2C-X's and the indole of tryptamines may bind to F340 but in such a way that it's impossible to correlate 2,5-dimethoxy substitution with any concrete positions of the indole of tryptamines. I'm sure we will know what's going on and how both phenethylamines and tryptamines bind quite soon.


----------



## Solipsis

thenightwatch said:


> edit -- more silliness.... methylenedioxydiphenidine
> 
> 
> 
> 
> 
> 
> i miss shaggyfin =p



actually compounds like that are close to ones being made and taken... but I personally just worry a bit that those extra phenyl rings would make it stick to receptors and other stuff pretty damn long. Seems generally not what you want.

and yeah me too @ shaggy lol. sort of, he was a real to mod, too clueless.

I find it interesting how LSD and 25x-NBOMe's have a different electronic distribution going on in the 'middle' (benzylic phenyl of nbome) part. I'd like to check the available amino acid binding groups in the 5-HT2A pocket to match up with them to get a clearer picture of that. Cause if it's a bit dissimilar, who knows what options there are in between so to speak.  Same story for the diethylamine/amide.
Another question is why the tertiary amine is important in LSD but uncool with the PEAs afaik.

Also that NDEPA structure is known and discussed in PD by HansMeyer in his NXXX thread for those who don't know - most of you do.


----------



## pharmakos

Solipsis said:


> actually compounds like that are close to ones being made and taken... but I personally just worry a bit that those extra phenyl rings would make it stick to receptors and other stuff pretty damn long. Seems generally not what you want.



was pretty surprised when i looked closer and discovered that diphenidine/methoxphenidine has that amphetamine structure inside it.  makes me wonder if it really is possible to bridge the gap between dissociatives and 5HT-2A psychedelics and make a molecule that does both with about the same relative potency.


----------



## DL-ark

gabaergic diphenidine


----------



## pharmakos

i know very little about GABAergic chemistry.  would you mind explaining your inspiration for that one?^  i would like to know more.


----------



## sekio

> was pretty surprised when i looked closer and discovered that diphenidine/methoxphenidine has that amphetamine structure inside it.



in terms of 3d structure diphenidine is much more like pcp though.

and... putting gaba skeletons into things doesn't necessarily confer gabaergic activity.


----------



## DL-ark

sekio said:


> in terms of 3d structure diphenidine is much more like pcp though.
> 
> and... putting gaba skeletons into things doesn't necessarily confer gabaergic activity.



Well, I started with phenibut. But uh, I think I went overboard with extra methyls


----------



## Jonneh

More boring stimulants, along the lines of αMT/MPA:


----------



## DL-ark

Jonneh said:


> More boring stimulants, along the lines of αMT/MPA:



Uh, this might be pretty histaminergic. Might be good on TAAR1 though.


----------



## DL-ark

Increased mu affinity?


----------



## SeenSoFar

DL-ark said:


> Increased mu affinity?



If you want to go for increased μ-opioid affinity, why not go in this direction?






It seems so bloody obvious I'd have to wonder why it hasn't been explored yet... Has it?


----------



## Jonneh

DL-ark said:


> Uh, this might be pretty histaminergic. Might be good on TAAR1 though.



I agree, they could produce uncomfortable gastric effects. The wakefulness promotion could synergise with any TAAR1 activity, but it's hard to predict these things (cf. betazole and histamine).


----------



## DL-ark

SeenSoFar said:


> If you want to go for increased μ-opioid affinity, why not go in this direction?
> 
> 
> 
> 
> 
> 
> It seems so bloody obvious I'd have to wonder why it hasn't been explored yet... Has it?



I am fairly certain that what gives pethidine such affinity for mu-opioid are the oxygens as well as the the piperidine. Maybe having a methoxy/hydroxy somewhere on there. Oxygen is essential to opioid activity.



Jonneh said:


> I agree, they could produce uncomfortable gastric effects. The wakefulness promotion could synergise with any TAAR1 activity, but it's hard to predict these things (cf. betazole and histamine).



I was saying it may have some affinity for TAAR1, but im sure it would synergistic even if it wasn't.


----------



## SeenSoFar

DL-ark said:


> I am fairly certain that what gives pethidine such affinity for mu-opioid are the oxygens as well as the the piperidine. Maybe having a methoxy/hydroxy somewhere on there. Oxygen is essential to opioid activity.



You may be right, although I'm fairly certain that I've seen a couple compounds with a similar substitution pattern that have opioid activity. I'd have to go back and find them to be sure though.

On another note, here's a random one. I was messing around drawing a compound that might have opioid and psychedelic activity when I ended up drawing this:






I doubt if it would have any psychedelic activity, but it does overlay quite well with many opioids in 3D, such as dextromoramide.


----------



## SkyblueMolly

The library doesn't allow chemaxon. Only the computer center does. I had to use paint since I'm at the stinking library!
Here's a picture of 2-indolylcyclohexylpiperidine, 2-IOCP. It's a stronger, less toxic version or BTCP.




Here's insomfinil. It's a superior wakefulness enhancer because it produces fluorenol as a metabolite! Insomfinil, the superior modafinil.




Here's InsomfinilPhenylPiracetam, or IPP-48. It's a combination focus enhancer and wakefulness enhancer. It a combination of phenylpiracetam and insomfinil.




Here's 5-Ethyl-MPA, 5-Ethyl-Methiopropamine.


----------



## pharmakos

DL-ark said:


> I am fairly certain that what gives pethidine such affinity for mu-opioid are the oxygens as well as the the piperidine. Maybe having a methoxy/hydroxy somewhere on there. Oxygen is essential to opioid activity.



the obvious choices to my noobself


----------



## SeenSoFar

After some further thought on combined MOR/5-HT2A agonists, I came up with the following. It's not a serious effort, it's kind of silly, but it might very well be active as an opioid, it overlays quite well with various fentanyl analogues in 3D.






Also, here is another possible mixed opioid/psychedelic, but this one is actually reasonable to assume that it's active. In fact there's no reason for it not to be.


----------



## DL-ark

Left to right then down...

Dirty Gabaergic (whether it stays together or not, it should still breach the BBB and have an effect on GABA)
Glutamate antagonist, maybe gabaergic but unlikely. Could possibly have opioid activity. Should be pretty neuroprotective, maybe for alzheimers?
My addition to SeenSoFar's psychedelic opioid quest. The 4-position bromine should be able to be any halogen.


----------



## SeenSoFar

That's very interesting! You've come up with a couple very interesting compounds there!

You know, I was doing some skimming of papers, and I found that my 3-acetyl-morphine-miprocin-sulfate-diester monstrosity may actually be a very interesting compound indeed because it may just result in the release of 4-HO-MiPT and 3-O-Acetylmorphine-6-O-sulfate, which apparently is a much more potent compound than morphine, heroin, and the like. I'd really like to sample it now. I'd be excited to see what happens!


----------



## DL-ark

SeenSoFar said:


> That's very interesting! You've come up with a couple very interesting compounds there!
> 
> You know, I was doing some skimming of papers, and I found that my 3-acetyl-morphine-miprocin-sulfate-diester monstrosity may actually be a very interesting compound indeed because it may just result in the release of 4-HO-MiPT and 3-O-Acetylmorphine-6-O-sulfate, which apparently is a much more potent compound than morphine, heroin, and the like. I'd really like to sample it now. I'd be excited to see what happens!



I'm certain that the opioid feel in that case would be fairly overpowering compared to the psychedelia.


----------



## SeenSoFar

DL-ark said:


> I'm certain that the opioid feel in that case would be fairly overpowering compared to the psychedelia.


I'm sure it would, but I love the feeling of psychedelia behind a massive opiate high.

Here's another one for you all. It overlays with fentanyl in 3D exactly. I think it would be a very interesting one to have a go with.


----------



## Cone

*Potential Potency of Flunitrazepam RC?*






Wouldn't the potency of this "RC" be higher than Flunitrazepam because of the steric hindrance of the chlorinated benzene?

I know the methylamino group makes this RC more "fun" than Clonazepam.

Not sure if this fits in this forum or BDD. Sorry mods.

EDIT: APPARENTLY MY PHOTOBUCKET PICTURE WON'T LOAD, but the point still stands. Imagine the image in your head I suppose.



adder said:


> I did my best to imagine what I thought was obvious, but honestly I doubt that anyone could have guessed what you had in mind.:D Look up the structural formulas of flunitrazepam and clonazepam, because these have very little to do with them, one is completely wrong with the nitrogen at position 4. lacking one bond and the other one isn't even a benzodiazepine.



Fixt :^)

EDIT: apparently it wont load again, but all the double bonds and a nitrogen is now on the second pic 

I got lazy when drawing them I guess.


----------



## adder

I suppose the compound in question is N-methylclonazepam (that is clonazepam with a methyl group on the nitrogen or flunitrazepam with a chloro group in place of the fluoro group - clonitrazepam?). I won't speculate much, but I would imagine this is a benzodiazepine with a very long half-life just like clonazepam (probably a bit less long-lasting, but it's going to be metabolised into clonazepam anyway), it could be more potent on a weight basis (1.5-2x clonazepam), and even if it's not, the perceivable effects should be stronger and the come-up faster because as a tertiary amine this one should penetrate the blood-brain barrier more effectively than clonazepam. However, I have some doubts that it's superior in effects to flunitrazepam. With that chlorine sticking out at C2' it may still cross the blood-brain barrier slower than flunitrazepam, but perhaps it won't matter.

I don't know the SAR for specific subunits of GABA(A) receptors, but chlorine in place of fluorine can change a lot how a molecule binds to a receptor if the part of a molecule with either takes part in binding. I guess the best example is 4-FA vs. 4-CA.


----------



## Jabberwocky

^do you mean 2D?  only thing that can fully overlay w/ fent in 3D is fent.. right?


----------



## SeenSoFar

No, I mean in 3D. The 3D structure is what counts for binding. You can have things that look quite similar in 2D but that has a very dissimilar 3D structure. This, in the other hand, overlays with the fentanyl analogues that have a tertiary carbon on the piperidine ring almost exactly. Obviously the extra ring changes things a bit but not by much, everything ends up in the right place for good activity as far as I can see. Obviously it would have to be assayed to know for sure, but I would bet money on it being active.


----------



## ebola?

heading into overly philosophical territory:

if we think about it, all of these models are abstractions which obscure various aspects of chemical interactions, none really "reflecting nature".  At root, these molecules are emergent patterns of multiple wave functions set in mutual relation, describing electron clouds' propensity to manifest as particle interactions which induce emerging aggregate entities with intelligible qualities as a whole (eg, as compounds, ions locked in interaction, polymers contorted due to emergent patterns of folding (eg, proteins), etc.) (and even this mathematized formulation abstracts from the place of observation in this process).  But engaging the raw, non-composite phenomena involved tends to require unwieldily complex mathematics, but is also cast in terms unclear, ambiguous entities alien to those of the everyday; put bluntly, whatever one's imagined conception of wave-particles set in interaction, it will prove incomplete and misleading, even incoherent.  

So to make things tractable, we pile on simplifying axioms that might reveal certain characteristics of interaction, as the computation required to literally model everything involved, as interacting electrons and more rarely nucleons, causally bound in a complex way, escalate too drastically with modest numbers of particles, even under limitations of sensibly coarse discretization of space and time.  Worse still, continuous modeling is mathematically intractable in principle (see the 3 body problem).

So even a 3D space-filling model of ligand-active site docking will contain these distorting abstractions and computational frameworks (but very useful distortions in terms of highlighting hydrogen bonding, Van Der Waals forces, etc.)  But if reality could be modeled trivially, would we actually gain anything from modeling it?

ebola


----------



## sekio

3d space filling models are pretty accurate as far as things go, w.r.t. their proof by NMR, X-ray diffraction, and the like.


----------



## ebola?

Right, but again, confirmation is cast in terms the way our instruments (of manipulation and observation) structure what can be manipulated and which aspects of the results of this manipulation will manifest as visible and intelligible; indeed, as a complex, the experimental and theoretical apparatuses play a key role in structuring what aspects of a fluid, ambiguous, flux before us we pull out as intelligible (but this flux does even more in structuring what aspects of it can appear as intelligible). . .

Now, I'm not saying the models are "bullshit" or even "false"...as we use corresponding tools to navigate and manipulate the world _for us_, we in turn change the world 'as such' (but in ways we don't understand), fashioning a world in our image (but also entailing novel, emergent dynamics to follow).

ebola


----------



## sekio

We can do some pretty amazing stuff with atomic force microscopy (like looking at reaction products before and after, like tiny ball and stick models), if that counts for anything.


----------



## adder

Cone said:


> Wouldn't the potency of this "RC" be higher than Flunitrazepam because of the steric hindrance of the chlorinated benzene?
> 
> I know the methylamino group makes this RC more "fun" than Clonazepam.
> 
> Not sure if this fits in this forum or BDD. Sorry mods.
> 
> EDIT: APPARENTLY MY PHOTOBUCKET PICTURE WON'T LOAD, but the point still stands. Imagine the image in your head I suppose.



I did my best to imagine what I thought was obvious, but honestly I doubt that anyone could have guessed what you had in mind.:D Look up the structural formulas of flunitrazepam and clonazepam, because these have very little to do with them, one is completely wrong with the nitrogen at position 4. lacking one bond and the other one isn't even a benzodiazepine.


----------



## Cone

adder said:


> I did my best to imagine what I thought was obvious, but honestly I doubt that anyone could have guessed what you had in mind.:D Look up the structural formulas of flunitrazepam and clonazepam, because these have very little to do with them, one is completely wrong with the nitrogen at position 4. lacking one bond and the other one isn't even a benzodiazepine.



I got lazy when drawing and didnt double check my work. I didn't think it'd be a problem since its basically chlorinated flunitrazepam. Clonitrazepam would be a good name, no?

I'm actually more interested how halogens substituted at this position affect the potency, onset, and mechanism of action of a benzo (hypnotic, anxiolytic, onset, etc.)


----------



## adder

I'm confused now what compound you really mean. Is it flunitrazepam with the fluorine atom substituted with a chlorine atom? If yes, then the compound in question is "clonitrazepam", there's no better name actually for such a compound, I guess. In your image you have a chlorine atom on the 7th position while flunitrazepam and clonazepam have nitro groups there and that confused me.

I don't know much about different halogens effects at C2'. You would have to group benzodiazepines according to their substituents at the nitrogen, C3, C7, and C2', then look at their affinities at different GABA(A) subunits, and eventually draw conclusions. Here's a thread in which various subunits are listed with benzodiazepines binding to them, however it's not specific enough to draw precise conclusions. One thing you can notice though is that BZDs with 2'-fluoro all have high affinity towards alpha-1, which is related to amnesia and ataxia.

Fluorine at C2' will also be the best for a fast onset of action, it should attract the hydrogen atom from the neighbouring carbon atom from the aromatic ring making a molecule more lipophilic. It could be that it's there for the electronic effect on the phenyl ring, I've read an abstract stating that the 2',6'-difluoro analogue of diazepam is a potent compound, and 6'-fluoro increases the electronic effect of 2'-fluoro. Steric effect likely plays a role too, a chlorine atom is much bigger, and clonazepam is a bit more potent than flunitrazepam, which on the other hand could be attributable to higher affinity at some subunit due to a secondary amine rather than a tertiary amine. Honestly speaking, analysing stuff like this inevitably ends with some questions that can't be answered if you don't know to what residues of receptors a compound binds to, unless there are groups of compounds with different structure binding to the same receptors and it's possible to notice some analogies.


----------



## SkyblueMolly

This is a modified molecule of nomifensine. I call it fensine! It should be just like NZT without side effects, or like nomifensine without the blood cell destroying properties.




Here's another one. Cheryfensine.




Here's another one. Maybe this one is NZT. Norzatrensine.




Xenoninsinol.




Indofensine




This one is nomifensine. It already exist, but is here for reference purposes.


----------



## DL-ark

Is it possible that the nitrogen on the indole in tryptamines binds to the same spot in 5HT2A as the nitrogen in phenethylamines?

This would explain why N dimethylation among other things doesnt work with phenethylamines.


----------



## sekio

Nope... the N on PEAs hits a much different site than the indole N. I think I remember reading it has to do with the pH of the amine.



> This would explain why N dimethylation among other things doesnt work with phenethylamines.



Even just N-methylation pretty much chops activity down by a large factor, and indole N is already secondary. Hence why you don't see more "N methyl 2C-D" etc.



> This is a modified molecule of nomifensine. I call it fensine! It should be just like NZT without side effects, or like nomifensine without the blood cell destroying properties.



You'd like this paper. "Fensine" & its cousins are NDRI drugs... so they will unfortunately be expected to have the usual cocktail of NDRI side effects


----------



## sekio

"Ethoxetamine"... I guess


----------



## DL-ark

sekio said:


> Nope... the N on PEAs hits a much different site than the indole N. I think I remember reading it has to do with the pH of the amine.
> 
> 
> 
> Even just N-methylation pretty much chops activity down by a large factor, and indole N is already secondary. Hence why you don't see more "N methyl 2C-D" etc.




Well, maybe not N-Methyl, but N benzyl... Think about how the N in the indole is bonded on the phenyl, so maybe the phenyl is equivalent to the n-benzyl on phenethylamines?

Still a long shot, but idk.


----------



## LordJewington

methyl N,N-dimethyl-tryptophan ester
This looks like it would probably be psychoactive and easy to synthesize. Thoughts?


----------



## DL-ark

LordJewington said:


> methyl N,N-dimethyl-tryptophan ester
> This looks like it would probably be psychoactive and easy to synthesize. Thoughts?




I think puting an methyl ester on the alpha position is going to cause some problems. it is pretty big and unweildy, and with likely metabolize to N,N dimethyl tryptophan which as far as I know, is inactive. Although, I have posted on here suggesting that alpha carboxylation of DMT could result in it being decarboxylating via aromatic amino acid decarboxylase, and serving as a prodrug for DMT. It would then be able to be taken orally without problems, and would have a longer effect.


----------



## LordJewington

DL-ark said:


> I think puting an methyl ester on the alpha position is going to cause some problems. it is pretty big and unweildy, and with likely metabolize to N,N dimethyl tryptophan which as far as I know, is inactive. Although, I have posted on here suggesting that alpha carboxylation of DMT could result in it being decarboxylating via aromatic amino acid decarboxylase, and serving as a prodrug for DMT. It would then be able to be taken orally without problems, and would have a longer effect.



Shulgin addressed essentially the same idea here: http://www.cognitiveliberty.org/shulgin/adsarchive/dmt.htm

N-methylated tryptophan would not make it into the brain, which is where most aromatic-L-amino-acid decarboxalase is expressed. Its also doubtful that n-methylated tryptophan would be a suitable substrate for the enzyme. 

 Getting it past the BBB is why I thought of esterfying it (also because the compound could be made in two simple steps from tryptophan.) As you correctly point out, however, the ester bond would be unlikely to survive first-pass metabolism, and so the compound is unlikely to be orally active. However, taken intravenously I think enough of it would make it past the blood-brain barrier before the liver got a hold of it. You could also try covering up the carboxylic acid with an amide:




That's getting a little bit more synthetically complicated, but it might well be orally active and software predicts that it would be a strong GPCR ligand. 

Alpha substituted tryptamines haven't been explored very much, as far as I can tell. The only ones that I know of have had either a simple methyl or ethyl in the alpha position. So, the SAR doesn't seem to be known well enough to say what a methyl ester in the alpha position would do to the activity.


----------



## DL-ark

LordJewington said:


> Shulgin addressed essentially the same idea here: http://www.cognitiveliberty.org/shulgin/adsarchive/dmt.htm
> 
> N-methylated tryptophan would not make it into the brain, which is where most aromatic-L-amino-acid decarboxalase is expressed. Its also doubtful that n-methylated tryptophan would be a suitable substrate for the enzyme.
> 
> Getting it past the BBB is why I thought of esterfying it (also because the compound could be made in two simple steps from tryptophan.) As you correctly point out, however, the ester bond would be unlikely to survive first-pass metabolism, and so the compound is unlikely to be orally active. However, taken intravenously I think enough of it would make it past the blood-brain barrier before the liver got a hold of it. You could also try covering up the carboxylic acid with an amide:
> 
> 
> 
> 
> That's getting a little bit more synthetically complicated, but it might well be orally active and software predicts that it would be a strong GPCR ligand.
> 
> Alpha substituted tryptamines haven't been explored very much, as far as I can tell. The only ones that I know of have had either a simple methyl or ethyl in the alpha position. So, the SAR doesn't seem to be known well enough to say what a methyl ester in the alpha position would do to the activity.



Has shulgin adressed something like alpha-carboxylated MDPEA/MDA? Or an alpha carboxylated 2c? oh man an alpha-carboxyl 2c-e could be a very good alternative for getting around the law....


----------



## sekio

from what I recall, "tryptamino acids" are not promising drug candidates due to their metabolic lability & higher polarity than equivalent alkylated tryptamines/PEAs.


----------



## LordJewington

sekio said:


> from what I recall, "tryptamino acids" are not promising drug candidates due to their metabolic lability & higher polarity than equivalent alkylated tryptamines/PEAs.



Once you cover up the carboxylic acid group with something, polarity becomes much less of an issue. The predicted octanol/water partition coefficient logP for methyl N,N-dimethyl-tryptophan ester is 2.146 vs 2.297  for DMT. Total polar surface area is 45.334 which is high compared to DMT's 19.029, but caffeine makes it across the BBB with a TPSA of 61.836. (all figures calculated using molinspiration) 

I'm fairly confident that if taken intravenously, the ester would make it into the brain with no problem. The real question is what would happen once it gets there considering that alpha substituted tryptamines haven't been explored very much


----------



## sekio

the problem is the ester often doesn't stay there... aren't they susceptible to carboxylesterases (e.g. serum butyrylcholinesterase) though? i know chymotrypsin would bust the esters up in the gut. esters are more susceptible to hydrolysis than amides, iirc.

it really would not be that difficult to test in vivo the activity of e.g. tryptophan methylester. it would probably take some thought and care to methylate it selectively w/o doing a pictet spengler though.

... apparently people have tested direct brain injections of a few amino acid methyl esters into rats (DL-p-chlorophenylalanine, L-lysine, L-tryptophan) and noted that they "increase food consumption" through a "non serotonergic effect".  

And another curious paper: The Major Alkaloid of _Pultenaea altissima_ F. Muell. ex Benth., N,N,-Dimethyl-L-tryptophan Methyl Ester. So it's naturally occuring.


----------



## LordJewington

Right, the ester bond would be unlikely to survive the gut, much less first-pass metabolism. That's why I'm not suggesting that it would be orally active (though the amide that I posted earlier might be.) Taking the drug intravenously gives it a much better chance of getting into the brain unmolested by the liver's enzymes.



DL-ark said:


> Has shulgin adressed something like alpha-carboxylated MDPEA/MDA? Or an alpha carboxylated 2c? oh man an alpha-carboxyl 2c-e could be a very good alternative for getting around the law....



I'm not aware of any alpha-carboxilated species coming from Shulgin. They wouldn't exactly be easy to synthesize unless you have the corresponding amino acid to begin with.  For example the following compounds could be trivially synthesized from phenylalanine, tyrosine and DOPA respectivly.












The first one has an interesting meth-amphetamine-ish look about it.


----------



## SkyblueMolly

I'm interested in what an intermediate molecule's duration and activity would be like. 
2-Benzylpiperidine is very weak and short lasting, Methylphenidate and Ethylphenidate are somewhat stronger, but also short lasting. Desoxypipradrol is extremely long lasting and superpowerful. I would like to see something intermediate in duration. 6 hours to 9 hours. Not 2 hours. Not 16 to 30 hours.
Like a long lasting study-like stimulant.
Here's NRG-64, based on desoxypipradrol.


----------



## sekio

> 6 hours to 9 hours. Not 2 hours. Not 16 to 30 hours.
> Like a long lasting study-like stimulant.



concerta / focalin xr ? used as indicated on the label, of course, not chewing or crushing and certainly no extractions.

or ... caffeine


----------



## pharmakos

it might change the SAR a bit more than the molecule you proposed, but what about adding an oxygen to one of the rings on desoxypipradol to give your enzymes a better spot to break it down at?


----------



## sekio

diphenylpiperidinyl silanol (DPPS)





and spiro-mxe


----------



## SkyblueMolly

sekio said:


> diphenylpiperidinyl silanol (DPPS)
> 
> 
> 
> 
> 
> and spiro-mxe



Cool molecules.
I came up with another hypothetical molecule. It might act moslty as a dopamine reuptake inhibitor due to it's similarity to ethylphenidate yet higher stability. 
Phendrofury!




^ It might have the half life of 6 hours to 11 hours. Who knows?


----------



## pharmakos

sekio said:


>



squint your eyes a bit and that almost looks like dextromethorphan


----------



## SkyblueMolly

thenightwatch said:


> it might change the SAR a bit more than the molecule you proposed, but what about adding an oxygen to one of the rings on desoxypipradol to give your enzymes a better spot to break it down at?


Because two of the rings are phenyl rings. An oxygen can't bond in three places, only two. It's an interesting idea though.


----------



## pharmakos

i didn't mean replace a carbon with an oxygen.  i meant add a methoxy to a phenyl or a ketone to the piperidinyl


----------



## sekio

I think oxazoles like these have actually been made and investigated... if memory serves they are indeed like longer activity MPH analogs.


----------



## yaesutom

The LSZ or 2,4-dimethylazetidide version of 4-AcO-DET (not the green part)?  I'm curious to know what the effect of swapping the red methyls around do.. I would guess only one configuration is going to be highly active at the receptor?  I wonder how much stuff you can have up there at the nitrogen before it would become too weak (add another methyl like whats in green?)


----------



## Solipsis

Not sure, but LSZ may be way different than tryptamines because LSD with two ethyls is highly potent, but is potency relatively quickly lost when there are other amide substitutions? I can't really compare it quantitatively, you would need to make a table comparing LSD analogue potencies with the tryptamine series.
What I mean is: the fact that the ethyls of LSD are a critical part of the structure and tweaking them to be just right is meaningful doesn't mean the same is true for other psychedelics with N-substitutions. You can slap a lot more substutions on tryptamine amines and potency still stays reasonable.
Look at the NDEPA like compounds, and overlay tryptamines like 4-AcO-DET with LSD. The amine you are putting an azetidide on here matches the 6-position nitrogen of LSD, I believe, not the amide nitrogen.

Still fun idea, but the difference in effect and potency may be more marginal than you'd think.

I don't have drawing software on hand where I am sitting now, but I'd be interested in common psychedelic tryptamines with an N-acetyl like ALD-52. Shouldn't be much effort and it might tell us something about whether _that_ modification is meaningful, or mostly based in myth.


----------



## Black

SkyblueMolly said:


>



move the nitrogen one position further away, add a N-methyl and this also fits the schaumann rule.


----------



## SkyblueMolly

Here's a molecule that could be NZT-49 in real life. Norzatrensine.




It's based on nomifensine. I assume that the blood dissolving toxicity comes from the amino group directly attached to the phenyl group. Cyclylization could eliminate this while hopefully allowing this stimulant molecule to retain it's non addictive properties.

This one is methylpheniclone. It's a longer lasting version of methylphenidate. Hopefully, it's duration does not resemble the ridiculously long acting desoxypipradrol.







Here's beta(cyclopentyl)amphetamine. It's kind of a hybrid of cyclopentamine and amphetamine and should have a longer duration.





Here's redicusomfinil! It's rediculously crazy! Some of it's metabolites would be fluorenol and beta(cyclopentyl)amphetamine.





Here's Cyclopentaminsomfinil!





Here's indanylaminopropanylinsomfinil (IAPI-57)





Here's wininsomfinil.





Here's Killinsomfinil!





Here's rivaninsomfinil. It's a combination of insomfinil and rivanicline.





This last one is pretty much just for fun. Galactenol! The extreme wakefulness enhancer!


----------



## adder

thenightwatch said:


> squint your eyes a bit and that almost looks like dextromethorphan



This is levomethorphan and not dextromethorphan. And I doubt that DXM's methoxy group binds like methoxetamine's methoxy group. The cyclohexane ring of DXO is not even necessary for high affinity at NMDA receptors, the aromatic ring of PCP and the aromatic ring of DXO may bind to different residues, this is likely. (+)-metazocine lacks the cyclohexane ring and has a much higher affinity to NMDA receptors (Ki = 41 nM) than DXO and (+)-normetazocine is even more potent (Ki = 30 nM, source). DXO being 10 times more potent by weight than DXM could have a 400-600 nM affinity, that's a rough estimation though. Anyway, that leads to a conclusion that other metabolites of DXM, namely nor-DXM and nor-DXO may have a much greater role in dissociative effects than it is thought now.

I wonder whether the 2-phenyl analogue of metazocine or normetazocine would have a boosted affinity at NMDA receptors. Or the 6-phenyl analogue, a relative of (+)-methadone.






Perhaps dextrorotatory benzomorphans and morphinans could be related to dizocilpine in the way drawn below. Keep in mind dizocilpine's molecule is bent and the angle between two aromatic rings is close to 90 degrees.






All recreational dissociatives are hardly selective for NMDA receptors. Dizocilpine is far from being as recreational as ketamine for instance, diphenidine isn't much recreational for me either. What if recreational effects of dissociatives could be separated from NMDA antagonism? Perhaps they're more related to effects mediated through sigma and/or kappa receptors? Or these effects and NMDA antagonism are complementary and potentiate one another, but NMDA antagonism is not the driving force behind pleasurable effects.


----------



## Dresden

2-methylamphetamine
2-methylmethamphetamine
2,6-dimethyl(meth)amphetamine

Not sure how dangerous these are, though.


----------



## blueberries

Ok, so this is a little 'off-the-wall' so to speak but I realised looking at acid that it's insanely similar to tryptamines (I knew this before of course but this structure just hit me), so I cut out the two phenyl rings and took out a carbon from the propylamine chain attached to the second amine group. Also I realised that after forming a ring with the hydroxy at the 4 position, the third amine group would need a bond to form the extra ring with so I added another hydroxy at 5. So, any ideas if this would work or not, or is it too far away from tryptamine itself?


----------



## sekio

double ring hydroxylation, esp. ortho- or para-, is pretty much certain doom for a drug like molecule due to the ease with which it will form a quinone (oxidative cycling... people were all up in arms about dopamine being neurotoxic via this mechanism), relatively high polarity, and ease of metabolic destruction due to not one but two "handles" to accept e.g. sugars, sulfate, or glutathione. (c.f. bufotenin is weaker than 5-MeO-DMT in humans and lower b.a.)

this is also why IV dopamine is a rather poor central stimulant


----------



## blueberries

Damn. I was worried about this to be honest! However having said that I recently noticed a tryptamine analogue that bears remarkable similarities to quininones. Having said that the structure is completely different to what would be created by metabolism of this compound. It's http://en.wikipedia.org/wiki/Ro60-0213, also http://en.wikipedia.org/wiki/AL-37350A, which is a lot more similar to the compound in question (and the end product), minus the oxygen in the phenyl ring. It's also a 5-HT2a agonist too, which gives me some promise.

Wait, you're talking about complete cleavage of the amines right? If so then I think it would produce some poor _quinones_.

Also were you talking to me or someone else?


----------



## SkyblueMolly

I was drawing a random molecule, and it turned out to already exist.
It's called tolazoline.


----------



## yaesutom

> 2-methylamphetamine
> 2-methylmethamphetamine
> 2,6-dimethyl(meth)amphetamine
> 
> Not sure how dangerous these are, though.



Some places online are selling 2-methyl-amphetamine, i've found some info about it on Swedish forum saying it was active at 100mg and similar to regular amp or 2-FA/FMA.


----------



## SkyblueMolly

More random molecules!
Here's bchx-A!




Here's SV-1.




Here's SV-2.




Here's SV-3.




Here's SV-4.


----------



## sekio

SkyBlueMolly, have you considered taking up a line of work in Grubbs catalysis? It sounds like you like rings. And metal centres.


----------



## blueberries

Has this been done before? Or is there some rule that makes it impossible or neurotoxic or inactive or something?


----------



## pharmakos

the potential resultant if a known 2C-I metabolite somehow substituted for monoiodotyrosine in the thyroid gland's production of the T3 hormone (Triiodothyronine).


----------



## DL-ark

Here is a possible SNDRI a la dimethocaine, maybe selective for DRI? Possibly could possess some opioidergic activity if someone substituted some hydroxy groups into the structure.


----------



## SkyblueMolly

sekio said:


> SkyBlueMolly, have you considered taking up a line of work in Grubbs catalysis? It sounds like you like rings. And metal centres.



Intriguing! I had no idea there were Grubbs catalysts. I do like rings, but generally anything that is hydrocarbon based. Perhaps I have to stop procrastinating and study organic chemistry in a college and see where it goes.


----------



## SkyblueMolly

More molecular randomness!
Here's beta-phenyl-prolintane.




Here's alpha-fluoro-phenethylamine. It's probably an impossible molecule.




This one is phenylfencamfamine.


----------



## DL-ark

SkyblueMolly said:


> Here's alpha-fluoro-phenethylamine. It's probably an impossible molecule.


Hmm, that is interesting. I dont know how effective of a replacement  for amphetamine it would be, but it would serve as a very effective phenethylamine replacement. It wouldn't be easily broken down, and would likely still bind to TAAR1.


----------



## Hammilton

How would it be an effective pea replacement?  Probably highly reactive


----------



## Transform

With that said, I wonder if 4-F-phenethylamine would offer an MAO-B resistant alternative to PEA itself.


----------



## sekio

Alpha-halo-amines generally aren't stable.

I'm not sure the 4-fluorinated version of PEA would have enough bulk to actually stop it getting chewed on by MAO. Stuff like MDPEA isn't active.


----------



## DL-ark

sekio said:


> Alpha-halo-amines generally aren't stable.
> 
> I'm not sure the 4-fluorinated version of PEA would have enough bulk to actually stop it getting chewed on by MAO. Stuff like MDPEA isn't active.



Isn't MDPEA metabolized so quickly because it so closely resembles dopamine, even more so than PEA? If amphetamine isnt so easily metabolized, I'd think that a fluorine substitution should be enough, even if short lived (relative to amphetamine)

That said, the compounds stability is a concern, but I think it is an interesting chemical to think about.



Also, what about alpha difluoro PEA


----------



## DL-ark

Has anyone tested 2,5 acetoxy substitutions on psychedelic PEAs?

I think it would just metabolize to 2,5 hydroxy, no?

What about an acetyl on the O in NBOMe?


----------



## pharmakos

why?


----------



## DL-ark

thenightwatch said:


> why?


why not?


----------



## SkyblueMolly

More molecules!
Here's prolintane. It's for comparison purposes.




Here's prolintanol.




Here's prolintanone.




Here's promintane.




Here's promintanol.




Here's promintanone.




Here's propylhexedrinsomfinil.




Here's indanetralinsomfinil.




Here's fensinsomfinil.




Here's betaphenylamphetaminsomfinil.




Here's Amfluorenaminsomfinil.




Here's Amfluorenolaminsomfinil.


----------



## Dresden

3',4'-methylenedioxycocaine


----------



## sekio

Here's prolintanone. <-- alpha-PVP
Here's promintanone. <-- alpha-PBP


----------



## DL-ark

Dresden said:


> 3',4'-methylenedioxycocaine



I don't know how well that would work out considering cocaine isnt a phenethylamine/amphetamine, as well as the fact that cocaine already has affinity for SERT.

3,4-methylenedioxy methylphenidate, on the other hand...


----------



## Midnight Sun

hi all,

Got a few for y'all here... forgive the crudeness, chemdoodle kind of sucks 

first on the list, o-trifluoromethaqualone:





call me crazy but I think it's the answer to the designer quinazolinone woes... CF3 being a proper bioisostere of CH3.  As for all that fluorine electronegativity?  I dunno what that'd do     keep meaning to get a small batch of this one made but more important things keep happening 


no idea what to really call this one... PCM? 





not much to say here besides the 3-hydroxyphenyl & 3-methoxyphenyl substitutions also apply.  I'm not really into arylcyclohexylamines lol


I'll throw the meph kids a bone here real quick






-- though I'm not too sure how well that whole arrangement would work out in practice.  Fun to think about though 


5-EtO-DOM:





kinda wonder why shulgin never looked into alpha-methyl homologues of the tweetios, if only to increase their potency a little


also:





and its -fly analogue, no idea what to call these either 






I looked at this and saw a striking similarity to 4,5 MDO-DMT... I wonder if we could play amide musical chairs a bit here, if we lose the alkyl chain?  would also be interested in a 5-hemifly version.  

I have a couple others but maybe another time... hope these images aren't too oversize!  I'll come back and just link them if so.


----------



## Dresden

Beta-carbomethoxy-a-pvp and beta-carbomethoxy-mdpv.  These are ne/da reuptake inhibitors.  The beta-carbomethoxy group works great on two other ndri's, methylphenidate and cocaine.  Fruity delicious!


----------



## Midnight Sun

Dresden said:


> Beta-carbomethoxy-a-pvp and beta-carbomethoxy-mdpv.  These are ne/da reuptake inhibitors.  The beta-carbomethoxy group works great on two other ndri's, methylphenidate and cocaine.  Fruity delicious!



I don't think that'd translate too well, from what I can tell the polarity induced by the beta-ketone is kind of needed on that basic skeleton... see prolintane for how drastically the drug changes without it.

not like the world needs any more craptastic chinese bathtub crank anyway... but if you insist, 3,4 dichloropyrovalerone


----------



## DL-ark

Midnight Sun said:


> not like the world needs any more craptastic chinese bathtub crank anyway... but if you insist, 3,4 dichloropyrovalerone



Although I tend to agree, I read about such craptastic chinese bathtub crank being used way more than I could have possibly anticipated on bluelight. It seems that those who enjoy stimulants seem to really appreciate RC stims.


----------



## Midnight Sun

DL-ark said:


> Although I tend to agree, I read about such craptastic chinese bathtub crank being used way more than I could have possibly anticipated on bluelight. It seems that those who enjoy stimulants seem to really appreciate RC stims.



Don't get me wrong, many RC stimulants are great in their own right - the fluoroamphetamines, x-apb come to mind, and now with phenmetrazine analogues coming online too.  But all these x-pyrovalerones, and the rest of the "new gen" [dirt chemistry] cathinones can really go by the wayside as far as I'm concerned.  Seeing what China is passing off as drugs these days is ludicrous.


----------



## DL-ark

Midnight Sun said:


> Don't get me wrong, many RC stimulants are great in their own right - the fluoroamphetamines, x-apb come to mind, and now with phenmetrazine analogues coming online too.  But all these x-pyrovalerones, and the rest of the "new gen" [dirt chemistry] cathinones can really go by the wayside as far as I'm concerned.  Seeing what China is passing off as drugs these days is ludicrous.



Well, I don't have any sort of authority to discuss it anyway, seeing as I have never been one more stims (with an exception made for occasional amphetamine).


----------



## pharmakos

Midnight Sun said:


> kinda wonder why shulgin never looked into alpha-methyl homologues of the tweetios, if only to increase their potency a little



perhaps out of concern that the duration would become unreasonably long


----------



## Midnight Sun

thenightwatch said:


> perhaps out of concern that the duration would become unreasonably long



naw, afaik he didn't ever look very far into the ethoxy subs, probably didn't really think much about it when so many greater options were on the table at the time

but yeah, duration would be a concern I suppose.  Though for smart drug purposes, unless overstimulation is a problem across the proverbial dosage-board I wouldn't take much issue


----------



## SkyblueMolly

Here's one I just came up with. 
It's cyclohexylpiracetam! %)




Here's 2C-2P, or 2,5-Dimethoxy-4-(2-Propyl)-phenethylamine. It already exist, but it's super rare and also called 2C-IP.




Here's Ethylcyclohexidate. It's based on ethylphenidate.




Here's amphemitalin.




Here's Betacyclohexylprolintane. It would be like a longer lasting prolintane.




The molecule, Memorimax. Based on ISRIB.




Stimvector. Based on Cyprodenate.


----------



## DL-ark

Maybe this would work well as a MAOI/opioid that could be very effective for highly treatment resistant depression.




either that, or poison.


----------



## sekio

looks like leonurine's bastard child with mppp


----------



## DL-ark

sekio said:


> looks like leonurine's bastard child with mppp



Or tapentadol after falling into a vat of methyl radical


----------



## SkyblueMolly

*1-Ethyl-1-Cyclohexanol (1E1C) active?*

This page is to talk about 1-Ethyl-1-Cyclohexanol, or 1E1C for short. Since ECH(1-Ethynyl-1-Cyclohexanol) is active and 2m2bOH(2-methyl-2-butanol) and 2-Methyl-3-butyn-2-ol is active, 1-Ethyl-1-Cyclohexanol might be active.
1-Ethyl-1-Cyclohexanol might have a similar dose range to 1-Ethynyl-1-Cyclohexanol.
A picture of 1-Ethyl-1-Cyclohexanol (1E1C)




Does anyone have any reports on 1E1C? Has anyone tried 1E1C? 
The melting point is about 35 degrees Celsius.

I wonder if 1E1CP is active. 
Here's 1-Ethyl-1-CycloPentanol.




Any information on the effects of this compound?

Melting Point:	-10°C
Boiling Point:	155-160°C


----------



## Dresden

3,4,5-trichlorophenylpiperazine dihydrochloride
3,4,5-tri-(MeS)phenylethanamine hydrochloride
3,4-di-(CF3)-methamphetamine hydrochloride
3,4,5-tri-(CF3)phenylethanamine hydrochloride
2,4,6-tri-(MeS)amphetamine hydrochloride
2,4,5-trimethylamphetamine hydrochloride


----------



## SONN

there are not too many people that I know of that have tried 1-ethynylcyclohexanol. some people claim its not very good for you but some people have enjoyed its effects. F&B did it a couple times and seemed to like it as he mentions in the other thread.

from another forum about ECH:




> it would be a bad idea to co-ingest this with other substances (a good rule of thumb for any rc) as it fucks with your enzymes.
> 
> On another board I saw it called it a "extremely powerful self-catalyzed 'suicide' destructor of cytochrome p450" with a link to a study comparing it to the contraceptives norethidrone and norgestrel. i think this destructive power is due to the ethynyl group (which both contraceptives also have).
> 
> Propynylcyclohexane would probably avoid this problem and is also more potent.



Idk if that is true about ECH but I'm sure someone here does.


----------



## Zeds(NCO2CH2CH3)2

The above image is wrong it's 1-ethynyl cyclohexanol as sonn stated. 

I HATE this stupid BS why the hell do people make terminal alkynes as attempted CNS depressants.  These compounds are legit plasticizers they are UNDOUBTABLY carcinogens,  let's alkylate our DNA shall we? Let's let cytochromes readily epoxidate this and get fking wrecked.  And the quinone form is probably preferred, a suicide inhibitor of cytochrome id guess

NO TERMINAL ALKYNE DRUG are safe unless they are conjugated alkynes (couple cases of top drugs actually,  even antifungal.  These however cns depressant examples are so dangerous.

 Please to anyone who reads this,  DO NOT ingest these drugs.


----------



## Solipsis

Was the picture changed? Cause I'm seeing the 1-ethyl, no C triple bond C in sight... Seems that was intentional, and the OP is questioning the prospect on this alkyl analogue as an alternative.

Is the alkyne in ECH there as steric hindrance for alcohol dehydrogenase to protect against metabolism? If so couldn't the alkyne bond be substituted with say a halogen or some bioisostere that achieves the same but without the dangers Zedsdead mentioned? Cause the point might be that a simple alkyl isn't completely effective in achieving this, or maybe it is...


----------



## yaesutom

I would think 2 and 5 would be active.. probably 4 although it might screw with the body more (like bufotenin).  Is there any reason divinyl tryptamines haven't been made?  Its smaller than DALT.. and the DALT based ones aren't as psychedelic but maybe going down to vinyl would boost the psychedelia.

Is there a good reason why you shouldn't stick a halogen or other things up there like in 1?  

5 might be good.. 4-aco-PiPT


----------



## Dresden

N-vinyl groups spontaneously exist in equilibrium with R-N=CH-CH3 which then reacts with H2O to produce R-NH2 + CH3-CH=O.


----------



## Str

What are your guesses on the trifluoromethyl derivative of mephedrone? It has more than a 3 times longer biological half-life and a very different metabolic fate. (link)

Would it, with its similar size be closer to mephedrone or would the electron density make the effects match those of 4-Cl-MC and 4-Br-MC?


----------



## Dresden

I believe it is more similar to 4-MMC than 4-halo-MC's.  It's longer than 4-MMC's 1/2 life make 4-CF3-methcathinone an ideal compound for the world RC market.


----------



## adder

I was considering it a few months ago and even gave it a name trifludrone. :D Its pharmacologic profile has even already been studied along with 2- and 3-trifluoromethylmethcathinones (article). It wouldn't necessarily be better than 4-BMC or 4-CMC, I bet there's too much serotonin release vs. dopamine release, it would also be much more expensive to synthesize than plain mephedrone, and it's potentially a 5-HT2B agonist. Thus it would actually hardly make an ideal RC in my opinion. 3-CF3-methcathinone looks much better and it could be a great improvement over 3-MMC, but it seems even worse as a 5-HT2B agonist. 

Eli Lilly investigated norfluoxetine as an antidepressant but they dropped it because of cardiac side effects. It's funny that they're fine with fluoxetine on the market as if norfluoxetine wasn't produced as a metabolite.


----------



## Dresden

4-methyl-DMT


----------



## SkyblueMolly

Zeds(NCO2CH2CH3)2 said:


> The above image is wrong it's 1-ethynyl cyclohexanol as sonn stated.
> 
> I HATE this stupid BS why the hell do people make terminal alkynes as attempted CNS depressants.  These compounds are legit plasticizers they are UNDOUBTABLY carcinogens,  let's alkylate our DNA shall we? Let's let cytochromes readily epoxidate this and get fking wrecked.  And the quinone form is probably preferred, a suicide inhibitor of cytochrome id guess
> 
> NO TERMINAL ALKYNE DRUG are safe unless they are conjugated alkynes (couple cases of top drugs actually,  even antifungal.  These however cns depressant examples are so dangerous.
> 
> Please to anyone who reads this,  DO NOT ingest these drugs.



I was referring to the alkane, NOT the alkyne! I just wonder if 1-Ethyl-1-Cyclohexanol(an alkane) is active. Since it's molecularly similar to the alkyne, maybe the alkane is active as well. The above image IS what I intended. It describes 1-Ethyl-1-Cyclohexanol.


----------



## Dresden

beta-carboxymethyl-MDMA.HCl.


----------



## wezface

Fairly in love with this gal right now


----------



## blueberries

Hmmm...
Cocaine base sans the second group _and_ a whopping dihexane chain in place of the phenyl ring. What exactly would this achieve? I'm guessing you're going for in vivo metabolism to a more suitable candidate but then wouldn't a propyl group work better so to create that phenyl? With this either you'd get a 12 sided ring or two benzene rings, the former wouldn't substitute for cocaine or any of the tropanes, the latter however I'm not so sure but that phenyl seems pretty essential when comparing the other tropanes. Also the lack of the second group seems like the death of such a compound. I suppose you could ply for the MPH analogue but still, I'm doubtful.


----------



## sekio

benztropine

its an anticholinergic & really not very fun


----------



## SONN

3,4 - methylene dioxy - 5, methoxy phenethylamine? or amphetamine or cathinone for that matter

definitely notated wrong ^ but i'm sure many people have already thought of this molecule structure before. idk that was the first one I thought of haha


----------



## pharmakos

like this?  
	

	
	
		
		

		
		
	


	


https://www.erowid.org/library/books_online/pihkal/pihkal132.shtml


----------



## IndoleMeridian

4-MeO-6-APB. The APB analogue of MMDA.




And also the APB analog of DMMDA:




I'd imagine they'd be pretty identical to their parent compounds, just as 6-APB is to MDA itself. Also, perhaps more potent too, like 6-APB.

Also, in a similar likeness to 4-thiomescaline (a highlight from shulgin's PIHKAL), here is my proposition for 4-thio-lophophine (considering how good lophophine itself sounded):




also, it is known that a 4-thio substitution on any phenethylamine/amphetamine will give it MAOI properties. So 4-thio-lophophine would have qualities comparable to MAOIs+lophophine, "lophohuasca" if you will.

DOV, or 2,5-dimethoxy-4-vinylamphetamine:




^ this one can actually be synthseized from DOI or DOB. 2C-YN and 2C-V have been made this route from 2C-I, and 4-vinylamphetamine from 4-IA.

Also, we know adding DMT to magic mushroom culture will make it naturally convert to 4-HO-DMT. So here's something that could be made starting only from a regular grow set-up and 5-MeO-MALT added to the substrate:






^ any amateur mycologist care to try this one out as a home project?


----------



## Erikmen

That´s intriguing and nice!
How did you learn it?


----------



## IndoleMeridian

oh, what am i saying--i have plenty more ones to think of. ill go crazy today.

25B-NBOAc




^O-acetyl prodrug for 25B-NBOH.

LML (Lysergic acid 2,N-methylallylamide)




^alkenyl analog of LSB.

ECYPLA (Lysergic acid N,N-ethylcyclopropylamide)




^ring-conformed analog of EIPLA, which is currently the most potent dialkyl LSD analog known (unless you consider LSZ a dialkyl structure).

NBZF-mescaline (n-benzofuranyl-mescaline)




who knows, maybe this could be more potent than the NBOMe? one can only guess until they try.


----------



## IndoleMeridian

Erikmen said:


> That´s intriguing and nice!
> How did you learn it?



I didn't learn it---there are papers about the biosynthesis of synthetic psilocin analogues online. You can grow the 4-HO- analogue of any possible tryptamine given that its 4-position is not bonded to anything other than hydrogen.

http://countyourculture.com/2012/02/17/biosynthesis-4-substituted-tryptamine-derivatives/
http://onlinelibrary.wiley.com/doi/10.1002/jobm.3620290608/pdf


----------



## Erikmen

Okay! It seems interesting, although I don´t understand it too well.


----------



## Erikmen

SkyblueMolly said:


> This page is to talk about 1-Ethyl-1-Cyclohexanol, or 1E1C for short. Since ECH(1-Ethynyl-1-Cyclohexanol) is active and 2m2bOH(2-methyl-2-butanol) and 2-Methyl-3-butyn-2-ol is active, 1-Ethyl-1-Cyclohexanol might be active.
> 1-Ethyl-1-Cyclohexanol might have a similar dose range to 1-Ethynyl-1-Cyclohexanol.
> A picture of 1-Ethyl-1-Cyclohexanol (1E1C)
> 
> 
> 
> 
> Does anyone have any reports on 1E1C? Has anyone tried 1E1C?
> The melting point is about 35 degrees Celsius.
> 
> I wonder if 1E1CP is active.
> Here's 1-Ethyl-1-CycloPentanol.
> 
> 
> 
> 
> Any information on the effects of this compound?
> 
> Melting Point:    -10°C
> Boiling Point:    155-160°C



I´m glad you explained.


----------



## crmt28

Inorganic Psychedelics! Would any of these be possible? 

4-boryl-2,5-dimethoxy-phenethylamine / 4-methylboryl-2,5-dimethoxy-phenethylamine / 4-dimethylboryl-2,5-dimethoxy-phenethylamine
















or maybe oxyboryl compounds instead:

4-oxoboryl-2,5-dimethoxy-phenethylamine / 4-hydroxyboryl-2,5-dimethoxy-phenethylamine / 4-(methylhydroxyboryl)-2,5-dimethoxy-phenethylamine / 4-dihydroxyboryl-2,5-dimethoxy-phenethylamine


----------



## SkyblueMolly

More molecules.
Here's a random molecule! It's O-Methyl-Desomorphine. I'll call it mesomorphine for lack of a better name.


----------



## DL-ark

SkyblueMolly said:


> More molecules.
> Here's a random molecule! It's O-Methyl-Desomorphine. I'll call it mesomorphine for lack of a better name.


Shouldn't it then be desocodeine?


----------



## Solipsis

Lol mesomorph... was that the whole joke / punchline?


----------



## Dresden

3,4-methylenedioxy-BZP


----------



## IndoleMeridian

given the recent craze with 3-fluoro-phenmetrazine (and the legendary status of phenmetrazine itself), i think this would be good:

3,4-methylenedioxy-phenmetrazine


----------



## IndoleMeridian

Also, has this ever been tried before? Phosphate groups are strongly fat-soluble, and this theoretically should be more fat soluble than morphine.... the diacetyl groups in heroin are meant for increased fat solubility. Well, structurally, this would be to morphine what psilocybin is to psilocin:






Diphosphorylmorphine. Perhaps one could call it phosphorin?


----------



## sekio

> Phosphate groups are strongly fat-soluble



They're super polar and have an ionisable proton to boot, so, no? Phosphate acid esters are some of the most hydrophilic compounds you can make.


----------



## IndoleMeridian

sekio said:


> They're super polar and have an ionisable proton to boot, so, no? Phosphate acid esters are some of the most hydrophilic compounds you can make.



oops my bad. so would diphosphorylmorphine be more water soluble then?


----------



## Dresden

1-(3,4,5-trimethoxyphenyl)-2-pyrrolidinyl-(n)-pentan-1-one.hcl
1-(3,4,5-trimethoxyphenyl)-2-pyrrolidinyl-(n)-pentane.hcl
1-(1,3-benzodioxole-5-yl)-2-pyrrolidinyl-propane.hcl
1-phenyl-2-pyrrolidinyl-propane.hcl


----------



## Dresden

3,4-methylenedioxy-prolintane.hcl


----------



## Midnight Sun

It's late and I don't have much to bring to the table this time except this syncan:






feel free to substitute propofol for thymol if that tickles your fancy more, basically designed this with fairly benign metabolites in mind, thymol doesn't seem that terrible afaik as far as phenols are concerned...


----------



## Dresden

beta-(methyl)amino-napthalene.hcl


----------



## Dresden

5-ethoxy-DMT
5-(n)-propoxy-DMT
5-isopropoxy-DMT
2-chloro-DMT


----------



## Dresden

2-methoxy-hydrocodone.hcl (creates a 3,4,5-alkylated-trioxybenzene arrangenment not terribly unlike mescaline's)
2,3-methylenedioxy-oxymorphone.hcl  (creates an MMDA like arrangenment of alkylated aromatic oxygens)

Synthesizing these looks to be a tough problem, though.  I believe it would have to be done from scratch.


----------



## Dresden

N-3,4-methylenedioxyphenyl-(su)fentanyl.hcl
N-3,4,5-trimethoxyphenyl)-(su)fentanyl.hcl

In contrast with the above substituted morphinan narcotics, these four compounds are entireably, easily do-able from scratch.


----------



## Dresden

The benzene ring homologue of naphazoline, a stimulant vasoconstrictive used in certain brands of eye drops to do away with ocular redness.   Also, its 3,4-methylenedioxybenzene analogue.  These two are possibly dangerous.  Caution is advised.


----------



## IndoleMeridian

crmt28 said:


> Inorganic Psychedelics! Would any of these be possible?
> 
> 4-boryl-2,5-dimethoxy-phenethylamine / 4-methylboryl-2,5-dimethoxy-phenethylamine / 4-dimethylboryl-2,5-dimethoxy-phenethylamine
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> or maybe oxyboryl compounds instead:
> 
> 4-oxoboryl-2,5-dimethoxy-phenethylamine / 4-hydroxyboryl-2,5-dimethoxy-phenethylamine / 4-(methylhydroxyboryl)-2,5-dimethoxy-phenethylamine / 4-dihydroxyboryl-2,5-dimethoxy-phenethylamine



Interesting proposition. The selenium-substititued 2C exists in real life and didn't work, but these might.

I was also wondering if 4-silicon substituted 2C's would work.


----------



## Dresden

Indolic N-(n)-pentyl-LSD.


----------



## balea

I never really like chemistry to begin with due to the complexity of it. Yeah, I find it complex. 

But I must admit, that molecule drawing is epic! Good stuff!


----------



## sekio

RE: borane-2c compounds; "plain" boranes have a tendency to be, uhm, "energetic" compounds (triethylborane is used to ignite afterburners because it is hypergolic with oxygen - ignites instantly with no spark) and the boronic acids (B-OH compounds are both highly polar and have a tendency to trimerize). If you could make the boronic acid you would likely find it was inactive.

Silicon analogues of 2C drugs might be interesting, but silicon needs a quaternary carbon to be stable. Maybe sila-DOM - replace the carbon that has the amine on it with a Si?


----------



## SkyblueMolly

This would be a cool one to explore.
I call it Shell-247! It's based on O-2172. I wonder if it's active at all.


----------



## Solipsis

I think most or all DARIs or NDRIs need that amino function you lopped out, skybluemolly...

On that basis I imagine you will find that no receptor or transporter will find it 'legally binding'


----------



## SkyblueMolly

Solipsis said:


> I think most or all DARIs or NDRIs need that amino function you lopped out, skybluemolly...
> 
> On that basis I imagine you will find that no receptor or transporter will find it 'legally binding'



O-2172 is a research chemical with some DRI effects that didn't need the nitrogen group. The potency is around 1/3 that of methylphenidate and ethylphenidate. Perhaps Shell-247 may be 1/4 to 1/9 the potency of methylphenidate. Since things like prolintane, cyclohexylaminopropane(norpropylhexedrine, an active metabolite of propylhexedrine) and propylhexedrine are not very potent, but are still stimulating enough, and since O-2172 seems to be selective for dopamine, maybe Shell-247 may act as a mild to moderate stimulant. One could hope.


----------



## IndoleMeridian

SkyblueMolly said:


> O-2172 is a research chemical with some DRI effects that didn't need the nitrogen group. The potency is around 1/3 that of methylphenidate and ethylphenidate. Perhaps Shell-247 may be 1/4 to 1/9 the potency of methylphenidate. Since things like prolintane, cyclohexylaminopropane(norpropylhexedrine, an active metabolite of propylhexedrine) and propylhexedrine are not very potent, but are still stimulating enough, and since O-2172 seems to be selective for dopamine, maybe Shell-247 may act as a mild to moderate stimulant. One could hope.



Yep, that checks out. One can remove the nitrogen and keep activity, surprisingly. It seems actually you can do a lot to fuck up the amphetamine structure and it will still keep stimulant activity--even structure as simple and far removed as 2-hexanamine have some stimulant activity (if only psychedelics worked this way, most slight tweakings will ruin the activity completely!).

MY proposed stimulant is something that would be called 2-phenyl-3-methyl-oxazolidine. I based it off the structure of phenmetrazine (it is basically the same phenmetrazine structure, but with an oxizolidine ring replacing the morpholine). Here's how it'd look like:






based on structure alone, i'd guess it would be more potent than phenmetrazine, because it has the methamphetamine moiety (whereas phenmetrazine has the moiety of the much less potent ethylamphetamine).


----------



## Hammilton

The borane compounds might be doable, this compound exists: http://www.chemicalbook.com/ProductChemicalPropertiesCB6239279_EN.htm


----------



## Incunabula

Alright, nice  But I'm guessing only the 3 first have a chance of being active, the rest will be too bulky, imo.

Actually, the first one will probably have too little bulk, think 2CD, it'll probably be much less potent, if active at all. 

Number 2 in the first row is like 2CE with the second carbon substituded for boron, that one could be active I suppose. As well as the next one, being an analog to 2CiP.

If they're actually possible to synth it's a fascinating idea.


----------



## Dresden

4-piperonylpiperidine.hcl
1-phenyl-1-piperidin-4-yl-methanone.hcl
2-methyl-3-phenylpiperidine.hcl
2-methyl-3-(1,3-benzodioxole-5-yl)-piperidine.hcl


----------



## ebola?

> 4-piperonylpiperidine.hcl
> 1-phenyl-1-piperidin-4-yl-methanone.hcl
> 2-methyl-3-phenylpiperidine.hcl
> 2-methyl-3-(1,3-benzodioxole-5-yl)-piperidine.hcl



You, uh. . .wanna elaborate on these?

ebola


----------



## Dresden

The first one is the methylenedioxy analogue of 4-PMPD.
The next one is the benzylic oxo analogue of 4-PMPD.
The third one is the O-->CH2 version of phenmetrazine.
And the last one is the methylenedioxy version of number three.

They are all either stimulants or entactogens.


----------



## ebola?

How well characterized is the activity of 4-PMPD?  On paper it looks pretty good, though I wonder about its potency.

ebola


----------



## Dresden

It's hard for me to characterize its activity, other than to say one 'hit' is about 100 to 200 mg and that it's not meant to be snorted.  I'll wait for more ppl to try it before drawing any more conclusions.


----------



## sekio

Is this the next major mephedrone, I bet so, I call it MDPV-36, it is (c) sekio!!!!!!!! Doubles as heating oil in the winter.

Contact me for cheap patent licensing!!!!!


----------



## ebola?

Just saw a thread about this compound on reddit with a couple bioassays detailed, actually.  It's supposedly not particularly fun and pretty anxiogenic.  Ya don't say. . .

ebola


----------



## Dresden

Well I will say one thing about Seiko's creation:  It's fat soluble as hades.


----------



## sekio

The really fat soluble one is the napthyl analogue!


----------



## Dresden

Here's a bare bones attempt to replicate amfonelic acid's stimulant activity:  2-benzylpyridine.  Also, 1-phenyl-1-(pyridin-2-yl)-methanone and, of course, their methylenedioxy analogues.


----------



## Dresden

1-phenyl-2-pyrrolidinyl-propane.hcl
1-(1,3-benzodioxole-5-yl)-2-pyrrolidinyl-propane.hcl

The first one is a prodrug for amphetamine, while the second is a prodrug for MDA.
However, the off chance that each posses an intrinsic activity all its own cannot, at this time, be ruled out.
Both are currently 'legal' per se candidates for the research chemical industry.


----------



## Dresden

This one is a 'legal' prodrug of mescaline:  1-(1,2,3-trimethoxyphen-5-yl)-2-pyrrolidinyl-ethane.hcl
Because, why not?  The last mescaline rc I took, escaline, sucked.


----------



## Solipsis

@ the MDA pro-drug... wouldn't the pyrrolidinyl group first get metabolized to N-butyl? If so, it'd be a pro-drug for MDBA - which I have no idea about..
In other words: wondering about pyrrolidinyl chem metabolism, also good to know for the pyrro stims.


----------



## sekio

> wouldn't the pyrrolidinyl group first get metabolized to N-butyl?



That would only happen in a reducing environment (e.g. hydride). Oxidative metabolism is more likely e.g. metabolism to N-(4-hydroxybutyl)-MDA, but even then that is not a major route. I think the pyrrolidine ring stays intact a lot of the time. I think N-oxide and 2-pyrrolidinone metabolites are more common.

Stuff like e.g. MDPPP, MDPV, prolintane will provide models of pyrrolidine compound metabolism.


----------



## Dresden

The pyrrolidine group will be metabolized to 2-oxo-pyrrolidine then 2,5-di-oxo-pyrrolidine then to R-NH2.  The million dollar question is which rxn happens faster:  that one or the breakdown of the benzodioxole?  I'd say the amphetamine and mescaline analogues have a much better chance than the MDA version.


----------



## nickfurry

^ I'll have the amphetamine please. Actually, could possibly be a  beneficial addition to the ADHD medications, like an XR adderall. 

Here is my less beneficial suggestion:
2-(methylamino)-1-(5-methyl-thiophen-2-yl)propan-1-one, or 5-methyl-methiothinone / 5-methyl-methiopropaminone / MEPHETHRONE.

Edit: here it is in all its glory (?)





Eventually, some Chinese lab is bound to churn it out.

And you forgot 1-(4-methyl-phenyl)-1-piperidin-4-yl-methanone. What about 4-methyl-benzoylpiperidine?


----------



## Dresden

With the exception of mephedrone, four methyl aromatic pea's are too hardcore for me.


----------



## nickfurry

Do you guys think ring opened methylphenidate analogs would work, like DMAA? Or would they need some double bonds?

*Edit: *Just noticed that the one to the right, 2-piperidin-2-yl-propionic acid methyl ester_,_ is apparently available on the open market if someone is feeling brave... I sure as hell ain't touching it.


----------



## Solipsis

IIRC phenyl rings are quite different from cyclohexyls that lack the double bonds, as phenyl rings are aromatic systems. The double bonds represent electron pairs, and the three pairs in the ring team up to be shared in a way. They project electronegative charge perpendicular to the ring, which plays a role in a big number of interactions, including ones with receptor pockets >> amino acid residues that for example have their own phenyl ring that can sandwich with the phenyl ring in the ligand.
Hope I paid enough attention in class to reproduce this 

Anyway I think you'd have better luck deconstructing the piperidine ring, I actually have no idea whether that ring constrains the amine function spatially, or whether the 'aliphatic' part actually plays a role in receptor binding.

In other news:
please brew me some 4-HO-MALT or an ester of it, even if 4-xxx-DALT wasn't such a success, di allyl mayy be a bit too excessively substituted : P It seems inevitable to me.. 
I guess asymmetrical substitutions are a little bit more dicey to make, but not sure if there are particular challenges with that.


----------



## sekio

> please brew me some 4-HO-MALT



does that become 4-HO-Lager then?


----------



## Incunabula

I don't know what work has been done on methylphenidate analogs (although methylnaphthidate and isopropylphenidate seems to have entered the market recently) and I'm not even interested in stimulants, but looking at methylphenidate there's so many obvious posibilities.

One could attempt to change the benzene ring for any simple aromatic ring.
http://en.m.wikipedia.org/wiki/Simple_aromatic_rings

Or one could attempt to switch the piperidine ring for any five or six-membered heterocyclic ring.
https://en.m.wikipedia.org/wiki/Heterocyclic_compound

The piperidine ring could be switched for a thiane ring, for instance, or maybe a morpholine ring or maybe a thiomorpholine ring  there's so many obvious posibilities, that some one must have thought of it before. maybe it's obviously inactive due to something I don't know?


----------



## Dresden

Solipsis said:


> I guess asymmetrical substitutions are a little bit more dicey to make, but not sure if there are particular challenges with that.



Asymmetrically substituted precursor amines are more expensive--that's all.


----------



## Solipsis

Has the thiophene analogue of methylphenidate been considered? That seems like an obvious modification yet I have not heard about it before..

With MPA I am skeptical since meth is the kind of thing that I don't want the sketchy version of, I would hardly like to try the substance itself (I should have a small sample, may locate it next week).. and I guess the fluorinated versions which I have already tried.
But, with MPH the stakes are a little lower so to speak. Not sure if I am making any sense, but IME choosing which drugs are okay to try can sometimes be a little irrational.

@ Dresden: okay but that moves the 'problem' a step since the higher price probably is explained by it costing more work to make those precursors. So same thing: it is more complicated.

@ Sekio: lol :D


----------



## Incunabula

I never thought much about it, but now I suddenly saw the methamphetamine structure in methylphenidate, lol 8) So how about slapping some flourines on the benzene ring? (a la 2-FMA, 3-FMA, 4-FMA)

It's also fascinating that methylnaphthidate is active, surely must be possible to exchange the benzene ring for a benzofuran, indole,benzothiophene or what have you....?

Edit:
@Solipsis. Don't You think it's better to change the benzene ring for another aromatic six-membered ring, than a five-membered one?


----------



## crmt28

4-HO-DP2yT (N,N-diprop-2-ynyl-4-hydroxytryptamine)







From what I've heard the vinyl/propy-1-nyl shouldn't be possible due to tautomerism, but I'm not sure about this one. Any thoughts?


----------



## Dresden

2-methylamino-1-(pyran-4-yl)-propane.hcl (4-oxa-propylhexedrine).
3,4-dichlorophenethanamine.hcl (dopamine analogue).


----------



## Solipsis

crmt28 said:


> 4-HO-DP2yT (N,N-diprop-2-ynyl-4-hydroxytryptamine)
> 
> 
> 
> 
> 
> 
> 
> From what I've heard the vinyl/propy-1-nyl shouldn't be possible due to tautomerism, but I'm not sure about this one. Any thoughts?



I think propargyls  have been considered and were found to interact with each other adversely (I imagine intermingling / sticking together being both so electron dense at the triple bond)... but perhaps a propargyl combined with an alkyl (methyl, ethyl, propyl) works.



Fagott said:


> @Solipsis. Don't You think it's better to change the benzene ring for another aromatic six-membered ring, than a five-membered one?



I wouldn't concentrate one-dimensionally on that. If it is a bioisostere because of shape and electronic configuration, it makes the 'swap' effective, as demonstrated by MPA.

Benzofurans and indoles are pretty different from benzene rings, for starters they are polycyclic (multiple rings fused together)... and basically just not bioisosteres as far as I am aware (would be pretty surprised if they were).

I am seeing a lot of ortho-dichlorophenyls lately like Dresden mentions, what are those bioisosteres of - what is the particular effect of that modification?


----------



## Dresden

A lot of compounds like that interact with dopamine receptors in one way or another.
Plus, they cross the blood brain barrier a lot better than dopamine does, depending--again--on what the rest of the molecule looks like.


----------



## Soulfake

Cannabinoid with 3 fluoride punching fists



what happens if you put randomly dimethoxy´s at the phenyl units in drugs like fentanyl or bromadol? (It´s stupid but I like dimethoxy units, probably becouse of the sceletium tortuosum (kanna) alkaloids (mesembrine etc.)) 




Couldn´t a version of fentanyl in the potency of ocycodon be just as good? I thought those over-potent opioids don´t provide the (non tolerant) user as good experiences as lighter opioids so why don´t they just bring out the weakest analogues of fentanyl, bromadol etc. to the rc market?

edit: search for "marvin beans" (it´s free) the "MarvinSketch" sub-program is really fun to play with and you can learn many things about molecules. There´s also "Jchem" with a program that predicts metabolites etc. but I somehow can´t get it to work, weither online nor the desktop version (java errors at installation etc.).

would this metabolize into phenibut and o-desmethyl-tramadol? 





edit: more phenibut things:





phenibut with an extra gaba chain 
	

	
	
		
		

		
		
	


	





(I´m on clonitrazolam, always getting creative on benzos)


edit: what would happen if you would take for example if you had 100 similar compounds like different benzodiazepines, to make it easier, of similar strenght like 1mg Alprazolam, 1mg Etizolam, 1mg Flunitrazepam...etc.  (or adjusted to equivalent dosages of compounds with different strenght) until you have a mix with  100mg; would this be effective at all? Like instead of a 1mg dose of one compund you get 100x10mcg of different but similar compunds, would they sum up to give a new effects or would the dose of each be too low? I had this question on mind for a long time, I wonder how it could change the pharmacology for different drugs.


----------



## SONN

fascinating question but all I know is I would NEVER take 100 diff benzos at once for any reason whatsoever. I feel like my brain would melt no matter what the dosage.

but I always wondered that about the 2c-x drugs like what would 5mg of all your favorites be like at once but somethings telling me it would be a vasoconstrictive nightmare more than anything

I wish there was some way to make GHB longer or more specifically effect GABA-B agonism but its so simple and perfect there's really no way to change it without fucking it up


----------



## Nagelfar

If anyone wants to draw free license images of various cocaine analogues insofar as they fit the criteria of the following: are 3β-phenyl ring substituted analogues, 2β-substituted analogues, N-modified analogues, 3β-carbamoyl analogues, 3β-alkyl-3-benzyl tropanes, 6/7-substituted cocaines, 6-alkyl-3-benzyl tropanes or piperidine homologues of cocaine......  .....I want to begin to fill out my Wikipedia article "List of cocaine analogues" with more _proper_ images of true analogs. Then when it begins to look more like the "List of phenyltropanes" page, perhaps eventually a "List of methylphenidate analogues" page can be made.

Also the phenyltropanes list page is missing compounds of the "3‚-Alkylphenyltropanes" class, which there should be represented.

Anyone care to make such images here and keep from holding any intellectual claim to them I'll transclude them to the Wikipedia pages mentioned.

Any help would be appreciated.


----------



## greengummybear

i totally think that you could use chemicalize.org. the site uses the Creative Commons license and using the information generated shouldn't be illegal.

http://www.chemicalize.org
https://www.creativecommons.org/licenses/by-nc-sa/3.0/


----------



## Nagelfar

greengummybear said:


> i totally think that you could use chemicalize.org. the site uses the Creative Commons license and using the information generated shouldn't be illegal.
> 
> http://www.chemicalize.org
> https://www.creativecommons.org/licenses/by-nc-sa/3.0/



I just don't have time, I only have 1 hour of computer time at the local library a day at most. Besides, those aren't the standard Wikipedia-style white & black 2D skeleton images like are prevalent/pervasive through the online encyclopedia.

Besides, even if I wanted to, I couldn't save to this library computer, I'm locked out of desktop functions like running or saving from a paint program. Only internet browsing, posting to forums, etc. is enabled.

...

Also, might anyone make a simple B&W 2D image of cocaine with the benzoyl replaced with a phenacyl, and additionally even a tosyl (has anyone heard about these, phenacyl-methyl-ecgonine or tosyl-methyl-ecgonine, in any literature at all?)


----------



## Nagelfar

Maybe if someone knew of an online paint/draw type program or a way to save screen captures directly to an uploaded online site such as photobucket without it having to go through the desktop / be saved to a local drive. Anyone?


----------



## greengummybear

i could take screen shots of chemicalize.org renderings of chemicals and upload them so that you could hot link them. give me a list of chemicals IUPAC names, the requested resolution, size, and file format. 

i have a favor to ask in return. the Wikipedia page on 25B-NBOMe mentions the chemical is undergoing human clinical trials. this is misleading about safety. the dose they used in clinical trials was ~10ug. i fear people could make the mistake of thinking the chemical is safe because the chemical is used in human research. the fact human research involves tiny doses and recreational use involves dose over 100 times larger is important. i can find the link you could use as a citation if you could update the article on 25B-NBOMe.


----------



## Nagelfar

greengummybear said:


> i could take screen shots of chemicalize.org renderings of chemicals and upload them so that you could hot link them. give me a list of chemicals IUPAC names, the requested resolution, size, and file format.



I don't think that would work because I need new chemicals (not in their database) drawn.

What I need is mostly those from Singh's SAR of Cocaine paper (45 pages in on the page finder; pg. 970 or so as enumerated on the paper itself: the chemical structures 183a-(through)-d, 184a & b, 185a-d, 186-188 on 'Scheme 42', on pg. 50 (974) structures 196a-o, 197a-g, 198a-e, 199a & b, 200 & 201a-e ... and more down to page 61 or so.)



greengummybear said:


> i have a favor to ask in return. the Wikipedia page on 25B-NBOMe mentions the chemical is undergoing human clinical trials. this is misleading about safety. the dose they used in clinical trials was ~10ug. i fear people could make the mistake of thinking the chemical is safe because the chemical is used in human research. the fact human research involves tiny doses and recreational use involves dose over 100 times larger is important. i can find the link you could use as a citation if you could update the article on 25B-NBOMe.



I could do that but it's off topic, private message me the link and it certainly shouldn't be difficult.


----------



## Dresden

Soulfake said:


> Cannabinoid with 3 fluoride punching fists
> 
> 
> 
> what happens if you put randomly dimethoxy´s at the phenyl units in drugs like fentanyl or bromadol? (It´s stupid but I like dimethoxy units, probably becouse of the sceletium tortuosum (kanna) alkaloids (mesembrine etc.))
> 
> 
> 
> 
> Couldn´t a version of fentanyl in the potency of ocycodon be just as good? I thought those over-potent opioids don´t provide the (non tolerant) user as good experiences as lighter opioids so why don´t they just bring out the weakest analogues of fentanyl, bromadol etc. to the rc market?
> 
> edit: search for "marvin beans" (it´s free) the "MarvinSketch" sub-program is really fun to play with and you can learn many things about molecules. There´s also "Jchem" with a program that predicts metabolites etc. but I somehow can´t get it to work, weither online nor the desktop version (java errors at installation etc.).
> 
> would this metabolize into phenibut and o-desmethyl-tramadol?
> 
> 
> 
> 
> 
> edit: more phenibut things:
> 
> 
> 
> 
> 
> phenibut with an extra gaba chain
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> (I´m on clonitrazolam, always getting creative on benzos)
> 
> 
> edit: what would happen if you would take for example if you had 100 similar compounds like different benzodiazepines, to make it easier, of similar strenght like 1mg Alprazolam, 1mg Etizolam, 1mg Flunitrazepam...etc.  (or adjusted to equivalent dosages of compounds with different strenght) until you have a mix with  100mg; would this be effective at all? Like instead of a 1mg dose of one compund you get 100x10mcg of different but similar compunds, would they sum up to give a new effects or would the dose of each be too low? I had this question on mind for a long time, I wonder how it could change the pharmacology for different drugs.



I like your first two fentanyl analogues, but the 3,4-dimethoxy's need to be 3,4-methylenedioxy's, unless you want to go with 3,4,5-trimethoxy's.  That might just be awesome.


----------



## my_username

b-hydroxythiolofentanil:






7-nitro 5-pyridin-2-yl analog of temazepam (tenazepam?)


----------



## Dresden

Your fentanyl analogue would do better without the beta-hydroxy functional group.  

As for the added carbomethoxy (R-CO2CH3) group, I'm pretty sure that it is a shorter lasting bioisostere of the N-(C=O)CH2CH3 group where the middle methylene unit (-CH2-) has been replaced by an oxygen atom to form the ester.  Which gives me an idea!

beta-(C=O)CH2CH3-methylphenidate.  Should be a real long laster.


----------



## atara

5-methoxy-N-methyl-N-vinylethylidine-tryptamine, "5-MeO-MVET". 5-MeO-MALT/DALT have less body load than the other 5-MeOs, but 5-MeO-MiPT is the most interesting, so this might work both ways.


----------



## sekio

While we're at it.

Dimethylallyl-methyltryptamine or prenylmethyltryptamine. $ says this is a natural product, somewhere.


----------



## Nagelfar

Hey everyone, still need images at my: https://en.wikipedia.org/wiki/List_of_cocaine_analogues (List of cocaine analogues) ...any help would be appreciated. I've changed it quite a bit since even I last asked (it's now bigger than the list of phenyltropanes page, btw.)

Also I've started a: https://en.wikipedia.org/wiki/List_of_methylphenidate_analogues (List of methylphenidate analogues)

So anyone interested in any attestable examples of novel methylphenidate derivatives can draw them out, release them at Wikimedia Commons and I'll include them along with the citation of it's creation/use.

That's it, I'll stop using this as my personal image request mill. ;-p Thanks all.


----------



## perpetualdawn

Has this been synthed? Sorta hybrid between methylphenidate and MDMA


----------



## Nagelfar

perpetualdawn said:


> Has this been synthed? Sorta hybrid between methylphenidate and MDMA



Problem is, they have completely different modes of action. MDMA being a releaser by phosphorylation of SERT, and the MPH & cocaine type DARIs apparently having a unique ligand binding site which causes DAT 'inverse agonism'

However, increasing the anesthetic aspect of cocaine by adding that of menthol might be interesting, esp. since cocaine often gains potency with a substitution at the 2-beta position:





It's often found that cocaine and menthol are used together with the latter being an adulterant due to the numb/freeze sensation. I wonder if they bonded on the molecular level what the outcome would be. I call it "cocamentholene", the newest drug craze sweeping the inner cities. ;-P


----------



## Dresden

Like the 3,4-methylenedioxy version of 4-methylaminorex, the 3,4-MDO analogue of methylphenidate has never been tested or appeared on the research chemical scene to my knowledge.  And it's not for a lack of me and other people suggesting that they be made and tested.  In fact, someone posted an (unauthorized) picture taken of the blackboard of Alexander Shulgin before he died with the structure of 3,4-MDO-4-MAR drawn out with the caption, "Make Me," under it.

As for the cocamentholene, I would expect it to have greatly reduced activity compared to cocaine based on the analogy--which may or may not be an accurate one, admittedly (the only way to know any of this for sure is to make the compound and test it for activity)--that EPH is of greatly reduced activity to MPH, and MPH and cocaine share similar modes of action along with a carbomethoxy group as well.


----------



## Nagelfar

^Not necessarily, cocaethylene has greater dopamine affinity. Also compounds like:





AND






Are stronger than cocaine.


----------



## Dresden

It could be then that cocamentholene is more active than cocaine.  However, after the troparil and 4-F-cocaine big disappointments, I really only trust human reports of bioassays of tropane derivatives.


----------



## Nagelfar

Dresden said:


> It could be then that cocamentholene is more active than cocaine.  However, after the troparil and 4-F-cocaine big disappointments, I really only trust human reports of bioassays of tropane derivatives.



As one should with anything. Molecular neurochemistry is in the same dark as quantum physics, for the most part.

I filled out my List of 'methylphenidate analogues' wikipedia page with images:

















I wonder how many other, bridged, rings et al., have been substituted at the piperidine ring of methylphenidate... An endo-etheo bridge perhaps? A tropane?

Here would be an odd one: "cis-propenyl 2-{2-azabicyclo[2.2.2]oct-5-en-3-yl}-2-phenylacetate"


----------



## Soulfake

at least one of those should be as good as etizolam:






any more places to put nitrogen?





maybe theese could be nice muscle relaxants:


----------



## Nagelfar

I've always loved this one. Anyone have thoughts on it? Any guesses what it is?


----------



## sekio

It looks like a mess to me!


----------



## Nagelfar

Lol... oh my sekio, busting a gut. I think you remember me doing this one before, don't be so sly. I rendered it a little differently this time. Your response before was more aghast when I said what it was. lol


----------



## pharmakos

...is it supposed to be an opioid?


----------



## neurotic

perpetualdawn said:


> Has this been synthed? Sorta hybrid between methylphenidate and MDMA



we must call this 'ritalove'

and @Nagelfar, interesting thing about DAT 'inverse agonism'... and man i just looked at the List of cocaine analogues page, bro you sure like coke!! lol


----------



## Nagelfar

thenightwatch said:


> ...is it supposed to be an opioid?



Good eye, you noticed the morphine



neurotic said:


> @Nagelfar...bro you sure like coke!! lol



^....Any guesses what the other constituent is..?? ;-P ;-)


----------



## sekio

I think I remember this one now. It's a bastardized mitragynine-morphine hybrid.

I don't think the hemiacetal would like to stick around in water, though.


----------



## Nagelfar

sekio said:


> I think I remember this one now. It's a bastardized mitragynine-morphine hybrid.
> 
> I don't think the hemiacetal would like to stick around in water, though.



No, no no, there was a super-big hint I gave in the above post. Not mitragynine, it's not a hybrid with another opioid... but *something* else. (duh. ;-P )

here it is mixed with heroin (as is often done, on a non-molecular but simple co-occurring solution made level, among drug users)






The other constituent may be considered a 'restricted rotation' analog though to share as many parts with the morphine skeleton as possible. But there are variants of this compound which have second nitrogens close to where the morphine skeletons nitrgoen is, etc, and the other parts don't necessarily make it not do its function either, except for that it is restricted in its movement (the carbon ring would normally be freely rotating in the other substance it is a hybrid with)


----------



## Nagelfar

I wonder if structures like this:

bicyclo[2.2.2]octa-1,3,5,7-tetraene

this:

tricyclo[4.4.0.0³,⁸]deca-1,3(8),4,6,9-pentaene

or this:

tetracyclo[6.4.0.0⁴,⁹.0⁵,¹²]dodeca-1(12),2,4,6,8,10-hexaene

can exist in nature? essentially a benzene ring (instead of a cyclohexane ring) with an endo-etheno-bridge type structure in the center.(?)


----------



## sekio

No, they violate Bredt's rule.

Also, looking at your structures again..






I can count 3 violations of conventional organic chemistry knowledge in that little bit. A hemiaminal is normally not stable (loses water to an imine or hydrolyses to a ketone), a hemiaminal hydroxylamine even less so, and there's even a Bredt's rule violation 

The only other drugs that have carbomethoxy groups on them are stuff like cocaine and the phenyldates


----------



## Nagelfar

sekio said:


> Also, looking at your structures again..
> 
> 
> 
> 
> 
> 
> I can count 3 violations of conventional organic chemistry...



Perhaps it's a 2-quinuclidonium tetrafluoroborate like anti-Bredt molecule ;-P

You mean by that image not my benzene bridges but my morphine hybrid as well? I left an oxygen off because it would violate physics but my molecular building engine didn't catch any other exception, though I would almost guarantee it not be fool-proof.


----------



## sekio

Both those molecules you drew have that same moiety in them.


----------



## Nagelfar

sekio said:


> Both those molecules you drew have that same moiety in them.



Yeah the tropane/ecgonine (which is what I added to the ring in the morphine backbone while keeping some of its nuances like the double bond therein) is already quite bulky. Both are hard from-scratch synths as I understand it. So I'm not taken-aback when I find combining them to be a feat of impossibility. ;-p

What, so is this similarly alien to real-world physics? (My cocaine-ibogaine hybrid):


----------



## atara

literally mdma tho


----------



## Nagelfar

*phenyl-methylphenidate alterations*

It's interesting to note if you look at cocaine from an other-than-usual perspective:






It appears much like this analog of methylphenidate which has a phenyl for the benzene:






...and yet this "phenyl"-methylphenidate's binding potency is >5000 (bad affinity) whereas regular MPH is 324

I wonder if you changed the acetyl/acetate to the nitrogen like on cocaine if it'd be better, or is it the nitrogen that needs to be moved further away on the piperidine ring like the nitrogen is on the tropane of cocaine, or is the lack of oxygens on the phenyl a problem (from the example of phenyltropanes I wouldn't think this to be a necessity)? Does anybody have any DRI examples that would lead one more to changing the nitrogen or the acetyl as a higher priority for giving this 'phenyl' methylphenidate derivative more potency?

The 2-naphthyl MPH analog (i.e. HDMP-28) does such a thing (e.g. DMNPC), but it displays affinity either way:






So I'm leaning to changing just the nitrogen; making: "methyl 3-phenyl-2-(piperidin-4-yl)propanoate"






Any thoughts?


----------



## adder

DMNPC is like a naphthyl analogue of phenyltropane without the additional dimethylene bridge on the piperidine.

Also, drawing molecules like these on paper without keeping proper conformation of piperidine or tropane rings is pointless as you're going to draw false conclusions.






CPT, DMNPC, d-threo-methylphenidate

Methylphenidate likely interacts with DAT in a different manner from cocaine and phenyltropanes.


----------



## Nagelfar

adder said:


> Methylphenidate likely interacts with DAT in a different manner from cocaine and phenyltropanes.



In fact they're closer than many other MAT inhibitors, this 2014 publishing (pdf file) elucidates that their (cocaine & methylphenidate both)  binding site is distinct from that of other reuptake inhibitors, being at TMs 9-11 on DAT whereas others bind to TMs 10-12 (with overlapping loci for them and others at 1 & 7 additionally). (They are also tentatively classed, according to that paper, together as 'inverse agonists' in a form of positive allosteric modulation of DAT which other SNDRIs do not do)

Also, is there really a methyl on the nitrogen of the piperidine of d-threo-methylphenidate?

Anyhow to further illustrate the similarity of the phenyl/benzoyloxy-tropanes and the methylphenidate class of DRIs with respect to their binding compare the below:






It's β-CFT (a.k.a. WIN 35428, a.k.a. 4'-fluoro-troparil) overlayed with HDMP-28 (a.k.a. methylnaphthidate), which is not even using the DMNPC orientation of the methyl-acetate-like (which is at the 2β position in the enumeration of the cycloheptane ring numbering of cocaine & cocaine-like/phenyltropane structures) functional group, but the purely MPH placement.


----------



## adder

Yeah, there's no methyl on the methylphenidate's amine, I simply copied and pasted N-methylpiperidine, and then forgot to delete the methyl group.

Now that I compare them, the placement of the amine and the ester is almost exactly the same with a two-carbon spacer. Only the aromatic ring in phenyltropanes is farther from the amine, so that also explains why methylnaphthidate has a higher affinity than methylphenidate itself does. I guess I had a bad day yesterday.


----------



## roi

Methylenedioxypyroamphetamine, because why the fuck not?


----------



## neurotic

Is the molecular structure of DAT known or anything? Itd make it easier to hypothesize about possible effects of mph and cocaine analogues. After what Nagelfar posted i starter thinking that mph is like a cross between amp and coke, even tho molecularly more similar to amp, pharmacologically tending towards Coke. Its got something to do with the carbomethoxy group right? How could mph be improved? I dont think one would want SERT affinity, itd add too much fiendiness i guess.


----------



## sekio

The dopamine transporter is a pretty damn complex protein (620 amino acids). Its amino acid sequence is known but its 3d structure has only been predicted [ref].


----------



## atara

The success of HDMP-28 suggests that the benzofuran-5-yl "-enidate" should have similar effects with a less scary metabolic profile. 5-APB is more serotonergic that 6-APB, so we'll go with that


----------



## Nagelfar

neurotic said:


> After what Nagelfar posted i starter thinking that mph is like a cross between amp and coke, even tho molecularly more similar to amp, pharmacologically tending towards Coke. Its got something to do with the carbomethoxy group right? How could mph be improved? I dont think one would want SERT affinity, itd add too much fiendiness i guess.



SERT affinity seems to have *less* fiending than pure DAT affinity, was my thought from literature I've read. Upping SERT takes away the "more-ishness" of dopaminergics.

& molecularly it's closer to coke too, not just pharmacologically; that's what I meant to prove by the above 3D overlay (cocaine has more affinity for SERT because the benzoyloxy is longer than the phenyl, HDMP-28 has the naphthyl to accomplish this, and CFT has a fluorine to do the same)


----------



## Dresden

desmethoxy-(oxy or hyrdro)codone.  [oxycodone or hydrocodone with the aromatic methoxy replaced by a hydrogen atom]

roi,
I've thought of that one too, more than once.


----------



## Nagelfar

Using the highly potent 3β-alkylphenyltropane cocaine analogues (which are cocaine analogues _proper_ & not phenyltropanes, despite the "-phenyltropane" in the same, the longer alkylphenyl's are classed, by S. Singh and other specialists, in with the benzoyloxy's) I made a cross between 224e (the most potent of that lettered series; compare; "cinnamoylcocaine") with 224d & the usual oxygenation of the "coke original formula" (dumb humor; that is to say: authentic cocaine) and I get this:






It just looks sterically strong somehow. ;-P


----------



## atara

That molecule doesn't exist -- keto-enol tautomerism always favors the keto, except in a or 1,3 dicarbonyl.


----------



## Nagelfar

I have a habit of doing that, that's what the "tongue in cheek" about it being "strong" was all about. (usually unstable)



atara said:


> -- keto-enol tautomerism always favors the keto, except in a or 1,3 dicarbonyl.



Would it work without the oxygen, then?

…

I have more faith in this one, a mixture of four cocaine analogues:






It's a combination of about every type of substitution/modification (except the 6/7 position ones) including the most efficacious among those being:

(remember the lower the number the higher the affinity)

185c (DAT displacement of WINcomp. 35428 binding @ 25 ± 4),
220c (inhibition of mazindol binding @ 120 ± 10 {cocaine is only 280 ± 60} and dopamine @ 160 ± 10 {again coke is only 320 ± 10}),
196n (DAT disp. of WIN 35... @ 61 ± 6 {cocaine @ 89 ± 4.8}) & finally,
224e (IC50 of cocaine binding @ 2.10 ± 0.04 {cocaine @ 101 ± 26} dopamine @ 138 ± 9 {cocaine comparison @ 209 ± 20})

...of course, may it be noted, all of them together doesn't mean synergistic effects, but some complete unknown variable that could be anything (even nonfunctional at MAT), QSAR is so very odd in that way.


----------



## Pomzazed

ACK ACK ACK 

Why those functional group? It looks like a permanent poison!
Sulfonimide-ISOCYANATE ! (Really?) This looks like it instantly forms covalent binding?
Bromoacetamide moeity? (the bromo is event at the reactive alpha-position regarding the carbonyl)


----------



## sekio

Maybe it's a dual covalent binding agent!


----------



## Nexus_Tripper

BK-Fluoroescaline
beta-keto-4-(2-fluoroethyl)-3,5-dimethoxyphenethylamine


----------



## pharmakos

why the BK version?

also, 4-Thiomescaline is already one of the most potent 3,4,5-subbed phenethylamines.  i wonder if lengthening that 4-position group will increase potency like the change from 2C-D -> 2C-E -> 2C-P.  interesting idea.


----------



## Nagelfar

Pomzazed said:


> ACK ACK ACK
> 
> Why those functional group? It looks like a permanent poison!
> Sulfonimide-ISOCYANATE ! (Really?) This looks like it instantly forms covalent binding?
> Bromoacetamide moeity? (the bromo is event at the reactive alpha-position regarding the carbonyl)



Hey, I made up none of those functional groups, those were all used and published in papers in looking for a suitable antagonist to the cocaine binding site from the starting point of cocaine. I just put them together on one molecule.

...and there's nothing necessarily wrong with covalent binding. Phosphorylation causes internalization just the same in the case of substrate releasing agents, and that a neurotoxin does not make (at least in the senses that I've seen drugs deemed neurotoxic, and whatever neurotoxic effects amphetamine has at high doses I don't believe receive such appellation due to it's intended MoA as a releasing agent).


----------



## Nexus_Tripper

thenightwatch said:


> why the BK version?
> 
> also, 4-Thiomescaline is already one of the most potent 3,4,5-subbed phenethylamines.  i wonder if lengthening that 4-position group will increase potency like the change from 2C-D -> 2C-E -> 2C-P.  interesting idea.


BKs have a longer duration and lower potency. If the high potency of 2C-EF carries over to its 3,4,5 analog, this would be active in the single milligram range. The BK would make it less potent.


----------



## pharmakos

the non-beta-keto is probably going to have a really long duration already.  i'd stick with the higher potency personally.


----------



## roi

3-Hydroxy-Ephenidine

Ephenidine is to diphenidine what PCE is to PCP - replace the piperidine ring with an ethyl group. I wonder if the 3-Hydroxy derivative carries any μ-opioid activity.


----------



## neurotic

Nagelfar said:


> SERT affinity seems to have *less* fiending than pure DAT affinity, was my thought from literature I've read. Upping SERT takes away the "more-ishness" of dopaminergics.



umm i was thinking that the simultaneous 5HT/DA release/increase was what caused the incontrollable fiendiness i.e. mephedrone and more importantly, our beloved cocaine.

DAT-knockout mice still get rewarding effects from cocaine (curiously tho, apparently they will get rewarding effects from stuff such as fluoxetine, which non-DAT-knockout mice won't get (http://www.biomedcentral.com/1471-2202/8/42))

i (a layman) always thought that it was this 5HT/DA thing that made cocaine SO fiendy. i mean, i can do methylphenidate (very dopaminergic i believe, DAT/NET affinity ratio 10 to 1, against cocaine's 3 to 5) and not redose once, and be completely fine. i can do it, get high, comedown (meh, the high is over) and i'm done. it's not unmanageable or even hard at all. but with coke it's damn near impossible (if you're snorting) and ABSOLUTELY impossible when IVing. when i'm snorting, i'm constantly thinking about the next line, and when IVing i'm only not painfully craving the next shot when i'm rushing. i always assumed this difference was due to mph's lack of serotonergic activity.

i could be wrong tho


----------



## Nagelfar

roi said:


> 3-Hydroxy-Ephenidine
> 
> Ephenidine is to diphenidine what PCE is to PCP - replace the piperidine ring with an ethyl group. I wonder if the 3-Hydroxy derivative carries any μ-opioid activity.



....Now replace one of those phenyls back with a piperidine and you have something methylphenidate-ish.



neurotic said:


> umm i was thinking that the simultaneous 5HT/DA release/increase was what caused the incontrollable fiendiness i.e. mephedrone and more importantly, our beloved cocaine.
> 
> i (a layman) always thought that it was this 5HT/DA thing that made cocaine SO fiendy. i mean, i can do methylphenidate (very dopaminergic i believe, DAT/NET affinity ratio 10 to 1, against cocaine's 3 to 5) and not redose once, and be completely fine. i can do it, get high, comedown (meh, the high is over) and i'm done. it's not unmanageable or even hard at all. but with coke it's damn near impossible (if you're snorting) and ABSOLUTELY impossible when IVing. when i'm snorting, i'm constantly thinking about the next line, and when IVing i'm only not painfully craving the next shot when i'm rushing. i always assumed this difference was due to mph's lack of serotonergic activity.
> 
> i could be wrong tho



Perhaps, differing mechanisms of release of the NE & DAT as an adjunct to SER release together may mediate expression or pathways of certain SER receptors and not others, so thusly a SNDRI would have the inverse effect of just an SRI.

Always good to hear the appraisal of a connoisseur, however I must say. ;-j



neurotic said:


> DAT-knockout mice still get rewarding effects from cocaine (curiously tho, apparently they will get rewarding effects from stuff such as fluoxetine, which non-DAT-knockout mice won't get (http://www.biomedcentral.com/1471-2202/8/42))



The fluoxetine phenomenon may have to do with the same reason that NET will uptake DA if all of DAT has it's reuptake pumps inhibited; when the DA system is absent: NE (& by extension likely some aspects of SER) take over the neuro-physiological jobs & functions of DA; so drugs with affinity to different systems will become analogous to drugs of that 'overtaken' system.


----------



## sekio




----------



## endotropic

^do you think those will have stimulant activity?  And what do you think putting the nitrogen one carbon further from the aromatic ring will do?


----------



## pharmakos

are they opioids?


----------



## sekio

top 4 are tapentadol analogues, bottom are methadone analogs.


----------



## pharmakos

i wonder how interesting a pure dextro- analogue of methadone would be as a dissociative...


----------



## Nagelfar

I'm still thinking my image at the bottom of this post has an interesting angle (pun intended) from which it is derived.

The below is taken from the idea of the HDMP-28 & DMNPC being homologues with regard to the positioning of the carbmethoxy (methyl acetate), and using the methylphenidate orientation and adding, as close to a second carbmethoxy as possible, another where it'd be in the DMNPC/phenyltropane 2-beta position orientation. Resulting in the below:






_cf.:_






Perhaps the whole thing could be incorporated but would the oxygen favor another spot leading to a fusion across to the benzene/phenyl in such a case or similar unstable quality? e.g.:


----------



## endotropic

sekio said:


> top 4 are tapentadol analogues, bottom are methadone analogs.



Oh weird, u-opioid agonist NET inhibitors, I need to read more about those.


----------



## sekio

more mdone analogs


----------



## pr0d1gy

The n-methylpyrrolidine modification seems interesting. I'm going to search around and see if any analogs of tapentadol containing pyridine rather then phenol. Might such a modification enhance the SNRI properties? Also curious about substituting the alcohol for a thiol, seems pretty simple and obvious so I'm sure some literature exists.

It might be interesting to consider a in which mu activation is secondary to SNRI properties.


----------



## Dresden

bk-mescaline
4-OH-JWH-018
5-MeO-JWH-018


----------



## Incunabula

Dresden said:


> bk-mescaline



A more stimulating, longer lived and less potent mescaline? probably less stable too 

I haven't tried bk-2CB myself but I don't think it sounds like the beta-keto adds anything good to 2CB at all. So yeah, besides legality I don't really see the fascination with bk'ed phenethylamines.




thenightwatch said:


> also, 4-Thiomescaline is already one of the most potent 3,4,5-subbed phenethylamines.  i wonder if lengthening that 4-position group will increase potency like the change from 2C-D -> 2C-E -> 2C-P.  interesting idea.



Yes, that _is_ an interesting idea  If that's the case, the thioethyl and thiopropyl could be as potent as many 2C's.

On a sidenote, I think the 2,4,6-pattern really hasn't got enough attention. TMA-6 held up against TMA-2 actually makes that pattern quite promising, imo.


----------



## Dresden

I realize that most bk-pea's are worse than their corresponding non-bk-pea forms, but I thought of bk-mescaline in terms of legality.  As for TMA-6, have you ever tried it?  It completely sucks IMO.  And TMA-2 is only slightly better.


----------



## sekio

thioethylmescaline would be a cool drug to do for sho


----------



## pharmakos

fluoroethioscaline

also, re: this post i made earlier



thenightwatch said:


> why the BK version?
> 
> also, 4-Thiomescaline is already one of the most potent 3,4,5-subbed phenethylamines.  i wonder if lengthening that 4-position group will increase potency like the change from 2C-D -> 2C-E -> 2C-P.  interesting idea.



somehow i completely forgot that 4-thioescaline and 4-thioproscaline were already explored in PiHKAL.  and while they are indeed more potent than, they seem to be a bit dirtier feeling than 4-thiomescaline.

all information that i readily knew once upon a time, but somehow i forgot.  hm.


----------



## Incunabula

Dresden said:


> I realize that most bk-pea's are worse than their corresponding non-bk-pea forms, but I thought of bk-mescaline in terms of legality.  As for TMA-6, have you ever tried it?  It completely sucks IMO.  And TMA-2 is only slightly better.




Okay, sure, I get the idea with the bk-mescaline 

The biggest turn off for me with bk-psychedelics, is that they also seems to be less psychedelic than their non-bk counterparts.

Yes, I have both tried TMA-2 and 6, I know the latter better than the first, since I had some tolerance the two times I took the first. Neither of them are really among my favorite psychedelics though.

Anyway, what I meant was, that if one was to look at TMA-6 as the compound that held the promise of that orientation, in the same way that TMA-2 was the one that gave a hint of what the 2,4,5-orientation had in store. I mean 2 and 6 are equal in potency, and as you say, 2 might be just slightly better qualitatively.

But on the other side, psi-DOM doesn't sound good at all, which doesn't bode well for 2,4,6. I guess.



thenightwatch said:


> all information that i readily knew once upon a time, but somehow i forgot.  hm.[/QUOTE]
> 
> I know what you mean :) good find anyway.


----------



## roi

With the current rate of shitty stims, sooner or later we'll see this:


----------



## Nexus_Tripper

This is standard 2C-B-FLY, a safe, refined analog of 2C-B






This is 2C-B-DragonFLY






This is Bromoscaline-FLY






This is Bromoscaline-DragonFLY






This is DOB-FLY






This is DOB-DragonFLY






This is Mescaline-FLY






This is Mescaline-DragonFLY



Of all of these chems, the only two that are available are 2C-B-FLY and DOB-DragonFLY_._ The unknown ones should either be great psychedelics, as in the case of 2C-B-FLY, or deadly drugs, as in the case of DOB-DragonFLY.


----------



## Incunabula

Nice one, nexus. I hadn't thought of "flying" mescaline and it's analogs, but why not. I really wonder how they would feel qualitatively? So Difficult to imagine.


----------



## SteamboatBillJr

Nexus_Tripper said:


> This is standard 2C-B-FLY, a safe, refined analog of 2C-B
> 
> 
> 
> 
> 
> This is DOB-DragonFLY [aka. Bromo-DragonFLY]


Why do you say 2C-B-FLY is safe? You must have a reason.

I think we have insufficient information on 2C-B-FLY. I could find a few dozen reports on Erowid. Lots of 2C-B-FLY reports were from mislabeled Bromo- DrganoFLY. The mislabeled batch the vendor and other people died from. They have the single excerpt from Shulgin on Erowid mentioning the dose is ~10mg and nothing else.

I recall Shuglin's most recent book "The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds" having a limited amount of additional details. You'd have to purchase the book so you could get to this data. We can't say this chemical is safe. The most accurate thing we could say is this chemical was used in very few humans and strongly resembles the fatally toxic Bromo-DragonFLY.


----------



## Nexus_Tripper

SteamboatBillJr said:


> Why do you say 2C-B-FLY is safe? You must have a reason.
> 
> I think we have insufficient information on 2C-B-FLY. I could find a few dozen reports on Erowid. Lots of 2C-B-FLY reports were from mislabeled Bromo- DrganoFLY. The mislabeled batch the vendor and other people died from. They have the single excerpt from Shulgin on Erowid mentioning the dose is ~10mg and nothing else.
> 
> I recall Shuglin's most recent book "The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds" having a limited amount of additional details. You'd have to purchase the book so you could get to this data. We can't say this chemical is safe. The most accurate thing we could say is this chemical was used in very few humans and strongly resembles the fatally toxic Bromo-DragonFLY.


i suppose 2C-B-FLY isn't proven to be safe, there is no reason to believe that it is dangerous.


----------



## SteamboatBillJr

You labeled Bromo-DragonFLY with non standard names. Your labeling could confuse people about the dangers of Bromo-DragonFly.

Two of those images show Bromo-DragonFLY. The other images show close structural analogues of Bromo-DragonFLY. Bromo-DragonFLY caused nasty fatalities and such extreme vascular constriction people received amputations. 

https://en.wikipedia.org/wiki/Bromo-DragonFLY


----------



## Dresden

1-(3-methylphenyl)-1-(1-piperidinyl)-cylcohexane [3-methyl-PCP].


----------



## pharmakos

i'd try that.  probably lasts a crazy long time, though.  could maybe use a keto on the cyclohexyl ring to give your enzymes a point at which to start breaking the thing down.


----------



## UnspokenVoice

A few pages back I read some interesting stuff. I'm an IV Fentanyl junkie except I can afford it but violating the law disturbs me and there isn't a doctor in this country that I can pay to script it to me. Well, I could probably find one somewhere, I can actually pay. So, I was reading and noticed some Fentanyl analogues. This is legal for research chemistry and doesn't violate the nasty US Analogue Legislation? It can be stronger molecularly? I tried the mighty Google and I have searched this site. Err... I can't find anything about how one becomes an RC and orders up some freshly minted analogue from China and some bunnies for testing. (I won't eat or harm the bunnies unless they go feral. Then I may shoot and eat said bunny.) So setting up a corporation is easy and inexpensive. How does one become a RC and make this legal? Sorry about not drawing a random molecule, my chemistry education was many years ago and I don't think it would be helpful in any sense of the word. Please note that I am not asking for sources for RC chemicals. I think I can find that on my own or with local and personal assistance.


----------



## sekio

> . This is legal for research chemistry and doesn't violate the nasty US Analogue Legislation?



all analogues of fentanyl are illegal in the USA. analogue act says anything that is chemically similar to a schedule 1 drug like fentanyl is illegal. (and in fact the whole reason the analogue act got put in was because fentanyl analogues were appearing left and right in the 1980s and it was meant to ban them) sometimes people order it anyway in flagrant violation of the law but they're risking big prison time.

we are not here to help you learn about how to order anything from anywhere either. BL does not discuss sourcing. it's against the rules here.


----------



## Dresden

If you're thinking about opening a research chemical selling corporation in the US, you should just forget about it.  The last people that tried that, way back in the early days of the "legal" online drug market, got like 415 years in a federal penitentiary, where you will be subject to complete isolation from other human peers for the length of your stay.  And I would recommend heroin over fentanyl analogues, and I would normally never recommend H for anything other than to unwind every once in a while.  The penalties for fentanyl analogues are even more draconian than for fentanyl itself, and the risk of overdosing is quite high.


----------



## Nagelfar

roi said:


> With the current rate of shitty stims, sooner or later we'll see this:



I was doing things *similar* but *not quite* a couple days ago on my Marvin Beans Sketch that I finally figured out to get on my home non-connected laptop.

Here's one that may be promising, reminds me of desoxypipradrol, but uses the phenyltropane configuration of the phenyls off of the piperidine instead of the MPH configuration with the nitrogen et al:






Even reminds me a bit of nocaine or phenmetrazine.


----------



## Dresden

I also think that 3-methylmethamphetamine is worth a try.  And I bet O-methyl-oxycodone (as opposed to HO-oxycodone) is powerful.


----------



## UnspokenVoice

Dresden said:


> The last people that tried that, way back in the early days of the "legal" online drug market, got like 415 years in a federal penitentiary, where you will be subject to complete isolation from other human peers for the length of your stay.



That is what I am trying to avoid, so thank you very much for the information. I extract from mylar patches and find it cleaner and easily measured by patch size cut. It is pretty much always consistent and I go smaller and will do multiple sites instead of one big one. Thanks though. I find fent so much cleaner. I buy bulk Duralgesic only. If it is jelly then I don't buy it. I do have some in my safe but if I use the jelly I always just wear it - no shooting while wearing. I live alone in the true middle of nowhere (long story) so it is safety first which can suck at times but I got lucky and don't want to lose this life just yet.

I am also a citizen by my native heritage (though I need a passport now - dumb asses) of Canada. I am sure I could get it there and then get it here but I am not going to risk it. Risk vs. reward... I already have to cross a number of state lines when my order falls off the truck. I usually have at least 500 of them. I use about two per day during the cold months. I use less when it is warm.

To be clear that is about two 100mcg patches.


----------



## UnspokenVoice

sekio said:


> sometimes people order it anyway in flagrant violation of the law but they're risking big prison time.



Yeah. Thank you for the quick and accurate information, it is *NOT WORTH THE RISK* for me. I already have a source (I could get like 5k at once if I order and wait) but the trip back across all those state lines scares the hell out of me some times. I had a friend bringing some H up this same direction (not for me) and they got nailed. The feds got them and then pretty much every state they went through could prove it and did. When they got out of federal prison they then went state to state to state. They are finally "free" (on probation with the feds and, somehow, several states) and I am certainly not wanting anything like that.


----------



## Nexus_Tripper

SteamboatBillJr said:


> You labeled Bromo-DragonFLY with non standard names. Your labeling could confuse people about the dangers of Bromo-DragonFly.
> 
> Two of those images show Bromo-DragonFLY. The other images show close structural analogues of Bromo-DragonFLY. Bromo-DragonFLY caused nasty fatalities and such extreme vascular constriction people received amputations.
> 
> https://en.wikipedia.org/wiki/Bromo-DragonFLY


Bromo-DragonFLY is the same thing as DOB-DragonFLY, but DOB-DragonFLY is the proper name. Also, DOB-DragonFLY is only there once.


----------



## Nagelfar

I took the nitrogen and the carbmethoxy and placed both of them "half-way" between where they are on the cocaine-analogs/phenyltropanes and methylphenidate and it's derivative compounds: so each have their proper ratio apart from one another for proper functioning at the transporter binding ligand site; however, with either in the exact area between where they'd be in either cocaine or MPH, respectively.

....and it ends up looking like an NMDA-receptor antagonist a la _ketamine_ or _methoxetamine_, though it should be a stimulant. Thoughts? (on NMDAr activity, for instance, versus stimulation? Maybe it's a shorter stimulant like "pemoline", for instance)?


----------



## SteamboatBillJr

Nexus_Tripper said:


> Also, DOB-DragonFLY is only there once.



You're correct on this point. I looked again, I was wrong.


----------



## roi

3-methyl-2C-B, similar to 2C-G. Probably no really easy/cheap synthesis for this one.


----------



## Incunabula

Thats so funny Roi  I was just thinking about this one last night. It's kind of a ring-opened 2CB-fly, but with obvious parallels to 2CG too. It's probably difficult to synthesize, and I guess there's no reason it should be more potent or interesting than 2cb-fly.






I guess the same could be done with Ganesha, and theoretically still retain some activity. Not that Ganesha doesn't sound difficult enough to make already. Sorry for making the images too big, but I'm on my tablet, and resizing doesnt work for some reason.


----------



## neurotic

^ why not close these 3 and 4 methyls into a MD ring, forget about the one in the fifth position and make a dimethoxy analogue of MDA... i'm sure someone has come up with that idea before though (hell im sure people already came up with MD rings on every molecule already)... you could call it DO-MD or something


----------



## Incunabula

You mean forget about the 6-position methyl, right? The 5-position is the methoxy, which is indispensable for it to be a psychedelic.

Shulgin made the compound you suggest. It's called DMMDA. 
https://www.erowid.org/library/books_online/pihkal/pihkal082.shtml


----------



## neurotic

Fagott said:


> You mean forget about the 6-position methyl, right? The 5-position is the methoxy, which is indispensable for it to be a psychedelic.
> 
> Shulgin made the compound you suggest. It's called DMMDA.
> https://www.erowid.org/library/books_online/pihkal/pihkal082.shtml



oh yeah, sure, my mistake... and interesting, i'd think it'd be inactive but shulgin actually reported it feeling like 75-100ug LSD... not bad at all

thought of a few phenidate analogs, first starting with N-methyl MPH and EPH






then amphetamine, methamphetamine and phenethylamine analogues of MPH... could make EPH ones too






i made one with a pyrdine in the place of the piperidine ring also but this image uploading thing is tiring lol

EDIT: just thought of the 'amphenidate' name for the amp analogue of MPH lol i personally like the way it sounds


----------



## adder

As nice as it sounds, it doesn't make sense. The "phenidate" part of the name in methylphenidate is basically a short name for *phen*yl(piper*id*in-2-yl)acet*ate*.


----------



## Nagelfar

neurotic said:


> EDIT: just thought of the 'amphenidate' name for the amp analogue of MPH lol i personally like the way it sounds



Reminds me of a Chinese film about homosexual amphetamine addicts named "_Amphetamine_", which is a play on words, because in Chinese "Am-phet-a-meen" (forget whether Mandarin or Cantonese; if it were a film out of Beijing or Hong Kong) sounds like "Is this my fate?"


----------



## roi

Whoo cannabinoid hybrids. Probably still CB-2 heavy.


----------



## Nagelfar

roi said:


> Whoo cannabinoid hybrids. Probably still CB-2 heavy.



The convoluted ones are always beautiful to my eyes. Looks like a variant of _Diclofensine_ a little bit.


----------



## Nexus_Tripper

neurotic said:


> ^ why not close these 3 and 4 methyls into a MD ring, forget about the one in the fifth position and make a dimethoxy analogue of MDA... i'm sure someone has come up with that idea before though (hell im sure people already came up with MD rings on every molecule already)... you could call it DO-MD or something


Because that already exists and is already called DMMDA.


----------



## neurotic

adder said:


> As nice as it sounds, it doesn't make sense. The "phenidate" part of the name in methylphenidate is basically a short name for *phen*yl(piper*id*in-2-yl)acet*ate*.



i couldnt come up with anything nice from aminophenylbutanate - 'amphebutate' sounds lame tbh - so i settled for that

also just noticed that the MPH PEA analog's corresponding carboxylic acid is a phenylalanine isomer



Nagelfar said:


> Reminds me of a Chinese film about homosexual amphetamine addicts named "_Amphetamine_", which is a play on words, because in Chinese "Am-phet-a-meen" (forget whether Mandarin or Cantonese; if it were a film out of Beijing or Hong Kong) sounds like "Is this my fate?"



now i wanna watch that movie lol


----------



## adder

I guess we'd have to name them "methylamphenidate", "ethylamphenidate", "methylmethamphenidate", and so on to differentiate between different esters. And these names aren't bad to be honest.


----------



## neurotic

indeed they sound nice

the 'standard' methyl ester could be simply amphenidate tho - i am obsessed with this name now lol

idk what activity to expect from them tho, not even how one could improve MPH - as much as others hate it i love it
any thoughts my fellow MPH/coke lover Nagelfar?


----------



## Nagelfar

neurotic said:


> idk what activity to expect from them tho, not even how one could improve MPH - as much as others hate it i love it
> any thoughts my fellow MPH/coke lover Nagelfar?



I gave some of my 'structural' thoughts on the last previous few pages. Nothing new has come to mind yet. I'd like to get binding info, rat drug discrimination "likeability" tests with the "restricted rotational" analog of MPH, personally, and see if it has better affinity when 'static' or when fluidly rotational in its branches.






I made a HDMP-28 version of the restricted rotational analog too:






It just gives me the "look-feel" of a 'good' stimulant. (of course, such is meaningless pseudo-intuitive science)


----------



## Dresden

I don't know, but 2-aminotetralin, which granted is only somewhat similar to that structurally, will give you seizures starting with 100mg.  I had high hopes for 2-benzylpiperidine, too, but it got uniformly bad reviews.


----------



## overeasy

do u know anything about tramadol? i used to take it 9 months ago i just got a script today and have taken 700ml so far today, i remove the time release and there is a perfect little small pill inside, anyways would like to know more about it.


----------



## Nagelfar

overeasy said:


> do u know anything about tramadol? i used to take it 9 months ago i just got a script today and have taken 700ml so far today, i remove the time release and there is a perfect little small pill inside, anyways would like to know more about it.



Check out _O_-Desmethyltramadol, which is actually an efficacious opioid. Fatal overdoses linked to it (not because it is on par with the likes of Fentanyl or any such, but rather because it laced some Kratom strains sold by certain vendors and it is more potent than morphine.)


----------



## roi

Speaking of O-DMT..


----------



## Incunabula

overeasy said:


> do u know anything about tramadol? i used to take it 9 months ago i just got a script today and have taken 700ml so far today, i remove the time release and there is a perfect little small pill inside, anyways would like to know more about it.


Here you go  
http://www.bluelight.org/vb/threads/409372-The-Official-Tramadol-Discussion-Thread


----------



## Dresden

overeasy,

I really did not particularly enjoy tramadol, but I'm no big fan of opiates.  I think it can give you seizures if you take too much.  To me it felt like an 'imitation' opiate, if that makes any sense.  Personally, I do not consider it to be a desirable recreational drug, but your mileage may vary greatly.


----------



## Nagelfar

Nagelfar said:


> Here's one that may be promising, reminds me of desoxypipradrol, but uses the phenyltropane configuration of the phenyls off of the piperidine instead of the MPH configuration with the nitrogen et al:
> 
> 
> 
> 
> 
> 
> Even reminds me a bit of nocaine or phenmetrazine.



Besides the above one I posted a page or few back, I made these at home on my Marvin Beans, starting from cocaine or methylphenidate:






I kind of touched on the bottom left one. The right two are piperidine style cocaine-influenced styrene analogs. The top one (on the right) really reminds me of some desoxypipradrol analogs.

Now the one on the upper left, is a totally gutted cocaine, it's no longer a ringed-fused tropane, but more open like dimethocaine or similar; with sulfurs replacing the oxygens (which doesn't seem to do much different than an oxygen beside lower the overall electro-negativity of the molecule) the _cis_-propenyl on the carbmethoxy is because of the interesting binding profile that such a change did at a phenyltropane's other "cocaine" binding site for MAT; effectively tersing the norepinephrine transporter (NET) away from affinity for *both* SERT & DAT without compromising either, as is usually done when affinity is changed (NET & DAT go up together or DAT alone, but not "allied" with SERT nigh ever like it is in RTI-11w. Just because I used it here doesn't mean it shall have any such effect, but it is similar to an ethyl in other instances but more extreme, and since ethylphenidate & cocaethylene are so pervasively similar to the shorter methyl, this might be an extension not diverging much similarly in it's capacity to bind).


----------



## sekio

Nagelfar, I think these are the kind of compounds that make synthetic chemists sweat in their sleep... I mean... substituted cyclopentadienes are generally considered bad enough, but that sulfur-laden abomination... and it's chiral, too...!

The one in the bottom left looks promising though. (And more importantly, accessible by known chemical methods & known to be stable)


----------



## Nagelfar

sekio said:


> Nagelfar, I think these are the kind of compounds that make synthetic chemists sweat in their sleep... I mean... substituted cyclopentadienes are generally considered bad enough, but that sulfur-laden abomination... and it's chiral, too...!
> 
> The one in the bottom left looks promising though. (And more importantly, accessible by known chemical methods & known to be stable)



Lol. Always enjoy your input sek... ;-P ;-j Too many isomers, that's the prob. with it, eh?


----------



## roi

Possible empathogens.


----------



## Nagelfar

roi said:


> …
> Possible empathogens.



I like this one, quite directly similar to monoamines themselves.

…Careful with that though, one simple hydroxyl-group added to dopamine at its six position makes a highly neurotoxic dopamine receptor annihilator which rapidly induces permanent Parkinsonism; it's called "oxidopamine"


----------



## pharmakos

octopamine's beefier cousin?


----------



## sekio

from another thread


----------



## pharmakos

is there solid SAR behind that?

edit -- ah i found the thread.  intended to be a fentanyl/methylphenidate chimera.  probably no opioid activity.

which reminds me.  i've tried to google what the morphine rule is, and never have been able to figure it out.  can someone explain it to me?


----------



## sekio

Morphine Rule
(Chemicals that have opioid activity generally have all of these)
1. A tertiary nitrogen with a small alkyl substituent.
2. A quaternary carbon.
3. A phenyl group or its isosteric equivalent directly attached to the quaternary carbon.
4. A 2 carbon spacer between the quaternary carbon and the tertiary nitrogen.


----------



## pharmakos

where is ShaggyFin when you need him.


----------



## Nagelfar

sekio said:


> from another thread



Rather proud of myself that I got sekio inspired to contribute to this cacameme thread. ;-P


----------



## sekio

more doodles


----------



## Nagelfar

sekio said:


> more doodles



Those tropane opioids are right up my alley. Couldn't something like phenmetrazine also be augmented to conform to G-coupled protein Mu receptors also, similarly (potentially)?


----------



## Nagelfar

My AMPA (ampakine)/DMPX (caffeine analog) hybrid:


----------



## Jabberwocky

I bet you someone has made this compound before, but I'd be interested in trifluorocarbon(TFC)-substituted psychedelic compounds. 2C-TFC and an analog of DPT with the last methyl group in propyl chain fully fluorinated.


----------



## roi

Pyrophenidone (α-Phenyl-Pyrovalerone) works - I wonder what else would be tolerated.


----------



## Incunabula

levelsBeyond said:


> I bet you someone has made this compound before, but I'd be interested in trifluorocarbon(TFC)-substituted psychedelic compounds. 2C-TFC and an analog of DPT with the last methyl group in propyl chain fully fluorinated.



Er, maybe there´s something  I´m missing here, but........wouldn´t that just be TFM, that is triflouromethyl? 2C-TFM has been made and tested, and it´s supposedly a pretty good psychedelic 

Also, and I know I´m being nitpicky now, but the right terminology would be "the last carbon of the propyl chain......" Not that it matters, I understand what you mean and it is an interesting idea.


----------



## roi

2-MeO-2'-Oxo-PCMo

2-MeO-PCMo appears to be similar potency as PCP according to this paper.


----------



## Dresden

4-methoxy-3,5-dimethylphenethanamine.HCl


----------



## pharmakos

^pretty straightforward molecule, there might be something about it in the literature out there somewhere.


----------



## Incunabula

@Roi and 2-MeO-2'-Oxo-PCMo

I´d rather have a go at the non-MeO, non-Oxo version. But I have absolutely nothing to base that on :D I still think I need to get me some of that 3-MeO-PCMo though.


----------



## sekio

> Pyrophenidone (α-Phenyl-Pyrovalerone) works - I wonder what else would be tolerated.



Roi, that's not the compound you drew, that's alpha-piperidinyl. It's an aminal (hydrolyses to 2 amines and an aldehyde)


----------



## roi

I know. It was never my intention to draw Pyrophenidone, follow the link :O


----------



## Hammilton

Those fentanyl methylphenidate hybrids are very interesting, that way you could be charged with possessing an analogue of two controlled substances lol.


----------



## Nagelfar

Hammilton said:


> Those fentanyl methylphenidate hybrids are very interesting, that way you could be charged with possessing an analogue of two controlled substances lol.



Long-time, no see, Hammilton; that brought you out of the woodwork too, I see. Good times.


----------



## Dresden

This is really a moot point, as if caught with any drug legal or not they will probably find you guilty anyway, but the analogue act only applies to Schedule I drugs.  MPH is Schedule II, and thus, legally / technically anyway, the Analogue Act does not apply to its analogues.


----------



## Hammilton

The analogue act applies to schedule 1 and 2


----------



## Nagelfar

sekio said:


> from another thread



I would add the nitrogen for where we need it to the MPH super-structure (as it seems a non-issue from similarly structured DRI analogs I've noticed) and remove the one oxygen also (which might pose a problem, but there are so many variants on the carbomethoxy part in DRIs that it's worth a go) to be closer to the fentanyl body. Methylfentidate perhaps?






The only real alteration is the extra nitrogen on the cyclohexane ring this way.

EDIT: I almost redacted my omission of the oxygen after looking at some fentanyl analogs (namely carfentanil and remifentanil) but then noticed it had the same omission in what would be the same place (the 2D images showing a true carbmethoxy type branch but in a slightly differing place which looked the same in a differing orientation from the WP images of the aforementioned compounds) they are universal in omitting the oxygen at that location (with alpha-methyl- shortening the adjacent branch and butyr- lengthening it, to an ethyl. But otherwise they're universally the same in terms of that oxygen)

I do know an oxygen at the 4′ position on the piperidine ring of MPH greatly hinders binding. Worse than enlarging the ring from a cyclohexane to something with more angles does. And of course, the methyl group on the carbmethoxy on cocaine and MPH is necessary for binding (i.e. cocaine is benzoyl-methyl-ecgonine, but benzoyl-ecgonine is not considered active, the same is true of ritalinic acid)

3-methylfentanyl has that methyl addition that seems conducive to both the binding properties of the DRIs and affinity to the mu GCPR.

Add that, and cross alfentanil with sufentanil, with the "methylphenidate" nitrogen, and add to the methyl on the carbmethoxy for my benzoyl-ecgonine rule being more functioning with the addition there like butyrylfentanyl to get this:






(Being that the nitrogen is where the oxygen was that skewed the binding of MPH, we may be out of luck on this one, though I know they're completely different cases as binding is construed and unless the "phenyl ethyl tail" can work without it somehow)


----------



## sekio

The N-CH-N moiety is known as an aminal & is unstable in presence of water usually. I have some doubts you'd be able to construct a 4-aminohexahydropyrimidine.




(water molecules not drawn)

Also, a ring with 4 nitrogens and 1 sulfur? 2,5-dihydro-1,2,3,4,5-thiatetrazole? You sir, are full of novel compounds that would make synthetic chemists sweat in their sleep. That particular ring is probably what is euphemistically referred to as an "energetic" material. (i.e. probably explosive)


----------



## Hammilton

Yeah that's one hell of a ring.  I'd wager that it'd be explosive, so getting it on the rest of the molecule would be tough


----------



## Nagelfar

sekio said:


> Also, a ring with 4 nitrogens and 1 sulfur? 2,5-dihydro-1,2,3,4,5-thiatetrazole? You sir, are full of novel compounds that would make synthetic chemists sweat in their sleep. That particular ring is probably what is euphemistically referred to as an "energetic" material. (i.e. probably explosive)





Hammilton said:


> Yeah that's one hell of a ring.  I'd wager that it'd be explosive, so getting it on the rest of the molecule would be tough



I was thinking of the best way to get more "bang" out of it during onset.


----------



## Nagelfar

Here, is this one better?:






Perhaps we should start looking at Tramadol analogs for this kind of thing.


----------



## pr0d1gy

Nagelfar said:


> Here, is this one better?:
> 
> 
> 
> 
> 
> 
> Perhaps we should start looking at Tramadol analogs for this kind of thing.



Geeze man some of your posts make total synthesis look not so bad. I mean this in an endearing way. Not this one in particular, but it's still really unlikely to be stable or synthetically attainable due to the amount of tautomerization possible.

PS try to say aminal fast without saying animal


----------



## sekio

Congratulations Nagelfar, you managed to come up with a synthetically_ less accessible_ structure. Hexahydrophosphinines are hard enough to get to, there is absolutely no way you'd make that heteroatom-laden beast and keep it in a flask... (1,3-azaphosphinan-6-amine)

Alkyl phosphines are pretty firmly entrenched in the "Doesn't Play Nice With Others" camp. Not only in terms of their accessibility, but also odor, toxicology, susceptibility to oxidation etc.

Now, try a compound with a 4 membered carbon-polonium ring


----------



## Nagelfar

sekio said:


> Congratulations Nagelfar, you managed to come up with a synthetically_ less accessible_ structure. Hexahydrophosphinines are hard enough to get to, there is absolutely no way you'd make that heteroatom-laden beast and keep it in a flask... (1,3-azaphosphinan-6-amine)
> 
> Alkyl phosphines are pretty firmly entrenched in the "Doesn't Play Nice With Others" camp. Not only in terms of their accessibility, but also odor, toxicology, susceptibility to oxidation etc.
> 
> Now, try a compound with a 4 membered carbon-polonium ring



The phosphine was, of course, a bit of a tease. Imagine a nitrogen there instead.


----------



## Nagelfar

O-desmethyltramadol with methylphenidate in mind:


----------



## Nagelfar

Nagelfar said:


> O-desmethyltramadol with methylphenidate in mind:



Lengthen the carbmethoxy so the tramadol oxygen can fit there, and throw in the nitrogen, and the nitrogen-phenyl-ethyl fentanyl structure for good measure:


----------



## atara

You can't phosphine. You just can't phosphine. It's not allowed. You will never -- there is never -- you can't put a phosphine in a drug. Full stop. Instant covalently-bonding-to-enzymes territory, right there. Phosphonic acids, maybe. Phosphoric monoamide esters and N-phosphorylimines, sure.

Also, both of those aminals are unstable.


----------



## Nagelfar

atara said:


> You can't phosphine. You just can't phosphine. It's not allowed. You will never -- there is never -- you can't put a phosphine in a drug. Full stop. Instant covalently-bonding-to-enzymes territory, right there. Phosphonic acids, maybe. Phosphoric monoamide esters and N-phosphorylimines, sure.
> 
> Also, both of those aminals are unstable.



My above quoted one from two above, or the last one after I quoted the other one in two different capacities? I would think the former one should be stable.


----------



## Nagelfar

Question; might a stable structure be formed that basic (heptatic, for example) human metabolism turns into an 'energetic' substance _in vivo_? This isn't atomic, but molecular, so I couldn't see free radicals or radiation resulting, what would the effect be in such an instance?


----------



## sekio

It depends.

"Energetic molecules" are generally only really "energetic" when you put a lot of them together (milligrams e.g.); when you have a biological system that functions at high dilutions you might be able to produce energetic compounds, but they would be reasonably expected to either react with cellular components or decompose catalytically rather than going kerboom.

There are mycotoxins that effectively act as prodrugs for hydrazine compounds, arguably those are energetic molecules being made (exothermic decomposition to N2 gas etc) but I think the main effect of the produced hydrazine is not decomposition but instead reactions with proteins.

In the normally reducing environment* of a mammalian cell I would not expect anything with a nitro group to survive, or some of the other "oxidising" moieties. 

* gross oversimplification


----------



## Nagelfar

sekio said:


> It depends.
> 
> "Energetic molecules" are generally only really "energetic" when you put a lot of them together (milligrams e.g.); when you have a biological system that functions at high dilutions you might be able to produce energetic compounds, but they would be reasonably expected to either react with cellular components or decompose catalytically rather than going kerboom.
> 
> There are mycotoxins that effectively act as prodrugs for hydrazine compounds, arguably those are energetic molecules being made (exothermic decomposition to N2 gas etc) but I think the main effect of the produced hydrazine is not decomposition but instead reactions with proteins.
> 
> In the normally reducing environment* of a mammalian cell I would not expect anything with a nitro group to survive, or some of the other "oxidising" moieties.
> 
> * gross oversimplification



Interesting. I was thinking of a specific way to target and kill off cells, like oxidopamine is used for, but in a more universal sort of application for whichever ligand. Bind and blow. ;-p ;j


----------



## Dresden

1-cyclopentyl-2-phenyl-ethane.
1-(1,3-benzodioxole-5-yl)-2-cyclopentyl-ethane.
1-(3,4,5-trimethoxyphenyl)-2-cyclopentyl-ethane.

Possibly some great research chemicals there.


----------



## Nexus_Tripper

https://i.imgur.com/STw7jsU.png

The N-cyano and N-fluro groups would be metabolized off, leaving large amounts of cyanide and fluorine. The 3-(2-bromomethyl) group would alkylize DNA, making this a strong mutagen, and the 4-iodo group would likely add massive serotogenic neurotoxicity.


----------



## pharmakos

so what you're saying is we'll see that on the RC market in a month or two


----------



## SteamboatBillJr

^Only in the places with absolute prohibition. When decriminalization in California is successfull perhaps we could get some additional change.


----------



## roi




----------



## Dresden

5-MeO-JWH-018.
4-OH-JWH-018.

Unless it's me taking it, then I'd rather use JWH-073 or 250 as the base.


----------



## roi

2-Fluoropentyl and 6-Fluorohexyl seem be possible as well.


----------



## pharmakos

Dresden said:


> 5-MeO-JWH-018.
> 4-OH-JWH-018.



lol 

the tryptamine connection inspired me to draw this:






its like LSD, but opened up and with a pentyl added to the nitrogen on the indole and an added JWH-style oxygen secondary to the indole on the other side.

might not need that added oxygen, but its funny that this is likely active as a cannabinoid.  you can put a lot of strange junk where JWH-018's napthyl group was and still retain some activity.


----------



## crmt28

thenightwatch said:


> lol
> 
> the tryptamine connection inspired me to draw this:
> 
> 
> 
> 
> 
> 
> its like LSD, but opened up and with a pentyl added to the nitrogen on the indole and an added JWH-style oxygen secondary to the indole on the other side.
> 
> might not need that added oxygen, but its funny that this is likely active as a cannabinoid.  you can pot a lot of strange junk where JWH-018's napthyl group was and still retain some activity.



Interesting! We could probably see 1-Pentionyl-LSD one day. It would probably end up very similar to 1P-LSD.

No idea if it could actually end up hitting CB receptors, though. Maybe with a few tweaks on the molecule.


----------



## Dresden

1-pentyl-LSD would be closer to the original JWHs.


----------



## blueberries

Almost definitely been thought of before but can't find much on it (in fact I think Shulgin referred to it in the Psilocin bit, but it could have been the methoxy). Can anyone give me some insight? Good/bad, strong/weak, visuals/non?






4-MeOH-DMT (Heh! M-ee-O)


----------



## blueberries

thenightwatch said:


> lol
> 
> the tryptamine connection inspired me to draw this:
> 
> 
> 
> 
> 
> 
> its like LSD, but opened up and with a pentyl added to the nitrogen on the indole and an added JWH-style oxygen secondary to the indole on the other side.
> 
> might not need that added oxygen, but its funny that this is likely active as a cannabinoid.  you can put a lot of strange junk where JWH-018's napthyl group was and still retain some activity.





This....just may work. Taking away the N1 and 4-keto groups to alleviate it's cannabinoid effects, it seems like a phenmetrazine style tryptamine analogue with the trimmings of LSD. I think you had it right without the extras, it could even be as potent as DMT or stronger, certainly easier crossing the BBB. Who knows, maybe even without the 1-keto-methylamine. It seems like it'd just be an extra bit to reduce potency.

So something like this:







EDIT: I'm an idiot. I knew I'd seen it before. This is N-Me-pip-T. Well, at least the hydroxy should be active!

EDIT2: It does, however, give insight into the workings of LSD and analogues to come, so perhaps beneficial in the long run.

EDIT3: How about this though?






Same number of atoms away from the previous amine as LSD and that ketone moves back a bit and joins the hydrogen (perhaps at a downward angle, like LSD?).


----------



## roi

Might work. And one more for Nagelfar:


----------



## blueberries

Or even:






I very much doubt any activity but it's nice to dream!


----------



## roi

β-Hydroxythio-3,5-dimethyl-4-fluorofuranylfentanyl


----------



## crmt28

Crazy 2C-B analogue, inspired by Glaucine, which basically looks like two DMPEAs glued together.




Not sure about the extra bromine or the N-methyl, but this compound  could have some interesting psychedelic activity. 

If not, maybe if we  changed changed the methoxy groups around, like the TMA series.

EDIT:

From what I've read on Wikipedia on similar compounds, it might not be psychedelic at all, since Glaucine isn't even active at the 5-HT2a receptors from what I've read. But it still could have interesting therapeutic potential as a non-addictive anxiolytic/analgesic like Tetrahydropalmatine.


----------



## sekio

that looks like some sort of peristent organic pollutant lol

someone needs to make one of the following: (nsfw for size)

*NSFW*: 










and more weird drug ideas





remacemide looks like a real weird drug! its metabolite is alpha-phenyl-amphetamine? and it's a dissociative???


----------



## Incunabula

Sekio, do you think that 2-Cl and 3-MeO Etoxadrol would overlay with ketamine and MXE in 3D? Or what is your reasoning behind that particular substituation?

Etoxadrol and Dexoxadrol are surely fascinating compounds


----------



## roi

PY-FUBINACA


----------



## sekio

> Sekio, do you think that 2-Cl and 3-MeO Etoxadrol would overlay with ketamine and MXE in 3D?



that's the hope :D

i want another MXE type drug on the market!


----------



## roi

I read somewhere a while ago that Etoxadrol and its analogues have not so nice side effects. Maybe the morpholine analogues of PCP are the way to go (unless the potency is messed up as with 3-MeO-PCMo).


----------



## sekio

> I read somewhere a while ago that Etoxadrol and its analogues have not so nice side effects



I read that too, I think I recall it was discontinued because it caused nightmares in some. Oh no! A hallucinogen that induces dreaming. These were the studies published in '76 on 28 test people, I think only 2 of them didn't like it, and that's because someone megadosed one and he was fucked up for a week straight.   Apparently it has a good tox profile, no major changes in chemistry were noted.

Doses were between below 0.75mg/kg (that was a typical anesthetic level) to 4.5 mg/kg (6-day fuckup) when administered IV, so between ~40 and 300mg. I bet it has good enough bioavailibility to be snorted or plugged though.

I also read etoxadrol is self-administered by monkeys just like cocaine or PCP. Dexoxadrol is also but not at the same frequency, it is negatively reinforcing.

So I want to see these being made availiable on the grey market! These are the dissociatives y'all want.


----------



## roi

> These are the dissociatives y'all want.



That would be Ephenidine/Isopropylphenidine/Diephenidine


----------



## pr0d1gy

sekio said:


> I read that too, I think I recall it was discontinued because it caused nightmares in some. Oh no! A hallucinogen that induces dreaming. These were the studies published in '76 on 28 test people, I think only 2 of them didn't like it, and that's because someone megadosed one and he was fucked up for a week straight.   Apparently it has a good tox profile, no major changes in chemistry were noted.
> 
> Doses were between below 0.75mg/kg (that was a typical anesthetic level) to 4.5 mg/kg (6-day fuckup) when administered IV, so between ~40 and 300mg. I bet it has good enough bioavailibility to be snorted or plugged though.
> 
> I also read etoxadrol is self-administered by monkeys just like cocaine or PCP. Dexoxadrol is also but not at the same frequency, it is negatively reinforcing.
> 
> So I want to see these being made availiable on the grey market! These are the dissociatives y'all want.



I can't seem to find much information on etoxadrol beyond the (S,S,S) isomer. What is known of the other stereoisomers? Are they inactive or undesirable for other reasons?


----------



## sekio

J. Med. Chem. 1988, 31, 2257-2263
Synthesis, Absolute Configuration, and Molecular Modeling Study of Etoxadrol, a Potent Phencyclidine-like Agonist
doi: 10.1021/jm00120a004






I think they are inactive, they are orders of magnitude less potent as dissociatives that's for sure.


----------



## Incunabula

sekio said:


> that's the hope :D
> 
> i want another MXE type drug on the market!



I hear ya :D

Another interesting line of research could be for enadoline analogs. Orally active k-Opioids, maybe not really promising as recreationals, but still very fascinating . I have no clue of the SAR though.


----------



## Midnight Sun

sekio said:


> that's the hope :D
> 
> i want another MXE type drug on the market!



maybe try 2-(thiomethyl)phenyl instead of the MeO?


----------



## Solipsis

Sum stuff i wonder about:






Inspired by the 2C-B-FLY that I just acquired 

Note that the bottom right one has nothing to do with 'chlorine-washed poultry', but rather what the shape of the molecular formula is reminiscent of, as with the FLYs.


----------



## Incunabula

Nice ones, Solipsis  Especially the mescaline-dragonfly. I think it´s probably one of the few dragonfly´s I´d actually like to try, if the dosage turn out to be somewere between mescaline proper and BDFly. How it will be qualitatively is really difficult to imagine, I think.

The one I´d most like to have a stab at though, is TFMFly. Enjoy your 2C-B-Fly, btw


----------



## Dresden

4-nitro-DMT
1-pentyl-4-nitro-DMT

Unfortunately, I see freak out potential here.


----------



## Solipsis

I'm interested in the effects of 2C-T-Fly actually, if only the toxicological effects in animals. I think 2C-T-X metabolism can be incredibly complex considering the big number of metabolites identified for one of them (I forgot which one). Constraining the methoxies should inhibit one of the metabolism avenues, like alpha-alkylation prevents another one. Then again preoccupying certain enzymes and the competition is not quite the same as eliminating a vulnerability in the molecule to metabolic attack at that position.
Anyway research on that could theoretically clarify what type of metabolites are more directly responsible for toxic effects or contraindications with toxic implications. That could help us to avoid certain 2C-T derivatives but not others.

Also... if a safe compound, it should make a fair middle ground regarding potency and duration considering 2C-T-FLY and SAR?

@ Mescaline-FLY, it might not be active at all... mescaline does seem to be a bit of an odd one in the mix, as proven by C30-NBOMe being inactive..

@ 4-Nitro-DMT and analogue cousins: what makes you say that there would be freak-out potential? I'd be really worried about the carcinogenic potential of nitroso metabolites and the like, especially aromatic nitro's are a really bad idea. Not quite sure what makes 2C-N or DON okay, the other substitutions perhaps offer enough steric protection to make those metabolic routes minor / slow compared to other ones.. Well fortunately I think DMT metabolism and perhaps also excretion somewhat is a specialty of the human body. 
Would 4-Nitro-DMT be too polar to cross the BBB? At least the polarity would make it somewhat psilocin like rather than 4-MeO-xxT like.

Not sure but I thought 1-alkyl trypts or ergoloids were inactive. You would need an amide like N-valeryl I think?


----------



## Incunabula

Solipsis said:


> @ Mescaline-FLY, it might not be active at all... mescaline does seem to be a bit of an odd one in the mix, as proven by C30-NBOMe being inactive.


Yes, of cause. We wouldn't know until some one tried it. 

Some interesting thoughts on 2C-T-Fly you have there. Hopefully we'll see some more new fly's available now that some one started making 2C-B-Fly again.
I'd say though, that going from my own 2 trials with it that I don't think that the fly-series compounds are going yield any new superdeep psyckedelics. 2C-B-Fly really is 50/50 a mild psyckedelic/mild empathogen.

Of cause I could be wrong.


----------



## Dresden

Lol, 2CN and DON are not anymore ok than nitro tryptamines.  It's the same type of thing, "Well, Shulgin invented this, so it must be safe," which makes people rail against chlorinated amphetamines but not DOC!  As far as the nitro tryptamines go, I just figured that, due to the extreme electronegativity of the centrally located nitrogen atom (which carries with it a + charge), it would be even more freakout prone than high dose shrooms, which are hard enough to handle on their own.  To my knowledge (which, granted, is quite limited), I don't think anyone has really made or tested indolic 1-N-pentyl tryptamines or 1-N-pentyl ergoloids.  The indolic 1-N-pentyl group certainly works for many of the JWH's though!  And for THC.

I would be truly afraid to try 5-nitro-tryptamine, I think.  (I have never done 5-MeO-DMT, but I have read some badly ending trip reports here when it was being sold as an RC.)


----------



## adder

Mescaline-FLY and Mescaline-hemi-FLY didn't fully substitute for LSD in rats even though they both had an increased affinity vs. mescaline for all subtypes especially for 5-HT2C. Both the FLY & the hemi-FLY analogues had a lower affinity at 5-HT2A but higher at 2B & 2C than escaline (source). However, escaline in this study also partially substituted for LSD.


----------



## Solipsis

Dresden said:


> Lol, 2CN and DON are not anymore ok than nitro tryptamines.  It's the same type of thing, "Well, Shulgin invented this, so it must be safe," which makes people rail against chlorinated amphetamines but not DOC!  As far as the nitro tryptamines go, I just figured that, due to the extreme electronegativity of the centrally located nitrogen atom (which carries with it a + charge), it would be even more freakout prone than high dose shrooms, which are hard enough to handle on their own.  To my knowledge (which, granted, is quite limited), I don't think anyone has really made or tested indolic 1-N-pentyl tryptamines or 1-N-pentyl ergoloids.  The indolic 1-N-pentyl group certainly works for many of the JWH's though!  And for THC.
> 
> I would be truly afraid to try 5-nitro-tryptamine, I think.  (I have never done 5-MeO-DMT, but I have read some badly ending trip reports here when it was being sold as an RC.)



Thanks adder!



No, DOC is not a serotonin releasing agent it acts in a pretty different way than haloamphetamines.. and I think that this particular toxicity is considered closely related to the pharmacological action.
As for  2C-N and DON... it matters whether metabolism of the nitro group is still a major pathway with all the other moieties in the molecule. That would determine the toxicity... so you are going on an assumption there.

Another assumption you make is that electronegativity of the 4-substitution in tryptamines is linear with the efficacy on the 5-HT2A receptor while the optimum may in fact lie more somewhere 'in the middle'. 5-Nitro would be more similar to bufotenin since the polarity is not shielded by an alkyl group.
Not that bufotenin and 'isomorphs' arent badass!

And 5-MeO-DMT instills a lot of awe in me, but has made me hardly anything but ecstatic and just plain 'beyond'... fortunately no terror, so psilocin remains more nightmarish for me.


----------



## blueberries

I have a feeling an etoxadrol synth could be on the cards, I'll find the literary material and pass it through but there needs to be a good backing for it to appear. I can do that also. I've wanted to try it since the first time I saw it, such a beautiful compound.

As potency is key, I devised this instead:






However before all this goes through, I'd like some more insight on my earlier compounds such as 4-MeOH-DMT and that LSD/indole merger I created.


----------



## Dresden

blueberries,
I don't think that compound is stable in water, but I'm not 100% sure.


Solipsis,
Yes, but the only surefire way to know is to synthesize and test them.  It could go either way.


----------



## Bagseed

I see an Acetal in there, so it's gonna probably hydrolyse into 1-Phenylpropan-1-one (would this be the right nomenclature?) and the respective diol.


----------



## Dresden

Yes, that is the correct nomenclature IIRC.  The more commonly used name, though, is propiophenone.


----------



## sekio

Etoxadrol/dexoxadrol are sterically hindered enough that they don't decompose in water instantly. (as evidenced from human trials... they managed to dose someone with enough of this shit that he was fucked up for 6 days. lucky fucker)


----------



## Bagseed

ok, interesting. how exactly would you determine if an acetal is sterically hindered enough to not readily hydrolyse (in acidic envorinment of course)?


----------



## sekio

I think the easiest way is measuring it experimentally. It depends strongly on the exact conditions, the polarity/solubility of the compound, et cetera. There are acetals that aren't very hindered (e.g. MDMA, some acetonides/formaldehyde acetals) but resist hydrolysis anyway, and there are bulky acetals that are easily deprotected (some benzaldehyde acetals).

I think the easiest to hydrolyse are methylene/formaldehyde acetals, even stuff like acetonides are pretty resistant.


----------



## Bagseed

^ actually now that you mention it, my roommate and I were talking about how the methylenedioxy group should be in some kind of equilibrium with the 3,4-dihydroxy version, but actually isn't (or rather much more in the acetal side).

I just recently finished my first organic lab at university, so I'm highly interested in these things but still not that knowledgeable about it.


----------



## roi

Derived from Delucemine. May work. One way to find out..


----------



## pharmakos

looks to me like it would work, assuming based on how the phenyls are positioned relative to each other in the same configuration as diphenidine.


----------



## roi

No idea if you can just move the nitrogen up there though.


----------



## pharmakos

right.  considering both of the inspiration molecules are active, it would seem odd to me if moving the nitrogen out only works with the one configuration of phenyls and not the other configuration.  as always, only way to know for sure is to make it and see.


----------



## roi




----------



## Hammilton

I'm unable to post drawings, so please forgive me, but I'd like to suggest the following compounds:

Replace the piperidine ring of W-18 with 5-nitrobenzimidazole, with the side chains attached the same as in Etonitazine.

1-phenyl-4-PCC (or I guess 1,4-diPCC).  This PCP with a 4-phenyl-4-hydroxy substitution on the cyclohexane ring.  4-PCC or just PCC is the name given to the primary metabolite of PCP, which has that 4-hydroxy.  IUPAC, if I remember my conventions correctly would be 1,4-diphenyl-4-(1-piperidinyl)cyclohexanol.  I'd also be interested in that 1-phenyl being replaced with a benzyl and phenethyl.  I imagine that the latter will be quite potent as its pretty close to BDPC, or Bromadol, but the desire is for potency between 1 and 3x morphine.  Something strong enough to make for plenty of doses per gram, but also weak enough that half a milligram isn't the difference between fun and funeral.


Looking at etonitazine more, I wonder if some sort of cannabinoid-opioid combination molecule could be acheived.  The chains aren't optimally placed for cannabinoid activity, but I bet something could be worked out.


----------



## blueberries

So something like this for the PCP analogue:






This one looks pretty nice in all honesty, an opioid without the potency of Bromadol. You could always have a 2-oxo group instead of the hydroxy. I feel it'd be similar but with a touch of NMDA antagonism too. It could be at risk of becoming a potent PCP analogue though, so better stick with the hydroxy for pure opioid content. 

Also, for a time I was very interested in the Etonitazene analogues but tried to wane them more to the Tryptamine field for a gain on potency and possibly some opioid effects and came up with these: 











I would have hoped they'd be potent tryptamines (former) or a mix of hallucinogenic and opioid content (latter) but they never seem to come out how you want them to in reality. I'd expect them to either be inactive or compounds reminiscent of pyr-T or 5-MeO-aMT (so high body-load, low dose, "ugly" hallucinogens).


----------



## Hammilton

I don't think you'll get 5HT2A affinity with those structures, I'm afraid it won't tolerate that bulky 2-(4-ethoxybenzyl) substitution, not with any affinity, for sure.  

I would think the only real chance of producing an active compound with similar ED50's (don't want cannabinoid activity with a 5mg/kg ED50 and opioid activity with a 50mcg/kg ED50)  for two receptors is to target MOR and CB1/2.


Yes that compound you drew is 1,4-diPCC.  That hydroxy is important, probably necessary for activity, or an ester.  I don't think it'll have NMDA antagonist activity.  2-oxo is a bad idea, the goal is an opioid.


----------



## chronular

Are there reasons why there haven't been studied (as far as I can tell)? I don't know how to name them.

My experience with DALT is that it has produces certain effects of DPT with almost identical character (weird energy, body vibrations, time dilation) while completely removing others (visuals, mindfuck). So maybe #1 would emphasize other properties of DPT?

DALT 
	

	
	
		
		

		
		
	


	




 DPT 
	

	
	
		
		

		
		
	


	




#1 
	

	
	
		
		

		
		
	


	




 #2


----------



## blueberries

I think because of the above reason. They're too bulky to be hallucinogens and too impotent to be the opioid that Etonitazine is. They're a strange intermediate between the two that has no use in modern science. It's a shame because the basic idea looks lovely.

Also that #1 would be (very) interesting but #2, as I've asked before, would be toxic I think. Vinyl metabolites do something nasty but I'd need someone else to tell me what!

A Methynyl though (triple bond) would be much better and I think a winner in all honesty but we've yet to see. I'd go for MYT personally.


----------



## Bagseed

blueberries said:


> A Methynyl though (triple bond) would be much better and I think a winner in all honesty but we've yet to see. I'd go for MYT personally.


would you mean an ethynyl group? R-N-(C=CH)2 ?


----------



## adder

#1 and #2 are unstable in water, they will hydrolyse to the corresponding aldehyde in no time.


----------



## Dresden

How about N-ethynyl-amphetamine?  Nice "legal" ethylamphetamine substitute perhaps or just another unstable compound in aqueous media?

Also, taking a cue from the hypnotic zolpidem, 2-(4-methylphenyl)-DMT, 2-(4-methylphenyl)-4-hydroxy-DMT, indolic 2-(4-methylphenyl)-LSD, and 2-(4-methylphenyl)-5-MeO-DMT.


----------



## blueberries

Bagseed said:


> would you mean an ethynyl group? R-N-(C=CH)2 ?



Yeah, sorry I don't know why I said Methynyl, it makes zero sense.


----------



## blueberries

adder said:


> #1 and #2 are unstable in water, they will hydrolyse to the corresponding aldehyde in no time.



Could be interesting nonetheless! N, N-Di(propyl-1-oxo)-Tryptamine!


----------



## pharmakos

has anyone ever tried putting a fluorine at the end of the n-alkyl groups of a tryptamine?


----------



## Dresden

I don't know, but beta-oxo-DMT might make a good research chemical.


----------



## blueberries

I know bk-aMT is supposed to be incredible, not sure about DMT though, I reckon it's worth looking into.


----------



## roi

Most bk-tryptamines are serotonin antagonists..


----------



## Dresden

Reduction of Ambien's (zolpidem's) N,N-dimethyl amide functional group to the N,N-dimethylethanamine (I'm not gonna say how, but it isn't hard to figure out) should produce a drug that packs quite a wallop.


----------



## roi

That should be a banging cannabinoid.


----------



## sekio

8-OH-quinoline (alcohol on the ester there) is a transcription inhibitor/putative cancer chemotherapy drug, I would not like that accumulating, no sir.


----------



## roi

All in moderation! BB-22 was quite enjoyable. Could always replace it with a naphthalene group (probably not the safest thing ever either though).


----------



## pharmakos

i went through a gram of BB-22 in a few months.  i felt EXTREMELY odd by the end of it.  looking back, its actually when a few of my current health problems started.


----------



## adder

blueberries said:


> Could be interesting nonetheless! N, N-Di(propyl-1-oxo)-Tryptamine!



If you only managed to ingest it without breaking it down in the process...  So it's like it could be interesting if we only lived in a different realm with different rules governing it, but unfortunately we're carbon-based lifeforms with lots of water inside.


----------



## pharmakos

adder said:


> If you only managed to ingest it without breaking it down in the process...  So it's like it could be interesting if we only lived in a different realm with different rules governing it, but unfortunately we're carbon-based lifeforms with lots of water inside.



injection straight to the cerebellum? =p







sekio said:


> 8-OH-quinoline (alcohol on the ester there) is a transcription inhibitor/putative cancer chemotherapy drug, I would not like that accumulating, no sir.





roi said:


> All in moderation! BB-22 was quite enjoyable. Could always replace it with a naphthalene group (probably not the safest thing ever either though).





thenightwatch said:


> i went through a gram of BB-22 in a few months.  i felt EXTREMELY odd by the end of it.  looking back, its actually when a few of my current health problems started.



after realizing that, the more i think about it, the more i think that BB-22 kinda messed me up when i smoked it last year.  i acquired it at the same time that i got my gram of 3-MeO-PCP, and i was definitely abusing both of them.  around that time i started noticing some issues with my bowels, some numbness in my lower extremities, and some odd heavy feelings in my lungs.  at the time i attributed all those effects to the 3-MeO-PCP.  but this year, i picked up some more 3-MeO-PCP, and didn't notice any of those side effects.  i thought that was odd, but figured it was attributable to other changes in my life.  but yeah, the more i think about it now.... i think that BB-22 was more of a culprit.

good information, thanks sekio.

BB-22, for reference: (NSFW for size)


*NSFW*:


----------



## Midnight Sun

I thought of this in the shower the other day.  not viable to make but interesting to think about 






ps: doing a fluorobenzyl sub on JWH-122 is really where it's at gaiz


----------



## crmt28

Psilocin with aminoindane-like structure.


----------



## pharmakos

Midnight Sun said:


> I thought of this in the shower the other day.  not viable to make but interesting to think about



whoa!  i wish i had thought of that!  looks like a winner!


----------



## Midnight Sun

crmt28 said:


> Psilocin with aminoindane-like structure.



Funny, I had thought of a similar perversion of TMA-6:






or, perhaps to stay truer to form:






Moving the 5-MeO to 6 doesn't seem to destroy activity and phens seem to respond well to constraint (planarity) so the question in my mind is what a more efficient 4-sub would result in.  it's kind of a moot point with indanyl psychedelics like 2CB-Ind, jimscaline & friends waiting to be explored, though

Edit: on the 1st image, per existing indanyls my amide is both too short a chain and in the wrong spot... but you get the idea

almost dragonfly-ish if you look at it



thenightwatch said:


> whoa!  i wish i had thought of that!  looks like a winner!



thanks


----------



## Dresden

From I've been taught, you can't have a N and an O sharing the same carbon (or 1 carbon away from each other, to state it differently).  As for the other one, it is probably not safe, as 100mg or more of the related 2-aminotetralin will send you to the hospital.  Also, I've done TMA-6 and didn't even enjoy it.  _I would love to try all four "5"-MeO-(5 or 6)-AP(D)B's, though._


----------



## sekio

Do we need a campaign against aminal abuse?





These guys are hydrolytically and enzymatically unstable, they are valid compounds indeed, but they have a tendency to decompose to ammonia and the parent aldehyde (!)


----------



## crmt28

crmt28 said:


> Psilocin with aminoindane-like structure.




Huh, that's actually a more interesting compound than I thought. I was looking on the LSD analogue *Midnight Sun *posted and made a similar connection.

Here's the same molecule on a different angle, plus the piperidine version aside. Looks very LSD like! I wonder if adding a double bond somewhere could help with the activity.


----------



## pharmakos

crmt28 said:


> I wonder if adding a double bond somewhere could help with the activity.



whatever you need to do to make it planar, i would imagine.


----------



## Midnight Sun

sekio said:


> Do we need a campaign against aminal abuse?
> 
> 
> 
> 
> 
> These guys are hydrolytically and enzymatically unstable, they are valid compounds indeed, but they have a tendency to decompose to ammonia and the parent aldehyde (!)



well now I know that %)

for shame I am bad drug designer.  go directly to jail, do not pass go



crmt28 said:


> Here's the same molecule on a different angle, plus the piperidine version aside. Looks very LSD like! I wonder if adding a double bond somewhere could help with the activity.



I was going to propose subbing a sulfur in there but... something's nagging me about it


----------



## Dresden

There needs to be a double bond where the O is to achieve planarity.  Switching O-->S isn't going to help because the molecule still won't be planar.  5-(CH3-S)-DMT might be interesting, though.


----------



## sekio

2 stimulants (already detailed in a patent... probable cocaine/mdma replacements, triple releasers/reuptake inhibitors) and a cannabinoid.


----------



## endotropic

The 2-phenyl morpholine's are very interesting.   Have the 2-phenyl 3-methyl morpholine's been tested?


----------



## Midnight Sun

Dresden said:


> There needs to be a double bond where the O is to achieve planarity.  Switching O-->S isn't going to help because the molecule still won't be planar.  5-(CH3-S)-DMT might be interesting, though.



You missed what I was saying, dude, but fair enough, I was half awake and made a vague post

Reason I suggested the sulfur was to move the nitrogen "left in X" - normally I'd have just done that with the oxygen there but per sekio that's bad juju.  Had nothing to do with planarity

Here let me draw:






This way you can have the nitrogen in it's holy grail spot like you have in LSD while maintaining the same # of lone pair electrons as you would with the oxygen... that was my thinking.  now go from there with planarity.

it's a weird looking sub, though

while I'm here and yapping about sulfur,






balanced releaser or hyperthermic hell?


----------



## Bagseed

^so this is basically MPA without the N-methyl and the sulfur on another position... what could this mean regarding activity?

edit: ok after having another look at your molecule: nevermind :D


----------



## Dresden

The sulfur amphetamine molecule has 5 bonds on 2 (numbers 3 and 4) carbons of its benzene ring and does not and will not exist.  However, you could try 2-thia-IAP (the 5 membered ring saturated version of your (almost) creation; I've often wondered about 2-oxa-IAP myself.  Note:  I'm using replacement nomenclature there.)  I've never seen a nitrogen-carbon-sulfur either in a molecule, I don't think.  Whether that means it's like nitrogen-carbon-oxygen containing molecules, which don't exist, or not I don't know, but I'm inclined to think nitrogen-carbon-sulfur molecules are chemically verboten as well.


----------



## Midnight Sun

Dresden said:


> The sulfur amphetamine molecule has 5 bonds on 2 (numbers 3 and 4) carbons of its benzene ring and does not and will not exist.  However, you could try 2-thia-IAP (the 5 membered ring saturated version of your (almost) creation; I've often wondered about 2-oxa-IAP myself.  Note:  I'm using replacement nomenclature there.)  I've never seen a nitrogen-carbon-sulfur either in a molecule, I don't think.  Whether that means it's like nitrogen-carbon-oxygen containing molecules, which don't exist, or not I don't know, but I'm inclined to think nitrogen-carbon-sulfur molecules are chemically verboten as well.



http://www.chemindustry.com/chemicals/01539609.html

Isobenzothiophene is a thing.  If you wanna be autistic about it then lol OK 1 extra double bond in the benzene


----------



## Nagelfar

Midnight Sun said:


> If you wanna be autistic about it then lol OK 1 extra double bond in the benzene



If we're posting in this thread, OF COURSE WE WANT TO BE AUTISTIC ABOUT IT!!!!11111 ;-P


----------



## sekio

> Have the 2-phenyl 3-methyl morpholine's been tested


Yes, these are the phenmetrazines.


----------



## endotropic

sekio said:


> Yes, these are the phenmetrazines.



Oh yea 

So now I'm wondering whether the PEA/Amphetamine SAR holds up on the phenyl side of phenylmorpholine/phenmetrazine, which naturally led me to wonder about methylenedioxy-phenmetrazine, which led me here: http://www.bluelight.org/vb/threads/296058-Radaxafine-(substituted-phenmetrazine)

I'm kind of surprised that one hasn't been tried actually.


----------



## Dresden

That and MD-MPH and MD-4-MAR.  Isothienobenzene may be a real chemical, but not the way you've drawn it.


----------



## roi




----------



## pharmakos

hm, how quickly would that get metabolized?  i don't know enough about pharmacokinetics, but my gut tells me that it would get eaten up pretty quickly.


----------



## sekio

while we're at it, someone needs to feed roi some phenylalanine, I bet he will say it's an amphetamine replacement with fewer side effects and more euphoria 8)


----------



## roi

You just lost that bet. Stop the random hate maybe...

Scepticism doesn't hurt, but unsupported "inactive" does.

Looking forward to the video of you eating your hat.


----------



## sekio

well, excuse me if your claim goes against all known SAR of amphetamines. i think claiming that a simple organic compound known probably since the 1800s is a stimulant should be backed up with at least one piece of literature data? 

do you realize that this means clandestine amphetamine manufacturers need not bother with the whole process of making phenylacetone and can just go PAA-->the amide in one step? do you really thunk nobody's tried that?? (hint: DEA has found people making phenylacetamide before, and it wasn't exactly mentioned as an active stimuylant, more like a fuckup!)

and you don't exactly have a history of posting any sort of analytical data to back up your claims, either? do you even know you have phenylacetamide? can you provide any sort of data to back up your claim? MS, NMR, melt point, fucking TLC or something? no?

how about you go back to shilling on drugs forum, clearly you don't have the ability to swim with the big fish here. big claims require big evidence and i see nothing but you trolloping around saying "oh this compound XYZ is a novel stimulant!!!!!!!!" - never providing anything but anecdotes.


----------



## Soulfake




----------



## pharmakos

....what is it?

looks neat.  also looks smelly.  and maybe toxic.


----------



## Erikmen

sekio said:


> well, excuse me if your claim goes against all known SAR of amphetamines. i think claiming that a simple organic compound known probably since the 1800s is a stimulant should be backed up with at least one piece of literature data?
> 
> do you realize that this means clandestine amphetamine manufacturers need not bother with the whole process of making phenylacetone and can just go PAA-->the amide in one step? do you really thunk nobody's tried that?? (hint: DEA has found people making phenylacetamide before, and it wasn't exactly mentioned as an active stimuylant, more like a fuckup!)
> 
> and you don't exactly have a history of posting any sort of analytical data to back up your claims, either? do you even know you have phenylacetamide? can you provide any sort of data to back up your claim? MS, NMR, melt point, fucking TLC or something? no?
> 
> how about you go back to shilling on drugs forum, clearly you don't have the ability to swim with the big fish here. big claims require big evidence and i see nothing but you trolloping around saying "oh this compound XYZ is a novel stimulant!!!!!!!!" - never providing anything but anecdotes.



I would bet all my 'chips' on Sekio because I know he is right about these issues.
Seriously he knows this very well.


----------



## Solipsis

Why doesn't everyone hold off on picking sides based on reputation or smarts, until we actually see some data on this - I think that is something we can all agree on?

Yes I totally agree the SAR doesn't make any sense, the ketone is not an alpha methyl bioisostere afaik hehe... and it would be so strange if the family of compounds was overlooked. But there may be something to the properties of metabolites.

It is right to ask for data here and right now it is not presentable, but just don't overestimate what you think you can know and mistake it for actual proof either. Just be patient.


----------



## Bagseed

roi said:


>


wouldn't these probably metabolize into the respective carboxylic acids?


----------



## Soulfake

thenightwatch said:


> ....what is it?
> 
> looks neat.  also looks smelly.  and maybe toxic.



I have no Idea what it could be, just randomly drawn molecules. metabolites (if the compound could be stabily produced) could be iodomethanethioic O-acid and chloromethanethioic O-acid, but I couldn´t find any data about them.


----------



## Dresden

Bagseed said:


> wouldn't these probably metabolize into the respective carboxylic acids?



Yes, but it would probably take a couple o hours to do so.


----------



## Nexus_Tripper

Escaline with a fluorine stuck on the end of the ethoxy group... Hybrid of Mescaline and 2C-T-21


----------



## pharmakos

i would try it.  i predict activity in the 20-30mg range.

purely based on intuition, i might be wrong.


----------



## Incunabula

Nightswatch? How'd ya change your name?


----------



## pharmakos

http://www.bluelight.org/vb/threads/699704-a-thank-you-perk-for-donators-account-name-change



alasdairm said:


> following the launch of the donations portal (see: Introducing Bluelight's Donations Portal!), we're pleased to announce that those donating $25 or more to bluelight now receive a one-time account name change as a thank you.
> 
> if you would like to take advantage of this perk, simply forward the receipt email you receive from maps to bluelight.admin@gmail.com, along with  the new name you are requesting. the abandoned accounts policy (see: change to the terms of the blua: abandoned accounts) will apply.
> 
> alasdair



you might even get a free name change if you asked, though.  i was always amazed the staff never made you change your name.


----------



## Incunabula

^^ Actually, I'd love to change my name, because I'm sick and tired of it. Don't know what I was thinking when I chose it, but it does have its good sides, like people remember it 

Thing is, Fagott is actually german for bassoon, but people don't get that. It's completely nonsensical, I'm not german, I'm not gay and I don't play the bassoon. So wtf was I thinking. lol.......might donate that 25 bucks for a name change :D

Sorry to say it, but I actually liked your own name better, Nightwatch, but I guess it's often like that.


----------



## pharmakos

eh, i was tired of thenightwatch.  everyone thought it had to do with game of thrones, or some vampire book/movie series.  i'm much more emotionally attached to the word pharmakos

here's what pharmakos means.  nsfw for length and offtopic.  note that the word originally had nothing to do with drugs.


*NSFW*: 



Pharmākos, in Greek religion, a human scapegoat used in certain state rituals. In Athens, for example, a man and a woman who were considered ugly were selected as scapegoats each year. At the festival of the Thargelia in May or June, they were feasted, led round the town, beaten with green twigs, and driven out or killed with stones. The practice in Colophon, on the coast of Asia Minor (the part of modern Turkey that lies in Asia) was described by the 6th-century-bc poet Hipponax (fragments 5–11). An especially ugly man was honoured by the community with a feast of figs, barley soup, and cheese. Then he was whipped with fig branches, with care that he was hit seven times on his phallus, before being driven out of town. (Medieval sources said that the Colophonian pharmākos was burned and his ashes scattered in the sea.) The custom was meant to rid the place annually of ill luck.

The 5th-century Athenian practice of ostracism has been described as a rationalized and democratic form of the custom. The biblical practice of driving the scapegoat from the community, described in Leviticus 16, gave a name to this widespread custom, which was said by the French intellectual René Girard to explain the basis of all human societies.

---------------------------

A pharmakós (Greek: φαρμακός, plural pharmakoi) in Ancient Greek religion was the ritualistic sacrifice or exile of a human scapegoat or victim.

A slave, a cripple or a criminal was chosen and expelled from the community at times of disaster (famine, invasion or plague) or at times of calendrical crisis. It was believed that this would bring about purification. On the first day of the Thargelia, a festival of Apollo at Athens, two men, the Pharmakoi, were led out as if to be sacrificed as an expiation.

Some scholia state that pharmakoi were actually sacrificed (thrown from a cliff or burned), but many modern scholars reject this, arguing that the earliest source for the pharmakos (the iambic satirist Hipponax) shows the pharmakoi being beaten and stoned, but not executed. A more plausible explanation would be that sometimes they were executed and sometimes not, depending on the attitude of the victim. For instance, a deliberate unrepentant murderer would most likely be put to death.[citation needed]

In Aesop in Delphi (1961), Anton Wiechers discussed the parallels between the legendary biography of Aesop (in which he is unjustly tried and executed by the Delphians) and the pharmakos ritual. For example, Aesop is grotesquely deformed, as was the pharmakoi in some traditions; and Aesop was thrown from a cliff, as was the pharmakoi in some traditions.

Gregory Nagy, in Best of the Achaeans (1979), compared Aesop’s pharmakos death to the “worst” of the Achaeans in the Iliad, Thersites. More recently, both Daniel Ogden, The Crooked Kings of Ancient Greece (1997) and Todd Compton, Victim of the Muses: Poet as Scapegoat, Warrior and Hero (2006) examine poet pharmakoi. Compton surveys important poets who were exiled, executed or suffered unjust trials, either in history, legend or Greek or Indo-European myth.

------------------------------

[1] The chain, pharmakeia-pharmakon-pharmakeus, appears several times in Plato's texts. A word not directly or literally used by Plato is pharmakos, which means 'scapegoat'. According to Derrida, that it is not used by Plato does not indicate that the word is necessarily absent. Certain forces of association unite the words that are 'actually present' in a text with all the other words in the lexical system, whether or not they appear as words in such discourse. The textual chain is not simply 'internal' to Plato's lexicon. One can say that all the 'pharmaceutical' words do actually make themselves present in the text. 'It is in the back room, in the shadows of the pharmacy, prior to the oppositions between conscious and unconscious, freedom and constraint, voluntary and involuntary, speech and language, that these textual 'operations' occur' (Dissemination, p.129). Derrida places the opposites, presence-absence and inside-outside, under great pressure. If the word pharmakos that Plato does not use still resonates within the text, then there can be no matter of a text being closed upon itself. What do 'absent' and 'present' mean when the outside is always already part of the inside, at work on the inside?

[2] In ancient Athens, the character and the ritual of the pharmakos had the task of expelling and shutting out the evil (out of the body and out of the city). The Athenians maintained several outcasts at the public expense. When plague, famine, drought or other calamities befell the city, they sacrificed some of the outcasts as a purification and a remedy. The pharmakos, the scapegoat, was led to the outside of the city and killed in order to purify the city's interior. The evil that had affected the inside of the city from the outside, was thus returned to the outside in order to protect the inside. But the representative of the outside (the pharmakos) was nonetheless kept in the very heart of the inside, the city. In order to be led out of the city, the scapegoat must have already been within the city. 'The ceremony of the pharmakos is thus played out on the boundary line between the inside and the outside, which it has as its function ceaselessly to trace and retrace' (Dissemination, p.133). At the same time, the pharmakos is on the borderl between sacred and cursed, '... beneficial insofar as he cures - and for that, venerated and cared for - harmful insofar as he incarnates the powers of evil - and for that, feared and treated with caution' (Dissemination, p.133). He is the benefactor who heals and he is the criminal who incarnates the powers of evil. The pharmakos is like a medicine in that he 'cures' the impurity of the city, but he is, at the same time, a poison, an evil. Pharmakos. Pharmakon. Undecidables. Both words carry within themselves more than one meaning. Conflicting meanings.

[3] Pharmakos does not only mean scapegoat. It is also synonymous for pharmakeus, or wizard, magician, poisoner. In Plato's dialogues, Socrates is often portrayed as a pharmakeus. Socrates is considered as one who knows how to perform magic with words. His words act as a pharmakon (as a remedy, or as a poison?) and permeate the soul of the listener. In Phaedrus, he fiercely objects to the ill effects of writing. He compares writing to a pharmakon, a drug, a poison: writing repeats without knowing. Socrates suggests a different pharmakon, a medicine: dialectics, the philosophical dialogue. This, he claims, can lead one to true knowledge, the truth of the eidos, that which is identical to itself, always the same as itself, invariable. This is the message of Socrates to the city of Athens. He acts as a magician (pharmakos) - Socrates himself speaks about a divine or supernatural voice that comes to him - and his most famous medicine (pharmakon) is speech, dialectics and dialogue that will lead to knowledge and truth. 

But Socrates also becomes Athen's most famous 'other' pharmakos, the scapegoat. He becomes a stranger, even an enemy who does not speak the proper language of the other citizens. He is an other; not the absolute other, the barbarian, but the other (the outside) who is very near, who is already on the inside. According to several prominent Athenians, he was of bad moral and political influence. His constant criticism undermined the faith in democracy of many Athenians. In 399 BC, Socrates was charged with introducing new gods and corrupting the young and sentenced to death. Having accused him as a force of evil, Athens killed him to keep itself intact. Athens kills the pharmakos (both the magician and the scapegoat).


----------



## Incunabula

Wow, that's really interesting  When I first read Pharmakos, I did think it had something to do with drugs.....But I get it now. It's were the meaning behind the english word pharmacy comes from. The scapegoat that is "sacrificed" to bring the evil out of town (or the body). Very cool. 

I totally get why you'd be tired of the nightwatch, what with Game of Thrones and all. I guess it's just that you're still thenightwatch to the rest of us, untill we get used to the new name, I guess 

I read Socrates defense speech from his trial, in school once. It's really hilarious. In the end he refuses to name a proper punishment for himself (after athenian custom), it could have been a fine or a pilgimage to a holy site or something like that. Because he refuses, which would have been the same as admitting he was guilty, he ands up getting the death penalty.
And still he just mocks all of the prosecutors as well as the whole town of Athens, exposing their hypocrisy.

I guess all this is completely off topic, but does it matter? I see the whole "I like to draw pictures of random molecules" thread as a kind of social thread anyway


----------



## roi




----------



## doppelgänger1

Would 6-AcO-6-nor-Ald-52 be active? Or would the AcO-group be removed completely leaving the N unsubstituted?


----------



## Dresden

You can have N-Ac or O-Ac, but not N-O-Ac.

N-Ac may be slightly active but is still less desirable than N-Me in this case because the latter better matches up with the ergoline DMT pharmacophore.


----------



## doppelgänger1

Yes, n-acetyl was what i meant.


----------



## Solipsis

Better make it 6-propionyl, since that is more slowly hydrolysed (which may be what makes 1P-LSD interesting), not sure if N-methyl is actually ideal, ETH-LAD is more potent than LSD but the ideal point is probably in between methyl and ethyl, not ethyl and propyl. Plus Prop being an acyl also adds oxygen as bulk. 

Forgetting about potency for a second, choosing the right acyl group (acetyl, propionyl, butyryl etc) could mean choosing a shorter acting LSD analogue. It is probably disappointing in reality, but there may be interest for business men's lunch trips?


----------



## Dresden

This one's a longshot.  It's also a shout out to testosterone.

2-methylamino-1-(1-oxo-cyclohex-2-ene-4-yl)-propane.HCl

See also 3,4-di-oxo-propylhexedrine.  This one avoids being aromatized to p-OH-methamphetamine.


----------



## blueberries

b-Oxymethylamine-methamphetamine or 4-MAR with it's ring broken. Would the N-Methyl work better as an a-Methyl to the beta amine or should it stay where it is?


----------



## Dresden

N and O don't exist with only one C spacer betwixt them.  4-MAR does obviously but it's in a ring and with a double bond.


----------



## blueberries

Why not? Also what if there were a vinyl bond at the alpha instead of the single on N? 

Plus would Aminorex (and Phenmetrazine to be honest) act as PEA/Amp? Could you create aminorex analogues in the same way as amphetamine ones, such as 3',4'-MDO-4-MAR? I mean, it worked with 3F-Phenmetrazine; it's more potent and speedier just like 3-FA in comparison to Amphetamine.


----------



## Dresden

I don't know why you can't have a non-cyclic, aliphatic N-C-O.  It's just what I was taught and have noticed after looking at thousands of Kekule structures.  As for the 3,4-MD-4'-MAR, yeah, I feel sure it would be active, and probably but not necessarily entactogenic.  I would also bet it's more neurotoxic than MDMA and maybe even MDA.


----------



## neurotic

Why neurotoxic?


----------



## doppelgänger1

Pemoline-version of 4-MAR and vice versa:


----------



## Dresden

Based on 4-MAR's known toxicity and the fact that 4-methyl-4'-MAR killed dozens.


----------



## sekio

> 4-methyl-4'-MAR killed dozens.


citation?


----------



## Soulfake

sekio said:


> citation?


http://www.ncbi.nlm.nih.gov/pubmed/24841869


> During the second half of 2013, a total of 26 deaths involving para-methyl-4-methylaminorex (4,4'-DMAR) were reported to the European Monitoring Centre for Drugs and Drug Addiction.


----------



## Dresden

I would be happy just to have some morpholin-3-yl-MPH right now.


----------



## roi




----------



## Hammilton

Does anyone know how the potency is affected by removing the alpha-methyl on methadone?


----------



## blueberries

Soulfake said:


>



I came up with something similar to that last one recently and it should be going into production. The great thing is it's also UK legal, so expect it within the next few months. This is it: 
	

	
	
		
		

		
		
	


	




Whats with the methyl-1-keto-ethoxy bond though? I feel it'd only add to it's opioid properties and reduce potency but looking at the one before it seems like that's what you're going for.

Also any 4-MAR analogue will be neurotoxic and vasoconstrictive but that's the price to pay for a pretty incredible compound (4'4-DMAR was a bit of a wet blanket though). Just don't go too far and limit your usage and you'll be fine.

Oh and roi, that second compound won't work, it's got too long of an amine chain and there's really no need for that 4-methyl. 4-MAR is essentially amphetamine to aminorex's PEA, same with Phenmetrazine. The first might but looks weird.

Also soon to come is 2'-MMD-4-MAR, which, most likely, will blow a few socks off! If it's anything like it's amphetamine counterpart it should act as a psychedelic in some way but based on the 4-Methyl it'll reduce the HT2a agonism pretty significantly so I'm think just a very potent empathogen. As someone mentioned earlier the MDO bond would work but not as heavily as with MDMA so the 2'-MeO should push it up into that zone (in theory). I think a normal aminorex analogue would bring that psychedelia up a bit more but it'd lack the power of the 4-Methyl so I went with that instead.

Another on the way is N-Me-Lophophine-NBOMe. Not my idea but removal of the a-Methyl should activate it unlike MDMA-NBOMe made and tested by Nichols et al. There's also a series of very exciting psychedelics but I should keep shtum about those for the meantime!


----------



## blueberries

Oh and quickly what would the effects of 3-EtO-PCP be like? I'm assuming lower potency and maybe some altered DRI effects but I wouldn't mind a second opinion.


----------



## roi

> 2'-MMD-4-MAR










> N-Me-Lophophine-NBOMe








Did I get that right?


----------



## Solipsis

roi said:


> Did I get that right?



You put the NBOMe as an extension of the N-methyl. That would yield a different name since it becomes an N-phenethyl instead of an NBOMe.
N-Me-Lophophine-NBOMe suggests that there is a tertiary amine, with a methyl substitution AND the NBOMe both on the N.

If that tertiary amine turns out active I will be amazed. Multiple wrongs usually don't make a right in SAR.


----------



## Soulfake

> Whats with the methyl-1-keto-ethoxy bond though? I feel it'd only add to it's opioid properties and reduce potency but looking at the one before it seems like that's what you're going for.



Yes exactly, I had a fusion of Tilidine and Fencamfamine (it´s basically nor-Tilidne with the cyclohexene replaced by norbornane) in mind when drawing it as they both have opioid and dopaminergic effects while nor-Tilidine is very short acting and Fencamfamine has a long half life (16h if I remember right))

I´m thinking about that molecule for a long time now, I have a feeling that it could be either great or inactive if the norbornane it too bulky for good opioid agonism.


----------



## Nexus_Tripper

Some fluoroamphetamines,,, These were inspired by the wonders of 4-FA, 2-FMA and FenFlurAmine.








Solipsis said:


> You put the NBOMe as an extension of the N-methyl. That would yield a different name since it becomes an N-phenethyl instead of an NBOMe.
> N-Me-Lophophine-NBOMe suggests that there is a tertiary amine, with a methyl substitution AND the NBOMe both on the N.
> 
> If that tertiary amine turns out active I will be amazed. Multiple wrongs usually don't make a right in SAR.



N-Phenethyl tryptamines are active and potent.


----------



## sekio

blackberries said:
			
		

> Oh and quickly what would the effects of 3-EtO-PCP be like?



I suspect it'd be tasty. That and 3-EtO-PCE.



			
				Nexus_Dripper said:
			
		

> N-Phenethyl tryptamines are active and potent.



At least some of them are, but I'm not sure they've been assayed in man?

Also, the "wonders" of fenfluramine? Like the whole heart valve thing? 4-trifluoromethylamphetamine is known and isn't a "friendly" compund.


----------



## Nexus_Tripper

sekio said:


> I suspect it'd be tasty. That and 3-EtO-PCE.
> 
> 
> 
> At least some of them are, but I'm not sure they've been assayed in man?
> 
> Also, the "wonders" of fenfluramine? Like the whole heart valve thing? 4-trifluoromethylamphetamine is known and isn't a "friendly" compund.



Fenfluramine is safe and healthy unless you abuse it and take it every day, in which case it will probably give you heart failure. Stupid pharmacutical companies sold it as some diet pill which killed its reputation.


----------



## blueberries

roi said:


> Did I get that right?



The first is opposite. You need to turn the aminorex part around so the methyl is on the bottom and the second; the NBOMe is only a benzyl instead of the PEA.


----------



## Dresden

blueberries said:


> The first is opposite. You need to turn the aminorex part around so the methyl is on the bottom and the second; the NBOMe is only a benzyl instead of the PEA.



There's nothing wrong with the 2'-methoxy-3',4'-methylenedioxy-4-MAR structure.  Due to free rotation of sigma (single) bonds, the methyl can be drawn up or down as long as the rest of the molecule is right.


----------



## Hammilton

How about the nortropane analogue of fentanyl?  I assume it's active, how is potency affected?  10x weaker maybe?  That'd be good


----------



## Soulfake

Hammilton said:


> How about the nortropane analogue of fentanyl?  I assume it's active, how is potency affected?  10x weaker maybe?  That'd be good



Would it look like the first molecule?


----------



## Dresden

Hammilton said:


> How about the nortropane analogue of fentanyl?  I assume it's active, how is potency affected?  10x weaker maybe?  That'd be good



I would look into N-methyl-3-carbomethoxy-4-(1-anilino)-tropane and N-PEA-3-carbomethoxy-4-(1-anilino)-tropane first.  Also fentanyl minus the R-(C=O)CH2CH3 but with an R-(C=O)-O-CH3 [carbomethoxy] group instead.


----------



## Nexus_Tripper

2-OxO-TCMo, MXMo, morphonorketamine, and 2-OxO-PCMo.


----------



## Nagelfar

The nor-tropane fentanyl is quite interesting! Some great novel concepts in the last page. I'm sorry for myself that I've been so busy I haven't the time to frequent this page as much.

Though of note, my Wikipedia article "List of Cocaine Analogues" is **Finally** completed. Check it out if you haven't this last month.


----------



## Dresden

Why nor?  I thought tertiary amines were best for opiates.


----------



## Nagelfar

AM251 on nor-buprenorphine


----------



## Dresden

1-(3,4,5-trimethoxyphen-1-yl)-1-(N-methylpiperidin-4-yl)-1-(propion-1-yl)-amine.HCl
1-(1,3-benzodioxole-5-yl)-1-(N-methylpiperidin-4-yl)-1-(propion-1-yl)-amine.HCl
1-(4-bromo-2,5-dimethoxyphen-1-yl)-1-(N-methylpiperidin-4-yl)-1-(propion-1-yl)-amine.HCl
1-(3,4-dichlorophen-1-yl)-1-(N-methylpiperidin-4-yl)-1-(propion-1-yl)-amine.HCl
1-phenyl-1-(N-methylpiperidin-4-yl)-1-(propion-1-yl)-amine.HCl

These have the potential to be some seriously far out drugs.  
I hope other people can read the nomenclature as I don't know how to post drawings.


----------



## roi

Fix the names and paste them into http://opsin.ch.cam.ac.uk/.


----------



## Incunabula

roi said:


> Fix the names and paste them into http://opsin.ch.cam.ac.uk/.



Lol. That's so awesome :D


----------



## Hammilton

It's still a tertiary amine, the n-methyl is removed (thus, nor) and replaced with n-phenethyl


----------



## Hammilton




----------



## Dresden

Thanks, roi!!!

* * *

All of this series save for SHIVA (inspired by Sasha Shulgin's GANESHA) are fentanyl "based."  Extreme dosing caution is advised.


























And, just for kicks:






Finally, my personal favorite:






SHIVA

For those who haven't read or don't remember GANESHA from PiHKAL:






GANESHA 

The association was made because Shiva and Ganesha usually show up together in one form or another.


----------



## roi

If you actually want to draw structures yourself, try MarvinSketch (it's free) and then upload the saved image to imgur.


----------



## Dresden

3 Great New RC Ideas!


----------



## Dresden

Plus three wildcards:


----------



## roi

The last one (3,4,5-trimethoxy-PVP) is supposedly coming soon.


----------



## Bagseed

what kind of activity are you expecting from the first two compounds? empathogen, stimulant?

edit: general question, could you guys recommend any ressources on the basics of (psycho-)pharmacology, SAR, etc.? I always wonder how you come up with these structures and why you choose certain groups/substitutions?


----------



## Dresden

Memorize as many structures as possible, try as many as you can, read trip reports on the rest, and try to find patterns.  It's an intuitive process.  Also, read PiHKAL by Alexander and Ann Shulgin cover to cover.  Finally, a degree in Chemistry doesn't hurt.

Chlorine Edition:









































Plus two oddballs:


----------



## Dresden

Bagseed said:


> what kind of activity are you expecting from the first two compounds? empathogen, stimulant?



I don't know.  That's why I called them wildcards.


----------



## Bagseed

4-chloro-DMT looks interesting. 

I actually am 3 semesters into a bachelor's degree in chemistry. didn't learn any pharmacology yet


----------



## Dresden

You have to take psychopharmacology as an elective.  I took 3:  One in the Chemistry department, one in the Psychology department, and one in the Psychobiology department.

You should definitely start reading PiHKAL, though.  (Pick up a generics Physician's Desk Reference while you're at it).  Here are two of my favorite quotes from it:






^--"Very hard on cats."

and






^--"And visions of sugarplums danced in their heads."


----------



## Dresden

While I'm at it...






^--See also Ambien's (zolpidem's) structure, a sedative-hypnotic.






The 5-EtO is supposed to take some of the unwanted oomph out of 5-MeO-DMT and is not as "illegal."






Could be a winner!  Is probably far out.






I couldn't decide whether to give this one a 7-hydroxy or 7-methoxy or 7-chloro.






Not the easiest thing to whip up probably.






Again, ditto:  Not the easiest synth, I would imagine.






(These last two are most definitely long shots.  What they do have going for them, though, is a quasi-alpha-methylethylphenyl backbone pharmacophore.)






Bet it would feel nice!






Funky!






The extra 2-methoxy activates the benzodioxole ring system even more.






"Quattro Methoxy"






The last one is supposed to be a synthetic cannabinoid.  Too structurally facile to be true?


----------



## Dresden

Some kind of hybrid.






Another hybrid, this one inspired by DMT and the JWH's.






Wonder if anyone has ever thought of trying this DMT intermediate which might be active in its own right?






More closely resembles the HO-CH2CH2NH-(C=O)-R of endogenous anandamide, of whose receptors LSD-025 is almost certainly an agonist.  Won't last as long as LSD, if it's even active.  Should cross the blood brain barrier well enough, though not as well as LSD, which may necessitate a higher dose.






I would try this homologue of LSD before 1-propionyl-LSD any day, as amido nitrogens are generally of a reduced potency when compared to amino ones.






n-amyl alcohol, supposed to be shorter lasting and less hangover prone than ethyl alcohol (the kind they sell at the liquor store).


----------



## Nagelfar

Hammilton said:


>





Dresden said:


>



Tickled pink, this trend I started. ;-j


----------



## Dresden

Like 3-methylfentanyl but shorter lasting and tastier?  (Esters smell delicious.)






Less damaging than the 4-methyl-amphetamines.  Still not good for you.






Because we can!


----------



## Dresden

Improved longevity (on par with methylphenidate) as compared with cocaine.






Trippy!






This one looks promising.


----------



## Dresden

p-cymene based amphetamine






propofol based PEA [CAUTION!]






thymol based amphetamine






A possibly sophomoric attempt to hybridize the amphetamine world with the cannabinoid one.






O-methyl-sesamol methcathinone, should be about 4x as potent as methylone.






a menthone (a chemical constituent of the essential oil of peppermint and pennyroyal) based amphetamine  [EDIT:  I just read up some more on menthone and found out it can be fatal if ingested, making this creation a no-go for human consumption]






More than 6-APB bang for the buck!






Why not?


----------



## roi

Probably very long duration + too damn expensive.


----------



## pharmakos

haha yeah that would be insanely expensive


----------



## SteamboatBillJr

Dresden said:


> Memorize as many structures as possible, try as many as you can, read trip reports on the rest, and try to find patterns.  It's an intuitive process.  Also, read PiHKAL by Alexander and Ann Shulgin cover to cover.



Especially the most important part, the introduction. Sadly the severity of legal consequences is worse now than then. Both PiHKAL, TiHKAL, and The Shulgin Index are excellent reads. When reading PiHKAL or TiHKAL read twice the first few pages.



			
				Alexander Shulgin in PiHKAL said:
			
		

> CAUTIONARY NOTE: READ BEFORE PROCEEDING
> 
> At the present time, restrictive laws are in force in the United States and it is very difficult for researchers to abide by the regulations which govern efforts to obtain legal approval to do work with these compounds in human beings.... No one who is lacking legal authorization should attempt the synthesis of any of the compounds described in these files, with the intent to give them to man. To do so is to risk legal action which might lead to the tragic ruination of a life. It should also be noted that any person anywhere who experiments on himself, or on another human being, with any of the drugs described herin, without being familiar with that drug's action and aware of the physical and/or mental disturbance or harm it might cause, is acting irresponsibly and immorally, whether or not he is doing so within the bounds of the law. -- Alexander T. Shulgin


----------



## Bagseed

regarding the deuterium mescaline... how would deuterium on the methoxy change activity? the should be the same size as normal hydrogen and have the same electron configuration. or is mass itself relevant as well?


----------



## Hammilton

Dresden said:


> O-methyl-sesamol methcathinone, should be about 4x as potent as methyone



This is what I hate about this thread, people just dump a shitload of drawings into it and put zero thought into them, and often what thought is put in is completely nonsensical half the time.  4x the strength of methylone?  Based on what? 6-methoxy-MDMA / N-methyl-MMDA-2 was significantly less potent than MMDA-2, and being inactive at 70mg (highest dose Shulgin tested) means, if it's active at all, it's less potent than MDMA which is definitely an active dose of MDMA.

Instead of all these drawing dumps why doesn't everyone take a couple ideas and really look into them some?  Sure, some ideas don't need a whole lot of looking into.  Isopropyl-JWH-695 doesn't need a whole lot of explanation, but if you think it'll be more potent say why.  If your goal in posting a compound is to generate thought and conversation about it put some in to start with?  If you're not posting them to develop interest and discussion in the compound, why are you posting?  Sometimes it seems like people are trying to draw every conceivable variation on the phenethylamine skeleton just for the sake of having them all drawn out somewhere.  If that's the goal someone could probably write a program that could go through a big list of substitutions and draw out every one of them on every possible position and every possible combination in every position.

TL;DR- there's too many pictures and not enough discussion of the compounds suggested.  If someone has a good idea it could be pursued by some capable members here, but there is a lot of chaff to go through for a couple bits of wheat.


----------



## Dresden

I could go into it more, yes, but I don't like sharing my logic with people who don't know how to invent but rather simply criticize.  

For example, 






Testosterone inspired amphetamine.

^--How much more information do you really need?  Are you dense?  (j/k, I know you're not dense!)


----------



## Dresden

Ok, point taken.  So I got a little carried away.  Allow me to cut through the chaff for you.  These two are potentially brilliant.  The first one is a cannabinoid and the second a cocaine analogue:






Just trust me.  And...






The ether bond is much more metabolically stable than an ester, making the cocaine analogue last about as long as MPH.






A little bit more of a longshot, but the R-CH2OCH3 works for sufentanyl; obviously, to me anyway, this second cocaine analogue has the potential to work for a very long time indeed.  And having lost the oxo off the benzyl, it will be a lot smoother and more focused than original cocaine; this is based on the analogy that methamphetamine (Ph-CH2-R') is focused and smooth, while methcathinone (Ph-(C=O)-R') is not [R' = 1-(methylamino)ethane].


----------



## Hammilton

I like the cannabinoid, it'd be interesting if it's active.  I saw one recently with a simple pyrrolidine on the N, but it's not very potent it seems.

The idea that removing that will make for a smoother ride is completely erroneous, the group is in a completely different place, serves a different function, and cocaine analogues don't bind in the same mode as phenethylamines.


----------



## Hammilton

Dresden said:


> I could go into it more, yes, but I don't like sharing my logic with people who don't know how to invent but rather simply criticize.



That's isn't inventing, it shows a basic lack of understanding, though.


----------



## Incunabula

Bagseed said:


> regarding the deuterium mescaline... how would deuterium on the methoxy change activity? the should be the same size as normal hydrogen and have the same electron configuration. or is mass itself relevant as well?



It's not really a new idea, and here's what we know.. I have no idea why roi thinks it will have a very long duration.


----------



## roi

Fagott said:


> It's not really a new idea, and here's what we know.. I have no idea why roi thinks it will have a very long duration.



https://en.wikipedia.org/wiki/Deuterated_drug



> Because of the kinetic isotope effect, deuterium-containing drugs may have significantly lower rates of metabolism, and hence a longer half-life.


----------



## Incunabula

Ah, I see. But Shulgin didn't find any prolonged duration with either 4-D or beta-D. And I think I trust Shulgin more than wikipedia 

From PIHKAL:
"The effects of 4-D and beta-D are similar to one-another, both as to dosage and effect. And with both, there is a close parallel to those reported from mescaline. It is reasonable to assume that the human body handles these materials in the same manner, although no metabolic studies have ever been published. "

From the trip reports in there, It sounds like they were almost indistinguishable from mescaline.


----------



## Soulfake




----------



## Dresden

I should have drawn 2-MeO-4,5-MDC, not its N-methyl homologoue.  And for hopefully the last time, cathinone dimerization is not a problem when cathinones are synthesized and stored properly.

And yes, it's not exactly inventing, but what I did is the first and a crucial step in the invention process.

Also, you have a tendency to overthink the drug discovery process and rely on largely worthless to the process biochemical markers.

Finally, "The greatest intelligence seems stupid."--Lao Tzu.


----------



## Nexus_Tripper

This new noid looks intense! It also has a lot of fluorine to deter potheads that try to smoke it (fluorine pyrolizes off when smokes and poisons anyone who tries to smoke this).


----------



## roi

Nexus_Tripper said:


> This new noid looks intense! It also has a lot of fluorine to deter potheads that try to smoke it (fluorine pyrolizes off when smokes and poisons anyone who tries to smoke this).



We're back to trolling, I see.

Here, have some cancer.


----------



## adder

> Also, you have a tendency to overthink the drug discovery process and rely on largely worthless to the process biochemical markers.
> 
> Finally, "The greatest intelligence seems stupid."--Lao Tzu.



If you want a ton of new useless RCs, then sure, you can just keep swapping substituents, then let people ingest it and report subjective effects. I know it's common practice and I don't think it's wise or fair with those testers if you can't even put some effort into lab tests first. Perhaps one compound in a million will be successful but think how many people could have been hurt in the process. There were quite a few compounds that had weird side effects, it's just impossible to predict how harmful all these untested drugs are and where they could bind. The pharmaceutical industry is what it is, focused on money, but imagine what would happen if they were inventing new drugs like that. It is not inventing anything indeed, it's a trial and error process with people ignorant of risks taking part in it.

As for me this thread is simply for having fun posting random structures. In some cases, yes, you can just add a double bond somewhere or play with bioisosteric groups and you've got a derivative with similar properties to the parent compound. But often impossible structures are posted here or they're so not promising that you would never even attempt synthesizing them. And posters don't even learn from comments of more experienced bluelighters or invest some time to research the subject. I've got nothing against having fun if that's what you want to do, making mistakes is also inevitable in the process of learning, but please have some respect for people who spend years learning science wrapping their heads around complex stuff. After all this often means learning from our ancestors' mistakes who conducted research and put a lot of effort to invent something completely new that made further progress possible, they did a lot more than sketching structures on a piece of paper. What is amazing is that true professionals are often very humble people who can't even recognise the importance of their work. I used to be a stupid kid who often acted arrogantly and thought that I got it all figured out even thought I only had some basic knowledge on the matter, and I did that because I wanted to be good at chemistry so much, not out of some selfish nature. As I look back, it's quite funny but I also hope I've learnt enough from my own mistakes, now I'm trying to always be aware of my deficits and to respect more experience people without jealousy.


----------



## Molecular_Man

Dresden said:


> I could go into it more, yes, but I don't like sharing my logic with people who don't know how to invent but rather simply criticize.
> 
> For example,
> 
> 
> 
> 
> 
> 
> Testosterone inspired amphetamine.
> 
> ^--How much more information do you really need?  Are you dense?  (j/k, I know you're not dense!)



It is not testosterone inspired.. It is nandrolone inspired.  The A steroid ring is nor.  It lacks a methyl-group.

Anyway this is fabulous!

If it can be aromatized into an estrogen, then it gives 4-Hydroxyamphetamine !


----------



## ebola?

hammy said:
			
		

> Instead of all these drawing dumps why doesn't everyone take a couple ideas and really look into them some? Sure, some ideas don't need a whole lot of looking into. Isopropyl-JWH-695 doesn't need a whole lot of explanation, but if you think it'll be more potent say why. If your goal in posting a compound is to generate thought and conversation about it put some in to start with? If you're not posting them to develop interest and discussion in the compound, why are you posting? Sometimes it seems like people are trying to draw every conceivable variation on the phenethylamine skeleton just for the sake of having them all drawn out somewhere. If that's the goal someone could probably write a program that could go through a big list of substitutions and draw out every one of them on every possible position and every possible combination in every position.



Well put.  I am considering putting a slightly reworded version of this in the first post of this thread, to serve as a guide.



			
				dresden said:
			
		

> I could go into it more, yes, but I don't like sharing my logic with people who don't know how to invent but rather simply criticize.



Well, criticism is a key part of vetting ideas for validity, no?



> Also, you have a tendency to overthink the drug discovery process and rely on largely worthless to the process biochemical markers.



We'll have to agree to disagree on this.  Because none of us can conduct novel empirical research at our desks, we're stuck with speculation based on only dubiously reliable and valid structural indicators a lot of the time.

ebola


----------



## Nagelfar

Über-Kokain:






= *S. Singh compound #s* "183c" + "185c" + "198a" + "220c" + "224b"

Check out the affinities of those all individually, and now image them together (I'm sure some may detract from the affinity of some other specific alterations, but it should at least be roughly functional, and likely better than the parent compound to some degree)


----------



## sekio

what the hell is that sulfur and nitrogen abomination hanging off of it? Does it really have an _isocyanate_ group on it? Talk about irreversible binding.

The oxazole analog of cocaine is something I'd like to see used in man at least once, though.


----------



## Nagelfar

sekio said:


> what the hell is that sulfur and nitrogen abomination hanging off of it? Does it really have an _isocyanate_ group on it? Talk about irreversible binding.
> 
> The oxazole analog of cocaine is something I'd like to see used in man at least once, though.



That's N-modified cocaine analog 220-c, with a SO2NCO at the R substituted N. Compared to Mazidol binding it is 120 ± 10 whereas cocaine itself is only 280 ± 60, for dopamine it is 160 ± 10, whereas cocaine proper is 320 ± 10, it's selectivity/binding is the only one that is inferior to cocaine; being 1.3 instead of 1.1; but seeing as it is likely covalent binding, and this is the least change of any of the N-modified structures from Singh's paper in terms of binding affinity, I think the other alterations for the better would bode well for this variant.


----------



## roi

Keeping it simple.


----------



## Nexus_Tripper

roi said:


> Keeping it simple.



MXiP? We haven't even seen PCiP yet...


----------



## roi

Somewhat surprising actually - PCPr seems to be equipotent with PCP (but is banned in most countries) and I'd expect similar potency with this structural isomer as well.

Something more *random*, DMAA/a-PVP hybrid.


----------



## Dresden

4 + 4 = 8
2 + 6 = 8
1 + 7 = 8

There's no real wrong way to get the right answer.  In the worst case scenario, a serendipitous find will have occurred.  And, to further clarify, I concede that binding affinity values and such can of course be valuable (but not until after the target compound has been synthesized and tested, obviously).


----------



## neurotic

kinda obvious though

in Nichols' furan analogues of MDA paper it was stated that a oxygen in the meta position was required for catecholaminergic activity. 6-APDB had a close pharmacological profile to MDA while 5-APDB was mostly a serotoning releasing agent. makes sense too when compared to 6- and 5-APB reports (6 being stimmy and 5 not)


----------



## Dresden

I'm not sure about that one, but from what I understand, DOA (4-amino-2,5-dimethoxyamphetamine) is inactive.


----------



## roi




----------



## neurotic

Dresden said:


> I'm not sure about that one, but from what I understand, DOA (4-amino-2,5-dimethoxyamphetamine) is inactive.



but i am looking for an empathogen, not a psychedelic. the SAR from psychedelics vs. empathogenic amphetamines is different, it was shown in that Nichols' paper where he coins the term 'entactogenic', IIRC. i.e. R being more potent isomer in the psych. amphs vs. S being more potent isomer in the empathogenic; N-methylation stops psychedelic but not monoamine releasing properties, etc...

a perfect example of this is MDA, which is both a psychedelic and an empathogenic amphetamine. if i'm not mistaken, for example, the R isomer is more potent as a 5-HT2a agonist, and the S isomer is more potent as a monoamine releasing agent.


----------



## Dresden

Like I said, DOA was inactive as anything IIRC.  Plus, I'm not entirely sure your molecule is chemically possible.


----------



## neurotic

i don't see the point of comparing it with the 2,5 phens/amps. none of them are empathogens/MRAs anyway. different SAR, different mechanism of actions... that nitrogen might not work for 5HT2a agonism but that's not the purpose anyway

swap that nitrogen over there for a sulfur for example. if it's active, it is not because 2C-T or 2C-T-2 are

i don't know if it's synthable though. benzoxazolinone exists, but i don't know if you can cleave that oxygen off. you could add an insaturation over there on the 2 position that would make it a benzoxazole and i think that's a more common one


----------



## Dresden

The SARs overlap quite a bit.


----------



## adder

As a matter of fact I think both benzoxazole and benzoxazoline analogues would be fairly obtainable synthetically.


----------



## Nagelfar

Could someone who knows how the acetyloxy would break-down _in vivo_ discern whether this would be destructive to receptor neurons or just a BBB penetrative delivery system for the parent exogenous copy of DA that forms its backbone?






What about this?


----------



## Nexus_Tripper

neurotic said:


> kinda obvious though
> 
> in Nichols' furan analogues of MDA paper it was stated that a oxygen in the meta position was required for catecholaminergic activity. 6-APDB had a close pharmacological profile to MDA while 5-APDB was mostly a serotoning releasing agent. makes sense too when compared to 6- and 5-APB reports (6 being stimmy and 5 not)



That's an analog of 5-IT. 5-IT is some epic stuff. And your analog would most certainly be active.


----------



## Dresden

If only it existed?  When I looked up "benzoxazole" and "benzoxazoline," I got the same structure, although from taking heterocyclic chemistry, I would imagine "benzoxazoline" to be saturated with respect to the 5-membered ring.






Did some more searching, and if Google can't find "benzoxazoline," I think it's safe to say it doesn't exist, guys.


----------



## adder

Perhaps "benzoxazoline" is not the official IUPAC name for 2,3-dihydro-1,3-benzoxazole, I don't think indoline is a proper IUPAC name either, yet it's fairly easy to obtain it from indole with good yields according to one paper, so I see no reason why you couldn't simply reduce benzoxazole to benzoxazoline in the analogous way. I can't find anything on it either and it makes me wondering if benzoxazole could differ so much electronically from indole that it can't be reduced that way. It's weird if nobody tried that yet.


----------



## neurotic

Yeah i don't know if it's the IUPAC name I just followed the reasoning oxazole/oxazoline/oxazolidine. I know that benzoxazolinone exists though, if that says anything. It's not synthed from benzoxazoline tho

As i said if the oxazoline is not possible there still is the oxazole


----------



## adder

Certainly there should be no problem with benzoxazole analogues and electronically they'd be between MDA and 6-APB, so one could suspect they may be worthwhile. But it just got me wondering how it is possible, with such sophisticated methods employed in heterocyclic synthesis that one could easily devote their whole career to research it, that plain benzoxazoline wasn't synthesized yet. I know it's not the forum to discuss synthesis, but if nobody finds any reference for it, I'll try finding some info in a couple of weeks.


----------



## Dresden

Aliphatic N-C-O's are not allowed.


----------



## adder

Hemiaminals derived from primary amines are generally unstable just like gem-diols and hemiacetals aren't stable either, however, acetals are fairly stable compounds, stable enough to be isolated and used as protecting groups. 1,3-benzodioxole is an exceptionally stable acetal, 1,3-benzoxazoline could be stable enough as well even though it can be seen as a derivative of a primary aromatic amine. Compounds like 1,3-oxazolidine and derivatives are often seen functionalized at the nitrogen atom and the carbon atom between N & O atoms and I guess it's due to stability issues. I'm not really sure, perhaps benzoxazoline is indeed too unstable to be isolated.

EDIT: never mind... 8)


----------



## Dresden

A guy at blacklight told me about this rule; it's funny no one mentioned it in college explicitly.


----------



## Dresden

Molecular_Man said:


> It is not testosterone inspired.. It is nandrolone inspired.  The A steroid ring is nor.  It lacks a methyl-group.
> 
> Anyway this is fabulous!
> 
> If it can be aromatized into an estrogen, then it gives 4-Hydroxyamphetamine !


Yeah, I knew it was some kind of androgen inspired.  Probably has to be taken every day for the full anabolic effects.  Should be great for sex!!!  (If you're a man.)


----------



## adder

You don't really learn chemistry through remembering simple rules, although they can be sometimes useful, because very often they just fail to work or you end up needing to remember so many rules that it takes much more time to do so than to understand what's happening. I gave you an example of 1,3-benzodioxole which might be seen as an acetal of catechol and formaldehyde (however, there is no equilibrium here between 1,3-benzodioxole and catechol+formaldehyde), the electron density from the ring must have a lot to do with the relative stability of the methylenedioxy bridge which survives under pretty rough conditions. Also, the formation of 1,3-benzodioxole from catechol is not as straightforward as mixing catechol with formaldehyde under acidic conditions. What I'm trying to say is that 1,3-benzoxazoline by analogy is not a plain hemiaminal ether either. You can't predict the properties of a molecule cutting a chain of atoms out of it and ignoring the rest.

I'm not saying it would be a stable compound for sure, I'm just saying you can't rule out the possibility that it's actually stable just because "aliphatic N-C-O is not allowed". It's actually not true at all, you can put various substituents on different atoms and you'd have compounds stable enough to be isolated and used as substrates.

The best way to find out would be to simply synthesize it unless it had actually been done already, but for some reason the results are stuck in some forgotten paper. 8)


----------



## Dresden

Thanks for the lecture, but I already have a degree in chemistry and am well aware of 1,3-benzodioxole's rare 2nd order aromaticity.

Anyway, pass the...


----------



## roi




----------



## adder

> Thanks for the lecture, but I already have a degree in chemistry and am well aware of 1,3-benzodioxole's rare 2nd order aromaticity.



I didn't mean to lecture you, I tend to get excited about new stuff, especially when it's related to my field of interest. Perhaps I wanted to provoke some discussion, but I'm sorry if you felt offended by my over-excitation.


----------



## pharmakos

i appreciated the lecture =p


----------



## blueberries

So, here it is:






It has the TMA-4 positional groupings but the 2-CL...it just doesn't fit. I can't make heads or tails of it. Please give me every bit of info you can scour for this one as I will likely be trying it next week. Why 2? It makes no sense. The 5 I understand but then the 3 pulls it back even further. Oh and did I mention? It's attached at the amine to Theophylline (well, a very close derivative). Is there anything that could go seriously wrong is my main question, if not, what's the likelihood of it actually being active and if you could scavenge a guess, what dose? (I'll be going from 1ug anyway but it's nice to know a rough figure. I was thinking something like 5-10mg but could be way higher/lower. I have no idea!)

Thanks in advance.


----------



## pharmakos

wait, that shit is on the market?  really?

looks like a HUGE unknown, i would not be the guinea pig.


----------



## blueberries

Not yet but it will be soon. There are 4 prototypes at the moment. Two displaying that orientation and two that are DOx. I am that guinea pig. I've been one many times before and this seems like it could be a boom or bust situation, plus it's already in transit and retailers are starting to get interested. If I don't then it could be a while to find another willing participant and even more time til it's on the market (if it's a boom then the sooner the better IMO).

Anyway I've always had a sort of...appeal to dangerous drugs (i.e MPPP, PMA, AFA (I actually coined this abbreviation, being the first to perform a full evaluation), Bromo etc) so guinea pigging is just another thing for me but this orientation, I just don't get. I'm sure there's no serious side effects as TMA-4 was pretty well handled, there are no real ties to neurotoxins like TMA-2 and it's attached to tea for christ's sakes but I just need to know if there is a slight chance it could turn sour.

If it looks all well and good then I'd still like to know just a little bit more about the compound from an advanced position, rather than my meagre pharmacological knowledge (I know the basics but I'm no chemist...yet!). Also it was designed by a fairly good chemist, unfortunately no information has been handed down to me apart from the IUPAC.

In all honesty I wasn't even planning on posting here, I was just going to titrate up and see what happened but it dawned on me that I need just a little background, apart from TMA-4 of course! The DOx are likely to be winners of course, also MDPEA-NBOMe is on the cards, although I wish it were TMDA or MDCBA (or TCB-MDA!). /That/ sounds very fun!

So, does anyone have advice?


----------



## roi

^Start with 50ug and work your way up?


----------



## pharmakos

blueberries said:


> Not yet but it will be soon. There are 4 prototypes at the moment. Two displaying that orientation and two that are DOx. I am that guinea pig. I've been one many times before and this seems like it could be a boom or bust situation, plus it's already in transit and retailers are starting to get interested. If I don't then it could be a while to find another willing participant and even more time til it's on the market (if it's a boom then the sooner the better IMO).
> 
> Anyway I've always had a sort of...appeal to dangerous drugs (i.e MPPP, PMA, AFA (I actually coined this abbreviation, being the first to perform a full evaluation), Bromo etc) so guinea pigging is just another thing for me but this orientation, I just don't get. I'm sure there's no serious side effects as TMA-4 was pretty well handled, there are no real ties to neurotoxins like TMA-2 and it's attached to tea for christ's sakes but I just need to know if there is a slight chance it could turn sour.
> 
> If it looks all well and good then I'd still like to know just a little bit more about the compound from an advanced position, rather than my meagre pharmacological knowledge (I know the basics but I'm no chemist...yet!). Also it was designed by a fairly good chemist, unfortunately no information has been handed down to me apart from the IUPAC.
> 
> In all honesty I wasn't even planning on posting here, I was just going to titrate up and see what happened but it dawned on me that I need just a little background, apart from TMA-4 of course! The DOx are likely to be winners of course, also MDPEA-NBOMe is on the cards, although I wish it were TMDA or MDCBA (or TCB-MDA!). /That/ sounds very fun!
> 
> So, does anyone have advice?



yeah idk man, thats such a huge unknown.  no in vitro binding data or anything?  also, what do you mean by DOx prototypes?  do you mean 2,4,5-orientation, but with a chlorine at the 2 or the 5 instead of the 4?


----------



## blueberries

Nah, I mean DOB and DOC (with the halogen at 4) but with the Xanthine attached (it''s basically Theophylline  but with the upper amine on the pyrolle down one position next to the lower amine). It's a huge unknown, absolutely nothing but the IUPAC was given to me but first monkey and all, I enjoy this stuff and if it works it'll be the biggest mind fuck of the century!!


----------



## pharmakos

would you draw that for me?


----------



## Str

Sounds like some RH-34 analog?


----------



## Nagelfar

My "cyclomethiodrone (TCAT)" + "RRA-TMP (restricted rotational threo-MPH)" hybrid.


----------



## roi

Thiophene instead of phenyl would certainly make a interesting phenidate.


----------



## Hammilton

Dresden said:


> 4 + 4 = 9
> 2 + 6 = 4
> 1 + 7 = 14
> 
> There's no real wrong way to get the right answer.



But there are an infinite number of ways to get the wrong answer.


----------



## sekio

i thought 5-chloro/5-bromo-MDA was known and active. so theoretically i'd expect the "5-iso-2c-c" compound type stuff to be active

as for the theophylline on the end... isn't that a feature of that one abused stimulant in the middle east? captagon or whatever? doesn't make me very nervous but it does suggest that it's gonna be less potent than a plan 2c compound


----------



## roi

https://en.wikipedia.org/wiki/Fenethylline

That one is around 25% converted to amph.

The DOB and DOC with the modified theophylline mentioned above:












Extended release DOx sounds rather shitty though.


----------



## blueberries

Damn, beat me to it! Well, here is the 2,3,5 in all it's glory.






I managed to get a bit more info on it too. It's an empathogen at around 100mg. The DOx are the same as roi's images. I imagine they will be psychedelic but ER DOx sounds not fun... They could be active close to 10mg based upon the above report but I'll start low anyway. The main thing is that the former is actually active! I'll have to explore higher doses to see if any psychedelia is present, but given there /is/ activity I'm much more hopeful than before!

EDIT: How did I not spot that Fenethylline?! I have it written down somewhere, just completely forgot about it. Also that 10mg was a complete guess, almost like I had a feeling it would be active there!! Weird. This could mean the 2,3,5 would be active at 25mg or so as an empathogen too though (without the theophylline). If it's a good quality empath then well, that'd be great!


----------



## Soulfake

Could this have any effects?


----------



## pharmakos

roi said:


> https://en.wikipedia.org/wiki/Fenethylline
> 
> That one is around 25% converted to amph.
> 
> The DOB and DOC with the modified theophylline mentioned above:
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> Extended release DOx sounds rather shitty though.



okay, yeah, i don't see the point of that stuff.  maybe for DOB to skirt past the analogue act, but that's totally pointless for DOC.  theophylline doses are significantly higher than DOx doses, so the theophylline probably won't have much of a pharmacological effect with these.

now, a theophylline ester of a phenethylamine/amphetamine that is active in the 100mg-300mg range would make more sense.


----------



## Hammilton

Strobamine, a weakish, but known DARI.  Not sure if it's been assayed in humans yet.


----------



## Dresden

Discuss?


----------



## roi




----------



## Nagelfar

Hammilton said:


> Strobamine, a weakish, but known DARI.  Not sure if it's been assayed in humans yet.



Reminds me of the adamantane D1 agonist named 'A-77636' which "partially substituted" for cocaine in animal studies.






Not really close though, I suppose it's the cycloalkane in the middle connecting the boat formation; otherwise not very similar; just dopaminergic, and then not even in the same way.


----------



## pharmakos

hah.  the adamantane theme here is not intended, just thought this up before i saw that post^ 






phenylcyclohexylamantadine

probably just silliness but its a funny thought


----------



## Dresden

This one looks great.


----------



## Dresden

Hell On Earth:






Plus, I know piperazines are usually neutral to crappy, but I can't resist suggesting these three:
















And this presumably dissociative indole alkyl amine:






* * *

"Complications of a Mastermind.
Last temptation of my kind.
Extra-planetary sign, when do we align?
All in time."--The Red Hot Chili Peppers.


----------



## Nagelfar

roi, your last contribution is interesting too. You don't see many cyclopropanes on monoaminergic-type drugs, but it's small enough you'd think it could work in some capacity.






The above is another one of my Super-Cocaines; this time based upon the benzoyl*thio*methylecgonine (but of course, not a benzoyl or methyl in this instance but augmented from Singh's 223f cocaine analogue for the phenyl branch + 219e's modification on the nitrogen and 200 replacing the carbmethoxy and 225c on the "6/7" tropane substitution position)


----------



## Dresden

sekio said:


> i thought 5-chloro/5-bromo-MDA was known and active.



5-halo-MDA's are known only to our imaginations, but I feel certain they are active (not the least reason of which is that 5-Me-MDA was reported by Nichols to be so).  Which reminds me of this (probable dud) I thought of once:






For some unknown reason, I named it GYPSY at the time.  Yes, I am insane.

* * * 

"The Master knows he is sick; therefore, he is not sick."--Lao Tzu.


----------



## roi

(6) 2-chloro-MDA/MDMA is a thing (1, 2), but only used as precursor. Has been deteced in some ecstasy tablets. Never heard of 5-halogenated-MDxx.

edit:  (6) 2-bromo-MDA is in PiHKAL, no effects at 350mg.


----------



## Dresden

2-methyl-MDA (really, 2-methyl-4,5-MDA, to be correct) is not active either, according to PiHKAL.


----------



## Dresden

In other news,






and






Possible carcinogenicity, however.


----------



## roi




----------



## neurotic

the second one could be active without the methoxy's

the piperidine probably would stop any psychedelia but big/weird substitutions on the alpha carbon and the nitrogen are usually tolerated on empathogens... just guessing


----------



## Nagelfar

Dresden said:


> The ether bond is much more metabolically stable than an ester, making the cocaine analogue last about as long as MPH.
> 
> 
> 
> 
> 
> 
> A little bit more of a longshot, but the R-CH2OCH3 works for sufentanyl; obviously, to me anyway, this second cocaine analogue has the potential to work for a very long time indeed.  And having lost the oxo off the benzyl, it will be a lot smoother and more focused than original cocaine; this is based on the analogy that methamphetamine (Ph-CH2-R') is focused and smooth, while methcathinone (Ph-(C=O)-R') is not [R' = 1-(methylamino)ethane].



^Love these, Dresden.



Nagelfar said:


> I was doing things *similar* but *not quite* a couple days ago on my Marvin Beans Sketch that I finally figured out to get on my home non-connected laptop.
> 
> Here's one that may be promising, reminds me of desoxypipradrol, but uses the phenyltropane configuration of the phenyls off of the piperidine instead of the MPH configuration with the nitrogen et al:
> 
> 
> 
> 
> 
> 
> Even reminds me a bit of nocaine or phenmetrazine.



The above and Hammilton bringing Strobamine to my attention inspired a reprise as thus:


----------



## BrotherRico

*Theoretical Psychedelics: 4-Propionoxy-N,N-Dimethyl Tryptamine*

I had the idea that the propionoxy group may be an acceptable 4 position substitution for tryptamines. I got the idea from ALD-52 and 1P-LSD. To those of you who don't know what the structure would look like, it's essentially 4-ACO-DMT with a methyl group sticking off of the top carbon of the acetyl group. 

I think the extra carbon will make this molecule slightly less polar than 4-ACO-DMT, while still having the necessary exposed oxygen. Given this information I believe it could be slightly more potent, however my only worry is that this extra carbon could cause some receptor incompatibility(if you believe that 4-ACO-DMT is psychoactive on its own and not just a prodrug of psilocin.) It could still be interesting if it turns out to be a psilocin pro-drug, but your guess is as good as mine. 

 If I had to guess I'd say that this compound could be synthesized from psilocin and propanoic anhydride, but I'm not a real chemist so I have no idea what procedures that would involve or even if it would be possible. 

I wanted to get some discussions on theoretical drugs rolling so please share your thoughts. Also could someone give me an idea of how to abbreviate this puppy? It's kind of tiresome to type 4-Propionoxy-N,N-Dimethyl Tryptamine every time. Lastly, feel free to discuss the other N alkylations with a 4-propionoxy substitution or even with a 4-Isobutionoxy-substitution(connect another carbon atom to that propionoxy group in the same place. Synthesized from psilocin and isobutyric anhydride). Really I would to like to hear what people have to say about them all but I didn't want to type them all out.

 I will start at least a couple more threads about theoretical psychedelics during my time here at bluelight so check those out too if you like. This is my first post and let me say I look forward to discussing my favorite subject with you all!


----------



## neurotic

check this thread out: I like to draw pictures of random molecules


----------



## BrotherRico

*Theoretical Psychedelics: 3,4-Dimethoxy-5-Ethoxy-Amphetamine*

This drug was inspired by Meta Escaline. From what I read in PIHKAL Meta Escaline sounds like a psychedelic that has some fantastic properties. The only problem is that it's not very potent. I hope that an amphetamine homologue might provide similar effects, but at a smaller dosage. If this still does not bring the potency to an acceptable level, then perhaps we could try subbing those oxygens for sulfurs, first one at a time, then in combinations. 

I would like to hear your thoughts on this particular compound. I am personally not as fond of phenethylamines as I am of tryptamines or lysergamides, but i think a few untested phenethylamines may still yet provide something excellent.


----------



## BrotherRico

*Theoretical Psychedelics: 6-Methallyloxy-6-Nor-Lysergic Acid Diethylamide - MAL-LAD*

I call it MAL-LAD for short. I thought this might be worth looking into when I saw the difference in effects between Allylescaline and Methallylescaline. I have no idea what the effects would be or how this would compare to AL-LAD but if anyone has any thoughts, please share. I think that it might be worth exploring homologues of the most exciting research chemical to come out in the past few decades.


----------



## Yeetbeat

I've merged your 3 threads together so they can be shifted over to NAPD so it can be merged into the above linked thread


----------



## ebola?

Hello, Brother Rico.  I went ahead and merged your thread with this mega thread in NPD.  You will find a lot of richly informed pharmacological speculation centered around varied rationale for novel compounds in here.  Welcome to the site!

ebola


----------



## Dresden

Brother Rico,

Your first one 4-propionyl-DMT will likely metabolize into psilocin just like psilocybin does, making them prodrugs of psilocin.  However, 4-(n)-propyl-DMT is / would be quite stable.  Below is its structure:






Or 4-(n)-propoxy-DMT if you'd rather:






Or even 3-dimethylaminoethyl-4-(1-oxopropyl)indole:






None of those 4-substituents are going anywhere fast, metabolically. 
As for 3-ethoxy-4,5-dimethoxy-amphetamine, Idk but I hated escaline.  And all methoxy-amphetamines are illegal in the U.S.
As for your MAL-LAD, I don't think di-N-substituted-O-alkyl groups are stable.  In fact, I know they're not.  However, if you lost the oxygen and instead ordered N6-CH(CH3)CH=CH2-LSD, then yeah that might work or would at least be makeable.

Also, you need to check out http://opsin.ch.cam.ac.uk and learn to draw out theses structures (provided you can name them) and post them here as .png's using the forumula: <IMG in brackets> http://opsin.ch.cam.ac.uk/opsin/(insert copy and pasted molecule name from the website you created there for it).png</IMG in brackets>.  By brackets, I mean ['s and ]'s. Doing so will greatly help getting your point across and may help you weed out the impossible structures as well.

But anyway, I like your way of thought and encourage you to continue posting more here!


----------



## adder

Weinreb amides (N-methoxy-N-methylamides) must be stable compounds as they can be easily stored and are used on an industrial scale. Anyway, isn't MAL-LAD supposed to be just N-(2-methylpropen-2-yl)-nor-LSD?


----------



## Dresden

Yes, well amides are one thing and amines another.  Amides are much more stable, as the lone pair on electrons on the N feeds some of its electron density into the partially positively charged carbon of the amide.  If you read my post carefully, you will see that I was referring to amines.  

As for what he means by MAL-LAD, yes, you may very well be correct.  Only he can tell us really.  I just saw the methylallyloxy part and assumed he meant with an O there, which is just another reason it pays the theoretical chemist to invest some time in exploring http://opsin.ch.cam.ac.uk IMO.


----------



## Incunabula

I'm sure MAL-LAD is active (understood as adder says as: N-(2-methylpropen-2-yl)-nor-LSD). But considering BU-LAD, it is a good guess that anything more bulky than an allyl/propyl group on the 6 position on LSD is probably going to decrease potency by a lot. But who knows until it's made, right?

Another obvious one is iso-PRO-LAD. That is 6-isopropyl-nor-LSD. Any reason to not attempt a halogen on there too? Like chloro or bromo.....or flouro?

Shulgin made FLOURETH-LAD ( or talked about it theoretically at least) I guess FLOURMETH-LAD and FLOURPRO-LAD are obvious possibilities too, although the names sound totally asinine.

Why not slap the psychedelics counterpart to the emphatogens methylenedioxy ring; triflouromethyl, on there ---->6-triflouromethyl-nor-LSD, and get it over with, lol


----------



## aced126

(5R,9R,13S,14S)-4,5α-epoxy-14-hydroxy-3-acetyl-17-phenylethylmorphinan-6-one

Can't figure out how to put the image of this on opsin onto here.


----------



## Soulfake

roi said:


>


wtf i wanted to post exactly the same benzo as you last night as well as it´s thiobenzo variant 











methamphetamine/methcathinone pro-drugs ? (edit: i forgot the 4-methyl at the cathinone)


----------



## Dresden

aced126 said:


> (5R,9R,13S,14S)-4,5α-epoxy-14-hydroxy-3-acetyl-17-phenylethylmorphinan-6-one
> 
> Can't figure out how to put the image of this on opsin onto here.



Try using simpler nomenclature.  Stereochemical letters and numbering are not required.  I would start by seeing if opsin recognizes "morphinan" first.  If not, nomeclature for that one could be a real b*tch.  However, it would just be so much clearer and more precise to see your structure.

If that still doesn't work, try explaining your molecule's name with things like, "It's like hydromorphone but with an N-phenylethyl instead of an N-methyl," or whatnot.  Just my advice.


----------



## aced126

Also, on the subject of lysergamides, I found this pretty good paper (skip to page 55) where the researchers synthesised a load of n-6 substituted lysergamides and compared activity. Isopropyl substitution on n-6 leads to half the potency of LSD and Butyl substitution leads to a tenth of the potency.

They also try to understand why the diethyl substitution on the amide N makes the molecule so potent, and so synthesised some dimethylaziridinyl diasteromers and actually found that one of them showed 1.5 times potency of LSD.

http://archives.drugabuse.gov/pdf/monographs/146.pdf


----------



## aced126

It's like oxymorphone, with an acetyl group on the 3 oxygen (where methyl group for codeine normally goes) and the nitrogen is substituted with a phenylethyl substitution.

Just realised though that the acetyl group would make the molecule less potent because even though it improves BBB permeability, the phenolic group is important in the binding region of mu...


----------



## aced126

http://opsin.ch.cam.ac.uk/opsin/(5R...xy-3-acetyl-17-phenylethylmorphinan-6-one.png 

This one with phenolic group already there.

http://opsin.ch.cam.ac.uk/opsin/(5R...y-3-hydroxy-17-phenylethylmorphinan-6-one.png

This one with 6 acetyl group.

http://opsin.ch.cam.ac.uk/opsin/(5α,6α)-4,5-epoxy-17-phenylethylmorphinan-3,6-diol 6-acetate.png


----------



## Dresden

You're so close now!  Just go to those webpages and copy the URL then type 
	

	
	
		
		

		
			
		
		
	


	




 with no spaces either time.  Voila!  You will have posted your images successfully.


----------



## Dresden

aced126 said:


> Also, on the subject of lysergamides, I found this pretty good paper (skip to page 55) where the researchers synthesised a load of n-6 substituted lysergamides and compared activity. Isopropyl substitution on n-6 leads to half the potency of LSD and Butyl substitution leads to a tenth of the potency.
> 
> They also try to understand why the diethyl substitution on the amide N makes the molecule so potent, and so synthesised some dimethylaziridinyl diasteromers and actually found that one of them showed 1.5 times potency of LSD.
> 
> http://archives.drugabuse.gov/pdf/monographs/146.pdf



"There's methyl and ethyl, but butyl is futile."--ancient drug designer maxim.

As for the dimethylazidirine LSD ("LSZ"), I've tried it, and it was a huge disappointment.


----------



## roi

Also I quite liked LSZ


----------



## sekio

> I don't think di-N-substituted-O-alkyl groups are stable. In fact, I know they're not.


Aldrich sells N,N-dimethylhydroxylamine, & N,N,O-trimethylhydroxylamine is apparently known and stable enough to have a CAS and is used as a precursor in at least one patent. (There's other O-alkyl substituents as well)


----------



## Incunabula

aced126 said:


> Also, on the subject of lysergamides, I found this pretty good paper (skip to page 55) where the researchers synthesised a load of n-6 substituted lysergamides and compared activity. Isopropyl substitution on n-6 leads to half the potency of LSD and Butyl substitution leads to a tenth of the potency.
> 
> They also try to understand why the diethyl substitution on the amide N makes the molecule so potent, and so synthesised some dimethylaziridinyl diasteromers and actually found that one of them showed 1.5 times potency of LSD.
> 
> http://archives.drugabuse.gov/pdf/monographs/146.pdf



Ah, yeah. I didn't know Nichols had made the Isopropyl sub. I guess it's too obvious to not have been done. Anyway, there you go, "MAL-LAD" would most certainly be less potent than the n-6 isopropyl. I came to think of CYP-LAD, it might be even closer to that in bulkyness.

Interesting paper that one, I will have to read it when I have time.

And about LSZ, yeah, it's the only lysergamide that ever gave me a bodyload. Horrible stuff. Lysergic acid 2-butyl amide (2-Butyllysergamide, LSB) is also supposed to be more potent than LSD proper. I really hope we will see that one, as well as LSP, available some time in the future.


----------



## Dresden

Yes, ya'll are right.  I do remember N-MeO-MDA (#111 from PiHKAL); however, it was inactive IIRC.






Still, for some reason R-N-O-R' doesn't seem to show up much, and I don't think it was what Brother Rico was talking about anyway.

Do you mean N,N-diethyl-2-butyl-lysergamide?  This:


----------



## aced126




----------



## Incunabula

Dresden said:


> Do you mean N,N-diethyl-2-butyl-lysergamide?  This:



Nope  I mean this: LSB


----------



## Dresden

Oh, ok.

Here are another two:






and






The first one looks incredibly mind blowing to me.


----------



## Nagelfar

Dresden said:


> In other news,
> 
> 
> 
> 
> 
> 
> and
> 
> 
> 
> 
> 
> 
> Possible carcinogenicity, however.



These remind me of the two compounds I posted on the right of the following image:



Nagelfar said:


>





aced126 said:


>



So what would it take to make the above fall into toe with the parameters needed to make a Bentley compound? Even if only functionally such as both if racemic?


----------



## aced126

What do you mean? This can't be made into a Bentley compound cos the double bond has been hydrogenated. I'd expect this compound to be reasonably potent however, but not in the range of some of the potent Bentley compounds.


----------



## Nexus_Tripper

Psychedelic Tryptamine Analogs
These have oxygen atoms strategically placed at both the four and five position for optimum effects.
http://i.imgur.com/UsTIjRc.png
http://i.imgur.com/67zoyX0.png
http://i.imgur.com/xSK8A9t.png
http://i.imgur.com/wLbhgmG.png


----------



## aced126

Simple yet interesting. Guessing the methoxy FG at 4 position would reduce potency compared to a hydroxy at that position, and similarly a hydroxy at 5 would reduce potency in comparison to a methoxy. These assumptions are based on comparisons between psilocin and 4-meo-dmt, and bufotenin and 5-meo-dmt. Nevertheless you never know...


----------



## Nagelfar

aced126 said:


> What do you mean? This can't be made into a Bentley compound cos the double bond has been hydrogenated. I'd expect this compound to be reasonably potent however, but not in the range of some of the potent Bentley compounds.



Oh sorry, nvm. It was posted betwixt so many of posts of lysergic type drugs that I thought it was a serotonin agonist, it looked close to an opioid just 'cause that was all that it was. ;p

So my question would then be: might there be an LSD-analog that's a morphinan, then, I suppose is what my curiousity was aiming at? Would it be closer to the NMDAR antagonist enantiomer of the structure or the opioid if it could be done?

EDIT:





Unrelated to the topic at hand, a Glutethimide / Pethidine intermediate of my own devising; a sedative hypnotic and opioid / slight DRI.


----------



## neurotic

different rigid MD analogues. thought of these after seeing the tetralin ones and MDAI


----------



## sekio

Dresden said:


>



This one has been made and tested in animals, apparently, as 12-methoxy-LSD.


----------



## Dresden

^--That's cool.

Anyway,

I just thought of another indole.  This one expanded my IUPAC nomenclatural vocabulary skills a bit, which you will understand when you see its name:






_N,N-dimethyl-2-(6H-indolo[4,5]furan-8-yl)-ethanamine_

Note the similarity between this tryptamine's indolo-4-(pseudo)vinyl substituent and LSD's indolo-4-"vinyl" position.

Finally for this post,






_N,N-dimethyl-2-(5-methylthioindol-3-yl)-ethanamine aka 5-MeS-DMT_

Obviously this one is just a simple O-->S (thia) analogue of 5-MeO-DMT, which is found in certain toads' venom.

Ok, just 3 more:






_1-(1-aziridinyl)-2-(indol-3-yl)-ethane_

Hellacious.






_N,N-dimethyl-1-amino-2-(5-cyclopropylindol-3-yl)-ethane_

Looks delicious to me.  And...






_N,N-dimethyl-1-amino-2-(5-(furan-2-yl)-indol-3-yl)-ethane_

Funky!

I don't know what to say here, other than all of these should be synthesized and tested for activity.


----------



## Nagelfar

cocaine with a cis-propenyl (a la as the phenyltropane "RTI-11w" has, but not where it has it at the 4' position of the carbon ring; but at the other putative binding site…) …at the end of the extended carbmethoxy (Singh's 201c analog), the benzoyl changed considerably, linkage and ring both, a methyl tail on the tropane at an area that isn't on the bridge (the so-called 6/7 substitutions), etc.


----------



## aced126




----------



## aced126




----------



## pharmakos

Dresden said:


>



i feel like that is most likely active.  whether "activity" means horribly toxic or incredibly psychedelic, idk, but it looks like a simple enough modification that it should do something.


----------



## Pomzazed

^ Aziridines are too unstable and will spontaneously form covalent bond with N or O which comes into contact.
It's even more reactive than epoxide in most of the case.


----------



## pharmakos

so if it does make it to a receptor intact it could possibly irreversibly bind?


----------



## yaesutom

Dresden said:


> ^--That's cool.
> 
> Anyway,
> 
> I just thought of another indole.  This one expanded my IUPAC nomenclatural vocabulary skills a bit, which you will understand when you see its name:
> 
> 
> 
> 
> 
> 
> _N,N-dimethyl-2-(6H-indolo[4,5]furan-8-yl)-ethanamine_
> 
> Note the similarity between this tryptamine's indolo-4-(pseudo)vinyl substituent and LSD's indolo-4-"vinyl" position.



I've heard speculation on these boards that 4-vinyl-DMT might be active and good/potent, and then there's the speculation about 4-HO-5-MeO-DMT so this is sort of a constrained version of that. Looks tasty to me. I really hope the research chem companies explore 4-XYZ-DMT's.


----------



## aced126

Rigid analogues of DET. Using Nichols' rigidifying technique to see what part the alkyl groups play in the bonding of the molecule to the receptor. However in this case bond rotation is possible which is not the case with amides.


----------



## Dresden

Oops, my bad then.  Scratch the aziridine thingy.  

As for the more XYZ-tyrptamines comment, I agree.  In TiKHAL, Sasha Shulgin largely ignored the various possible indole substitutions to focus on the N,N-ones instead apparently.


----------



## roi

Few stimulant ideas:





















Bonus:


----------



## Nagelfar

Dextrorphan + Salvinorin A, from my idea of a drug, the rationale of which is mentioned at this post/thread, that has the subjective affect of _Salvia Divinorum_ and is also a dissociative anaesthetic NMDAR antagonist, with the purpose of having the contrast of both altered states at once with one drug.






(P.S. I did the 'automatic "clean-up"' feature, and this is as straight as the cock-eyed chemical can be rendered, apparently)


----------



## pharmakos

wow.  looks like a masters project if you ever wanted to synth it.  very interesting.


----------



## sekio

aced126 said:


>



triazole-methylphenidate? wonder if it would be an antifungal too.



> so if it does make it to a receptor intact it could possibly irreversibly bind?



possibly, but in this case i would expect it to tautomerize to N-vinyl tryptamine & probably decompose from there.



> with the purpose of having the contrast of both altered states at once with one drug.



now if i was a betting man, i'd say this is more likely to be neither...


----------



## roi

..It's way to damn easy to invent new stimulants. So many options.


----------



## Soulfake




----------



## neurotic

I liked the nico DMT. Psilocin prodrug?


----------



## Dresden

Yes, in all likelihood.  

Speaking of "nico" (sort of), I've often thought about this one: 






2-methylamino-1-(pyridin-3-yl)-propane 

and






2-methylamino-1-(pyridin-4-yl)-propane

But, in today's methcathinone crazed RC market, these two are more likely to hit the mailboxes:






2-methylamino-1-(pyridin-3-yl)-propan-1-one

and






2-methylamino-1-(pyridin-4-yl)-propan-1-one

The third one has already been mentioned by someone in this thread IIRC.


----------



## Soulfake

neurotic said:


> I liked the nico DMT. Psilocin prodrug?



yes that´s what I had in mind.


----------



## Dresden

I like your N,N-dimethyl-4,4'-di-tryptamino-ether idea for its symmetry and relative metabolic stability if nothing else.  I was wondering, however:  Did you mean for the beta carbon to the N of your piperidine ring in your next to last structure above have a methyl group, or did you mean for the N-alpha carbon to have one instead?


----------



## aced126

Compounds inspired by Org 6582, a potent SSRI


----------



## Nagelfar

Now that I got that Bentley frame for this latest vehicle of my molecular masturbation, let's see how it does along-side any ol' rig. ;p


----------



## Nagelfar

The above are Metazocine (on left) & Org 6582 (to right); the former an opioid and latter a MAT reuptake inhibitor. Any idea from anyone on how to go about crossing these two in a way that keeps both functionalities? So very similar.

EDIT:

Here's my feeble attempt, but all I did was merge all of the features of both; if the chloro or oxy, for instance, hinders the functionality of the other, this is then untenable, but nonetheless, this is my go at it:


----------



## neurotic

scratch those last ones i drew... i looked at a few more pipradrol analogues and non-phenanthrene opioids. here's my second take at pipradrol/phenidate analogues with opioid activity. i'm with Nagelfar looking for opioids with MAT activity here...






the second one is just MPH and pipradrol mixed, probably no opioid activity but might be a stimulant who knows. i tweaked the piperidinyl and added a methyl group on the nitrogen hopefully for opioid activity below.






hopefully they also work as euphoric transporter inverse agonists like cocaine and MPH and not just seizure inducing reuptake inhibitors à la pethidine.

wondering how one could add some serotonin releasing properties as well, it could be called MDMorphine


----------



## Dresden

This one is really all you need.






2-methylamino-1-phenyl-propane.HCl

If you ever run across this one, your drug yoga will have gotten off to a very fine start indeed!


----------



## neurotic

^ i get a pop up saying "this drug is not available in your country!"

had a few more tries at a stimulant and opioid hybrid, starting from the phenyltropane skeleton this time


----------



## neurotic

that metazocine and Org hybrid confused the fuck out of me






here's an easier on the eyes view on it and its parents, FWIW


----------



## Nagelfar

neurotic said:


> that metazocine and Org hybrid confused the fuck out of me
> 
> 
> 
> 
> 
> 
> here's an easier on the eyes view on it and its parents, FWIW



Marvin Beans sketch doesn't render the most cleanly, and by the time you've hit "clean", trying to straighten it out manually will just likely create more bonds upon clicking on accident and I just don't bother.


----------



## neurotic

sure, i just thought you might find use for them or something. didnt mean to be annoying about it


----------



## roi




----------



## Nagelfar

roi said:


>



It looks like cocaine "doin' the robot" ;j


----------



## conscious-observed

I wish I knew more chemistry....


----------



## Midnight Sun

roi said:


>



beta-oxetane, dude

Though I read somewhere that it'd increase polarity further over the cathinones so idfk, could just be shit tier


^^^I'm liking what neurotic's got going on up there... some things reminiscent of diconal :D -- I was playing around with diconal/palfium structure a while back, it'd be fun to get an analogue of em made up sometime


----------



## chatsnap

I don't have any chemdrawing app or anything but I have a fairly simple idea - in PIHKAL, Shulgin mentions the lack of modification that can be made to halogen groups. Why not stick the halogen on the end of a carbon chain? i.e. DOM but with a bromomethyl group instead of just a methyl group.

Are there any obvious synthetic or biological barriers to this?


----------



## sekio

> Are there any obvious synthetic or biological barriers to this?



primary alkyl bromides and iodides tend to be reactive compounds that undergo SN2 reactions in the body, permanently attaching them to e.g. lysine residues and such.

alkyl chlorides/fluorides are more forgiving. (see: clomethiazole, DOEF).

but e.g. stuff like propyl bromide or methyl iodide is suprisingly toxic...


----------



## chatsnap

Ah totally forgot about SN2, it's been a long summer. 
Would substituents that are bulky enough to favour SN1 over SN2 be viable or would that be too much bulk at the 4 position?


----------



## sekio

You don't want the compound to undergo any nucleophilic substitutions at all, ideally.

I also don't think it's "bulk" neccesarily that promotes SN1 over SN2 reactions, rather it's whether or not the alkyl halide is primary, secondary, or tertiary (& hence determining stability of the resulting carbocation intermediate in SN1/E1 reactions)


----------



## blowpipe

"Bulk" does affect it. If the carbon is primary/secondary, but significantly sterically hindered, the attacking group simply can't "attack", and the carbocation is unstable, thus reducing the overall reactivity. But then again you'd have to employ a few tricks to make it bulky AND have the carbon primary/secondary, and that would most likely be too much "bulk".


----------



## Dresden

These two, I fear, would be too jittery in classic adrenergic fashion to be much enjoyable, but who knows, maybe they're great:






and






The first one should be a piece of cake to synth in one step from ma huang extract.  The second one, well, it's not the easiest synths in the world, but it's well within China's research chemical producing chemists' reach in case anyone wants to order a custom synthesis.  (j/k)

Note also that each of these two molecules have two chiral centers a piece leading to a total of 4 possible stereoisomers, which will negatively impact the drugs' potency potency per milligram produced ratio; however, since they are both diastereoisomers, chiral resolution should be much easier than if they were simple one chiral carbon containing enantiomers such as (R/S)-MDMA or (R,S)-methamphetamine, for example.


----------



## Soulfake




----------



## roi

Could that work?


----------



## aced126

I think the indane derivative could have more serotonergic activity than the tetralin one, although both will probably not be as potent as mephedrone. I don't think they will have much DA activity as well. 

The nitrogen can't rotate so will probably not be in the right conformation for good activity.


----------



## aced126

Couldn't find any benzylpiperidine

2-benzylpiperidine raises NE levels to the same extent of d-amph, with very little effect on DA. I wonder how pyrrolidine derivatives would behave in vivo. Maybe adding groups which could possibly increase serotonergic activity could make it a possible antidepressant?


----------



## flying-potato

roi said:


> Could that work?




I think sulfur double bond would led to a very unstable molecule. Maybe sulfured phenmetrazine analog would have a better chance to be stable enough.






@Aced126

I just asked myself about 2-amino-1-tetralone derivative activity.


----------



## Dresden

Soulfake said:


>



Soulfake, I like more than half of your above indole creations (the ones in the first two columns).  Still haven't figured out what, exactly, your fascination with the pyridinyl-3-(C=O)-R functional group is all about (except its somewhat similar structural relationship to nicotine?) but anyway, good work!


----------



## Dresden

aced126 said:


> Couldn't find any benzylpiperidine
> 
> 2-benzylpiperidine raises NE levels to the same extent of d-amph, with very little effect on DA. I wonder how pyrrolidine derivatives would behave in vivo. Maybe adding groups which could possibly increase serotonergic activity could make it a possible antidepressant?



aced126, 

I like your 2-benzylpyrrolidine structure above.  It wouldn't surprise me if it was super potent except that I also had high hopes for 2-benzylpiperidine (below) until people who tried it said it was a dud.  Adding an oxo [Ar-(C=O)-R] or carbomethoxy [R-CO2CH3] group on the methylene bridge between the pyrrolidine and benzene rings may be necessary for psychostimulatory activity (see illustrations at the bottom of this post).






2-benzylpiperidine

If you're looking for entactogenic versus solely stimulatory activity, then slapping on a 3,4-methylenedioxy unit on the phenyl ring (yes, it's a cliched substitution but for good reason) would be required the way I see it, and even then it's somewhat of a long shot:






1-(3,4-methylenedioxyphenyl)-1-(2-pyrrolidinyl)-methane






1-carbomethoxy-1-phenyl-1-(2-pyrrolidinyl)-methane






1-phenyl-1-(2-pyrrolidinyl)-methanone

And, just for kicks:






1-(3,4-methylenedioxyphenyl)-1-(2-pyrrolidinyl)-methanone

Could this last one be the future legal research chemical "molly"?  lol

If so, let's hope it's better than methylone:






1-(1,3-benzodioxole-5-yl)-2-methylaminopropan-1-one [to be rigorous] or 2-methylamino-1-(3,4-methylenedioxyphenyl)-propan-1-one [to use the more common prefix] aka "methylone"

(Yeah, I know I hate on methylone and bupropion too much, but they are just so inferior to other, better phenethanamines.)


----------



## Dresden

roi said:


> Could that work?



I don't see why not.  I mean, yes, it might smell bad or be toxic, but I don't see why it wouldn't be stable.  As far as I know, the R-(C=S)-R' functional group is known and isolable in many cases.  If anyone knows of any reason why it wouldn't be stable, please do share.  And if thione based drugs such as this one (which could be called thia-MDPV, using replacement nomenclature) don't turn out to be too toxic and/or noxious, I think I would probably rather have this one, which I named ENNIS (like PENIS without the "P" but with an extra "N") 10 years ago when I was in solitary confinement, off my gourd, for 3 months for disorderly conduct coming off a huge crack and IV cocaine bender and wrote reams of books of Kekule structures and cartoons which my mother later threw away.  Anyway, here it is:






ENNIS aka 2-methylamino-1-phenylpropan-1-thione

On the other hand, roi and aced126, all these tetralin and indan "amides" with an extra methylene group (R-CH2-R') between the carbonyl [R-(C=O)-R'] and the amine (R-NH-R') look completely specious to me.  My gut feeling may be wrong about that, but if so, please prove me wrong about it by posting the structure (if possible) and name or applicable link of one or more known such compounds.  Thanks.  

Also, all the tetralins and indans I know of get 2nd or 3rd rate reviews, and 2-aminotetralin is known to causes seizures (usually accompanied by trips to the emergency room where the best doctor there is pretty much guaranteed to know fuck all about what you actually took, even when or if you tell him or her) when taken at dosages of 100mg or above.  Why bother?






2-aminotetralin 

According to the published literature (which is not always right!!!), it substitutes or partially substitutes (can't remember which) in rats anyway for amphetamine at something like 6x or 8x the minimum dose required for the rodents to recognize amphetamine but causes seizures in humans at 100mg or above if they read this finding and cook up their own batch, which someone did.  Don't do it!


----------



## roi

There's a few substances that contain thioketones like Quazepam but..who knows if it works for other pyrrolidinophenones. One way to find out I guess.


----------



## Dresden

My biggest concern with cathinthiones at this point is not whether or not they can be synthesized (I think they can be) or whether or not they are psychoactive (I think they are) but that they will somehow turn out to be crazy noxiously toxic if ingested.


----------



## roi

Idea stolen from RTI-229.


----------



## aced126

I don't get it. Desoxypipradol must have a hydrophobic pocket for the extra phenyl ring, but DAT also accomodates a carbomethoxy group as well. Amphetamine SAR seems so confusing and contradictory...


----------



## Soulfake

Dresden said:


> Soulfake, I like more than half of your above indole creations (the ones in the first two columns).  Still haven't figured out what, exactly, your fascination with the pyridinyl-3-(C=O)-R functional group is all about (except its somewhat similar structural relationship to nicotine?) but anyway, good work!



thanks, I sometimes feel like drawing one molecule for fun and end up drawing more and more. 

I mainly thought of the pyridine group as a simple unit for a pro-drug. It is used for example in Picamilon to enhance gaba-uptake across the blood-brain barrier and generally improve it´s pharmaceutical effects so I thought it could interact positively with other substances too.


a few fencamfamine derivatives, the first one´s are only positional isomers so I think some of them could have potential as alternatives.


----------



## roi

PCP/Pethidine hybrid.


----------



## Raihiar

i'm not sure if this is the right thread, but i'll give it a try

some time ago i was handed a little anti-drug educational pamphlet, which, to be honest, was relatively well written and avoided most stereotypical propaganda / catch phrases etc.
in this i stumbled over a drawing of a molecule, that i have never seen before - and sadly it was just the picture, no text
It's got the 2c- backbone, but a very strange (uncommon, at least) group on the 4-position

here's the picture, maybe someone can shed a little light on it, and if it is not known yet, count it as my submission of a random molecule ^^


----------



## roi

That's 2C-T-12.

http://isomerdesign.com/PiHKAL/explore.php?domain=pk&id=2081


----------



## Raihiar

oh.. kinda embarrassed :<
i didn't know about that one, the substituent seemed really uncommon, and to be honest even unlikely.. 
but you learn something new every day - i've got some reading to do


----------



## SKL

I call it MFWDPV.


----------



## neurotic

Has this one been made yet? I'd think it has, given how obvious it is. I don't know PCP analogue naming guidelines so don't know how to go about finding it.






Roi's pethidine/PCP hybrid got me thinking about this and its lactone and butyrolactone analogues. These last two i assume haven't been made yet. Don't wanna draw them cuz it's too much of a hassle on the phone. Opioid active may be?


----------



## aced126

Would be called 2-phenyl-2-(1-piperidinyl)-cyclohexanone


----------



## neurotic

^ i didn't mean IUPAC names, i meant the informal ones that the community comes up with, while still following somewhat rules such as 3-Meo-PCPy, etc... anyway i figured that molecule should be named 2-Oxo-PCP, gave it a google search and was refered back to Bluelight, to a thread from our fellow poster adder, with a list of several PCP analogues he himself synthed and tried!!! i mean, how cool is that? and bromadol? wtfff adder you got yourself a fan 

oh and sorry if i brought up something from a past for some reason you're trying to forget or something. i tend to do that. but i'm seriously amazed.

i was gonna try thinking of a few different PCP analogues but after that thread i'll leave it alone lol

btw aced you mentioned something about desoxypipradrol analogues and amphetamine SAR earlier (just saw that post now). what if pipradrol and co follow a different SAR? i thought they were more phenidate/cocaine like drugs, which do have a different/specific site on DAT and stuff... idk


----------



## roi




----------



## aced126

Neurotic, I'd think that desoxypipradol would follow cocaine sar, but I'm confused as to why desoxypipradol has a very lipophilic beta substituent, and when replaced with a methoxy ester group (ritalin) it retains activity at about the same level (just shorter half life), which is what is confusing me. Also confused as to at what point the molecule becomes more cocaine like in moa. 2-benzylpiperidine has amphetamine like action. I wonder if beta substituents block the molecule from entry into the neuron through the transporter.

Roi, that is actually quite an interesting molecule. Both n-isopropylamphetamine and desoxypipradol have long half lives so I wonder whether this would be super long lasting.


----------



## roi

It's just isopropylphenidine with the phenyl rings replaced by thiophene. Should still be a dissociative with a ~3-4h peak I guess.


----------



## Dresden

2C-T-12 has a really ugly looking structure.

How do you name the lactones neurotic mentioned but didn't draw?


----------



## Dresden

Also, how about this little creepy-crawling looking, thiophenyl analogue of DOET stinking insect molecular idea?






Because it's pure art!!!


----------



## aced126

Would this have stimulant effects? It probably would have dissociative effects. Furthermore, if the secondary amine was a tertiary one, it would have the mu pharmacophore as well. Normorphine is a weak opioid itself and I'm guessing it's because if the hydrogen is involved in an H bond that would disrupt the ionic bond on the nitrogen which is crucial to opioid activity. Obviously the tertiary amine of this molecule would be lacking the parahydroxy group which would increase opioid activity a lot (although a metabolic byproduct could have a parahydroxy phenol group). 
As far as I know, I think one of the main roles the alpha methyl group plays in amphetamine is blocking metabolism by AAADC which normally breaks down phenethylamine (I read in some paper that pea was a potent euphoriant but due to the very short half life of 30 seconds the effects are negligible). An alpha-benzyl group could block metabolism but obviously might cause steric hindrance at the receptor. However this group would give the molecule it's dissociative effects.


----------



## roi

^That's Mephenidine, a metabolite of Lefetamine. Should be mainly dissociative, maybe a little bit stimulating.


----------



## aced126

Would this have stimulant effects? It probably would have dissociative effects. Furthermore, if the secondary amine was a tertiary one, it would have the mu pharmacophore as well. Normorphine is a weak opioid itself and I'm guessing it's because if the hydrogen is involved in an H bond that would disrupt the ionic bond on the nitrogen which is crucial to opioid activity. Obviously the tertiary amine of this molecule would be lacking the parahydroxy group which would increase opioid activity a lot (although a metabolic byproduct could have a parahydroxy phenol group). 
As far as I know, I think one of the main roles the alpha methyl group plays in amphetamine is blocking metabolism by AAADC which normally breaks down phenethylamine (I read in some paper that pea was a potent euphoriant but due to the very short half life of 30 seconds the effects are negligible). An alpha-benzyl group could block metabolism but obviously might cause steric hindrance at the receptor. However this group would give the molecule it's dissociative effects. 

Here's the tertiary amine version and some derivatives and what activities I think they will have. This is purely theoretical and will probably have no activity at all but oh well it's fun. This is also assuming that an alpha benzyl group instead of an alpha methyl group retains amphetamine-like activity. I don't know very much at all about dissociative SAR at all so please correct me/make suggestions.






This is actually lefetamine. It's an opioid, and seems to lose stimulant activity completely, guessing because of 2 methyl groups on N. Dimethylamphetamine seems to lose a lot of activity, and what is retained is when one or both of the methyl groups are cleaved off by the liver. Apparently benzphetamine is rather active as a stimulant, and has a tertiary amine. Other substitutions which lead to compounds like selegine seem to have different pharmacology altogether, with selegine being an irreversible MAO-A inhibitor.






parahydroxylefetamine. It should increase opioid activity a lot if I'm correct. Will however significantly decrease stimulant activity. Not sure about how NMDA antagonism is affected. My next topic of research shall be that.






Secondary amine now, which should increase stimulant activity a lot, but reduce opioid activity significantly as well. The methoxy group could increase SERT affinity possibly? 






I don't expect this to have mu affinity at all, however could this be both an NMDA antagonist as well as a 5HT releasing agent?






The 3,4-methylenedioxy substitution here is going to wreck opioid activity, so my attempt to possibly bring it back was making the nitrogen tertiary as well as adding a phenethyl group to it (n-phenethylmorphine is x14 more potent than morphine, and I don't think this is due to just increased lipophilicity). Could this retain dissociative activity? Probably not...






I'm not sure if a fluoro group would suffice instead of a hydroxy, but this could possibly increase SERT affinity as well, while possibly maintaining opioid and dissociative effects.






Hydrogenating the other ring should increase opioid activity but I'm guessing it might not retain dissociative activity. Expecting very little stimulant effects from this.

Will add more when I think of them. People correct me if I'm terribly wrong in my predictions on these molecules. In practical terms one effect of the 3 will probably overpower the other 2 such that when one administers enough of the compound to reach desired effects of one aspect, he will be overdosing from the other, be it say opioid induced respiratory depression or seizures.


----------



## aced126

Roi, is there anywhere where I can get data on diphenidine analogues? 

Also, does anyone know where I can find data on the effect of alpha substitution on phenethylamine. When I looked on wikipedia's page of amph analogues all I saw was alpha methyl and alpha dimethyl substitutions. Does anyone know what role the alpha substituion plays other than blocking metabolism?


----------



## aced126

Also would this retain dissociative effects? Probably already been made, it's basically fentanyl + diphenidine. I'm guessing the extra phenyl substitution would reduce opioid activity but since fent is so potent already...


----------



## aced126

From a couple pages ago, people were trying to create compounds with opioid + mat activity.

Here are some structures which I thought about which could work. Making the amine tertiary as well as retaining stimulant activity seems hard. 






Ok so in this molecule it has a ritalin backbone but the nitrogen is tertiary so one should in theory get both stimulant and opioid activity. The beta carbomethoxy group I'm guessing could hinder opioid activity so I have added a benzyl group to the nitrogen to hopefully increase BBB penetration as well as possibly increase mu affinity as well. The fact that benzphetamine retains stimulant activity could suggest this will as well, although this molecule will probably be ritalin like in action rather than amphetamine. Nevertheless there's a tiny chance it could work.






Same thing but instead a phenethyl substitution which should really increase opioid activity but probably decrease stimulant activity a bit more.


OT: could opioids (not purely high mu affinity euphoric and analgesic) be effective in treatment of depression?


----------



## roi

aced126 said:


> Roi, is there anywhere where I can get data on diphenidine analogues?
> 
> Also, does anyone know where I can find data on the effect of alpha substitution on phenethylamine. When I looked on wikipedia's page of amph analogues all I saw was alpha methyl and alpha dimethyl substitutions. Does anyone know what role the alpha substituion plays other than blocking metabolism?



There's some information like metabolism, just click through the references of Diphenidine, Methoxphenidine, Ephenidine, Fluorolintane. Sadly no binding data. Potency seems to be isopropyl > ethyl > piperidine > pyrrolidine. Their inventors claim they're DRIs in addition to NMDA antagonists, but that was never confirmed.

There's a prenyl-piperazine diphenylethylamine with a 3-hydroxy group that is a opioid, called AD-1211. Maybe 3-hydroxy-ephenidine (or diphenidine etc) would cause some opioid activity (similar to 3-HO-PCP), but it was never trialed afaik.

Fluorolintane (2-fluoropyrrolidinophenidine) had the strongest SRI effects subjectively, felt somewhat similar to MXE, however potency is not that high, a full dose is 200mg+.


----------



## aced126

Just looked at some prolintane derivatives; tertiary amine while retaining stimulant activity. Not only this but an alpha-propyl retains activity. Weird.

Searched these compounds on the net but no pharmacological data. Would love to get some data for these...
















Crap just realised prolintane derivatives have absolutely no opioid activity at all. Also just realised the s isomer of lefetamine induces seizures.


----------



## aced126

Ok got some more ideas for opioid/MAR hybrid compounds, based on prolintane and lefetamine. Might have some dissociative properties as well...






This is diphenidine but with a pyrrolidine ring instead of dimethyl. Should have opioidergic activity as well. Could possibly have stimulant activity?






Idea here is to introduce some SERT affinity while also letting the liver unmask a more potent opioid.






Apparently 4MTA is non-neurotoxic so might as well chuck this in.

Now I think the beta-cyclohexane derivatives of these compounds will be more potent opioids but will probably lose dissociative effects. I don't know what it'll do to stimulant activity. As we can see from prolintane derivatives alpha-propyl groups are tolerated, however the group has more degree of movement whereas a cyclohexanyl (and phenyl to be fair) group will be rigidified into its chair conformation. Example:











Moving away from opioids and towards serotonergic and dissociative hybrids











The former should be more dissociative.

Back to increasing opioidergic activity...


----------



## Dresden

Here's my first 2C contribution to this thread:






Never, to be perfectly honest, ever gotten off of any 2CX like other people do for some reason, and I've tried a small all-you-can-eat buffet's worth and sometimes in copious amounts (e.g., 50+ mg of 2CE).  

Otherwise, it appears to me that we, as a whole, have far too many prospective lead compounds and not enough time and/or money to synthesize and evaluate many (any?  not even one?) of them at all, which is a shame really.






^--Would have been time much better spent than was wasted on "escaline" in my estimation.






A longer lasting methamphetamine, as the C-D bonds are stronger than conventional C-H ones and are here placed strategically to minimize the 4-hydroxylation and benzylic oxidation to benzaldehyde or benzoic acid as is commonly observed in plain methamphetamine.






1-thia-6-MAPB (to use replacement nomenclature)






See also MMDA.






See also DOET.


----------



## Dresden

*Choose your favorite ONE novel, "random" chemical to bring into existence.*

For me, it has to be this one:






2-amino-1-(4-oxocyclohex-2-enyl)-propane.HCl aka Testosterone Inspired Amphetamine (TIA).

* * *

If bisphenol A (BPA) in plastics can be estrogenic in humans, I see no reason this little gem couldn't possibly be an androgenic stimulant, no?
If nothing else, aromatase will likely metabolize it to (the presumably active?) 4-hydroxyamphetamine.

Ok, how about you?


----------



## Hammilton

Lefetamine analogues benefit from meta-OH, not para (or at least not so much).  Instead of attaching the OH on the cyclohexane, you would probably see most potency by making that beta carbon quaternary and attaching the OH there.  I don't see any rationale for where it's drawn.


----------



## aced126

Thought the OH would be analogues to the 14-hydroxy substitution like in oxymorphone


----------



## roi




----------



## Soulfake

aced126 said:


> OT: could opioids (not purely high mu affinity euphoric and analgesic) be effective in treatment of depression?



Of course, as far as I know it was proven at least with Tramadol in a couple of studies. There´s just the problem with tolerance. A really mood-enhancing, stimulating and motivating opioid is Tilidine, (at least) in the short term much more than Tramadol and in the long term you don´t get as many problems with tolerance becouse the pharma products always contain 12 or 16mg Naloxone which also helps really well against gastrointestinal side effects. The metabolite of Tilidine also has dopamine-reuptake effects as far as I know.
I wonder why they don´t bring either Nortilidine (desmethyl) or a analogue of it to the market. Maybe an ethyl compound? Could anything be done on the phenyl ring like the usual 3-hydroxy unit? Tilidine is a pro-drug but quite strong becouse it´s very fast metabolized and active in 10-20 minutes so analogues of it would be more than enough.
(the last one in the picture is a random phenyltropane, hasn´t much to do with the tilidine analogues)


----------



## sekio

--> random molecules thread



> If bisphenol A (BPA) in plastics can be estrogenic in humans, I see no reason this little gem couldn't possibly be an androgenic stimulant, no?



BPA resembles estrogen much more closely than that cmpd resembles testosterone, check the space filling models of estrogen sometime. stuff like diethylstilbestrol also overlays nicely.

and as a rule of thumb any highly polar substitutions on the ring / dearomatization of the phenyl ring in amphetamine leads to weaker central activity


----------



## neurotic

That tilidine sounds like an interesting one, glad it doesn't require CYP2D6 membership - the reason i can't enjoy tramadol 

I think opioids for depression should be kinda tricky. I mean wouldn't the mood-lifting effects fade over time? It sounds analogous to BZDs for anxiety in that it should be very effective but unsustainable in the long term. Unless it's not the opioid effects you're saying should be useful for depression but some other mechanism like NMDA or something.


----------



## aced126

Wouldn't nortilidine be void of most opioid activity


----------



## Soulfake

aced126 said:


> Wouldn't nortilidine be void of most opioid activity



It should be more potent, Tilidine is only a pro-drug for it but is so fast metabolized that I think it doesn´t make a big difference other than pure potency/mg ratio (Tilidine is used in doses from 25 to 400mg, Nortilidine should be more in the dosage of Morphine. This article also states the dopamine-reuptake effects I mentioned as well as nmda-activity which could contribute to it´s antidepressive effects like with Tramadol (but a hundred times more enjoyable than Tram, it´s the most abused "light-opioid" in germany for example and I know no one who would switch it for anything else. It´s stimulating effects also feel more like coke (very pronounced "sunshine feeling") than amphetamine. 



> Nortilidine[1] is the major active metabolite of tilidine. It is formed from tilidine by demethylation in the liver. The racemate has opioid analgesic effects roughly equivalent in potency to that of morphine[2] but virtually all of the opioid activity resides in the (1S,2R) isomer.[3] The (1R,2S) isomer has NMDA antagonist activity. The drug also acts as a dopamine reuptake inhibitor.[4]


https://en.wikipedia.org/wiki/Nortilidine


----------



## aced126

Wow that's cool, are there any other non tertiary opioids?


----------



## Bagseed

I wish we had Tilidin in Austria... heard good things about that


----------



## Soulfake

Does anyone know how this drug is called and if it was available on the rc market in the recent years? By searching for the name I couldn´t find anything useable. I remember reading it was used as a designer drug in Israel but can´t find the article.

2-(dimethylamino)-1-(4-methylphenyl)propan-1-one






also some more molecules:


----------



## roi

That's 4,N,N-trimethylcathinone. N-methyl-Mephedrone. Should be a barely active prodrug. Dimethylone/Dibutylone were rather big failures as well.

It has been sold as 4-MDMC (4-methyldimethylcathinone).


----------



## neurotic

^ that's one sneaky use for 'MD'


----------



## blueberries

Dresden said:


> Here's my first 2C contribution to this thread:



My God. How did you get in my head!? That Ethscaline was my pride and joy for god knows how long (coming from that glorious DESOXY)! Plus most of the rest have been drawn and fantasised by me too many times. The deuterium analogues also sailed through many times but attached to 2C's ala 4D. Those MMDA analogues too. IMO the 5 is much too weak but brain movies. The 2 is much more applicable for recreation but at one point I sincerely felt that the 5-Methyl-MDA myth was actually perpetrated by 2-Methyl-MDA (still could be...).

Plus roi; I _love_ the PCP/Pethidine analogue. I did something similar with MXE and Ketobemidone.

Anyway; I got into these pseudo-halogens and found Cobalt Carbonyl. It'd be very bulky, sure, but you think it would allow it at 4, like this? It's a shot in the dark and even if you could use the Cobalt effectively, I don't want to know what would happen in vivo! It's another 2C-At type compound.






EDIT: Also on Tilidine, I should mention that when 4-MeO-PCP came out there was a certain supplier who had a lot of very dodgy compounds and foolishly (I was young) I got some DXM and 4-MeO from them. Both felt exactly the same at the same dose and I later heard a rumour saying that they were vending Tilidine instead. This corroborates my latter experiences of 4-MeO as it was _wildly_ different. Wild being the integral word. It was pure chaos and _not_ pleasant, unlike my 4-MeO experiences. I'm still glad I tried it though.


----------



## pharmakos

blueberries said:


> Anyway; I got into these pseudo-halogens and found Cobalt Carbonyl. It'd be very bulky, sure, but you think it would allow it at 4, like this? It's a shot in the dark and even if you could use the Cobalt effectively, I don't want to know what would happen in vivo! It's another 2C-At type compound.



brb drawing 2C-B12


----------



## atara

Metal carbonyls (except iron) are some of the most toxic compounds around. Not sure that's what we're going for.


----------



## clubcard

As Corante says 'Things I will never work with'.


----------



## blueberries

Exactly! Another 2C-At! I just wanted to know if it could actually be created though. I realise it'd be wholly unfit for consumption but I love the idea of having a compound, incredibly rare, fitting to the 2C archetype yet being completely untouchable. Kind of like forbidden fruit. 

I mean besides the rampant toxicity, if some superhuman immortal type were to try it there would be an affect, no? Similar to 2C-At; there _would_ be an affect if you could survive the toxicity/radioactivity. Who knows, maybe sometime in the future we'll get carbon tubing organs which make us invulnerable to any toxicity (probably still not Astatine though!). _Then_ we could try it!

EDIT: And a carbon tubing brain!! Taking into account the ancient philosophical question of whether consciousness could survive if a new brain were implanted with memories reprogrammed into it...but let's just say it would!


----------



## blueberries

Ok, now for a serious compound. I began researching Quinazolinones recently and after the RC analogues to come out and having tasted real Methaqualone, I figured there must be a way to retain the affect of MQ while increasing potency. I went through nearly every paper I could find but on each one it seemed to lose. I did happen to gleam some nuggets of information though, which are:

- Replacement of any integral positions (2, 2', 3' & 4') with a halogen results in loss of affect but gain in potency. Dead-end.

- Addition of alkyls at any of these positions also reduced affect. Another dead-end.

- The 4 position increases potency some 4x, the 3 position increases it some 6x.

- Metabolites of MQ include hydroxy's at 2, 2', 3' & 4'.

Therefore with point #3 & 4, I created this. If nothing else it should be as potent as MQ, if it adheres to the rule it should be perhaps 3x the potency or more with a similar affect.






Thoughts?


----------



## roi

DOBEZ


----------



## blueberries

Hmm, I like the idea. Perhaps better with a sulphur joining the two?


----------



## roi

DOBZ is a thing and apparently more potent than DOB?

http://isomerdesign.com/PiHKAL/explore.php?domain=pk&id=323


----------



## Dresden

I've always wanted to try this one but never have:






The closest I got to trying it was the following:






It was only so-so, as many cathinones are wont to be.

blueberries,

I tend to think you'd have better results with:


----------



## blueberries

Whoa! Of the Quinazolinone? I just don't think in all honesty. I mean the structure is so out of line..I just don't see how it would work. I mean it could be an MAOI from there let alone a specific GABAergic compound that matches itself with MQ. Not even GHB can reach it's infamy.
However I'd still like to hear an explanation of such a compound!

EDIT: Ok I was a bit drunk and completely misread that compound. Aaaanyway 6-Cl compounds do increase potency somewhat but still need to have something anchoring the 2 position (as seen here: http://www.google.com/patents/US3162634). Halogens in general also ruin the affect of the compound as I have tried personally. 

The only thing that works is alkyl bonds and well, not fucking with it...at all! MQ is just one of those divine compounds that can't have any analogue and unfortunately it hit the sweet spot at a low potency. Even with the 3-HO bond it still could have a similar potency or even have an altered affect but out of the possible combination it really is the best we can hope for.


----------



## Midnight Sun

blueberries said:


> Whoa! Of the Quinazolinone? I just don't think in all honesty. I mean the structure is so out of line..I just don't see how it would work. I mean it could be an MAOI from there let alone a specific GABAergic compound that matches itself with MQ. Not even GHB can reach it's infamy.
> However I'd still like to hear an explanation of such a compound!
> 
> EDIT: Ok I was a bit drunk and completely misread that compound. Aaaanyway 6-Cl compounds do increase potency somewhat but still need to have something anchoring the 2 position (as seen here: http://www.google.com/patents/US3162634). Halogens in general also ruin the affect of the compound as I have tried personally.
> 
> The only thing that works is alkyl bonds and well, not fucking with it...at all! MQ is just one of those divine compounds that can't have any analogue and unfortunately it hit the sweet spot at a low potency. Even with the 3-HO bond it still could have a similar potency or even have an altered affect but out of the possible combination it really is the best we can hope for.



what do you think about about an ortho-CF3 substitution?  posted that in here a while ago

It's so damned easy to make such an analogue that I'd get a chinaman to whip me up some but I always seem to find better things to spend my money on


----------



## Dresden

Oh, I'm not so familiar with methaqualone.  The only thing I know about it is that etaqualone didn't work very well and stories in rehab from old addicts from the 70s saying how messed up they used to get on methaqualone.  I have no idea that these two would work either, but anyway, they are pared down versions of amfonelic acid, one with a 2-benzyl and the second with a 2-piperonyl:






and






And just for kicks (note similarity to amphetamine):






I don't think I'd be willing to try this last one.  But yeah, woke up feeling aromatic this morning, I suppose.


----------



## clubcard

blueberries said:


> Ok, now for a serious compound. I began researching Quinazolinones recently and after the RC analogues to come out and having tasted real Methaqualone, I figured there must be a way to retain the affect of MQ while increasing potency. I went through nearly every paper I could find but on each one it seemed to lose. I did happen to gleam some nuggets of information though, which are:
> 
> - Replacement of any integral positions (2, 2', 3' & 4') with a halogen results in loss of affect but gain in potency. Dead-end.
> 
> - Addition of alkyls at any of these positions also reduced affect. Another dead-end.
> 
> - The 4 position increases potency some 4x, the 3 position increases it some 6x.
> 
> - Metabolites of MQ include hydroxy's at 2, 2', 3' & 4'.
> 
> Therefore with point #3 & 4, I created this. If nothing else it should be as potent as MQ, if it adheres to the rule it should be perhaps 3x the potency or more with a similar affect.
> 
> 
> 
> 
> 
> 
> Thoughts?



US Patents 3086910,3135659,3162534,3194806,3382246,3406173,3448109,3514466,3651230,396731,4276295,5283247

The BEST legal-lude isn't specifically mentioned - it was worked out using Intelligent Design and some time with Ames tests, affinity tests & metabolism tests. Like Pyrazolam - it exits the body unchanged so the dose doesn't have to be changed for the young, the old and those with comorbidities. I advise everyone to buy a copy of Vogals Handbook of Medicinal chemistry and Chemoffice. From there you will want unlimited Reaxys and lots of time. I'm interested if any of the chemists here still stick to rational design... if not, I'm interested in just how good these 'molecular guessing programs' really are. Tip - Watch out for AMPA affinity; all the later patents use the quinazolinones as a scaffold FOR AMPA ligands.

Hope this helps!


----------



## Dresden

I will bet you these "molecular guessing programs" are not good at all.  I wouldn't exactly call my design methodology "rational," either.  Far from it.

Anyway, here's some shortish acting synthetic "legal" cannabinoid wax [literally] that I threw together for the stoners among us who nevertheless can't get real THC dabs or plant matter atm:






And here's a JWH-018 variant:






Which may be made into a short acting psychedelic by the addition of a 4-hydroxy indolic substituent:






Or just all around powerful but fairly short acting by the addition of a 5-methoxy indolic one:






Anyway, just some Wax n' Facts (which are not yet known to be facts if they even are!) for your brain today.


----------



## pharmakos

from US law:



> *Schedule I*
> 
> ...
> 
> (d)(1) Unless specifically exempted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of cannabimimetic agents, or which contains their salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation.
> (2) In paragraph (1):
> 
> (A) The term "cannabimimetic agents" means any substance that is a cannabinoid receptor type 1 (CB1 receptor) agonist as demonstrated by binding studies and functional assays within any of the following structural classes:
> 
> (i) 2-(3-hydroxycyclohexyl)phenol with substitution at the 5-position of the phenolic ring by alkyl or alkenyl, whether or not substituted on the cyclohexyl ring to any extent.



i believe that molecule would fall under this definition.

blanket bans suck.


----------



## Dresden

Yes, but the *real* question is:  Is the compound legal in China, whose illegal compounds are listed specifically but not publicized or the subject of a blanket analogue act type ban, now?  If so, it can probably be made for the right price, but you just don't want to get caught importing it or possessing it or distributing it in the U.S. as with any Schedule I drug.

While I'm at it, anyone know anything about 4-OH-AMT?






Or 4-Cl-AMT?






I know 5-MeO-AMT is a horribly toxic, potent, sucksome drug.

Indolic N-pentyl-AMT might, potentially, be a winner of sorts, though:






You can probably tell I'm on Adderall.


----------



## Soulfake

I thought production and selling of illegal chems in china is legal if it´s for export only? Especially as many labs cooperate with the government like China Enrichment Labs (where "Eric Chang" works).






can you replace a sulfoyl-thiol with a methyl-sulfonyl-methane unit without loosing activity?


----------



## Nagelfar

My phenyltropane DRI + agomelatine NDDI hybrid.


----------



## Midnight Sun

so like, has no one considered the benzofuran analogue of aMT?  I sure hope it's in the pipeline what with 5-MeO-DiBF seeing the light of day

Loved 5-APB, which if it isn't obvious this would be an isomer of; wonderful balance of the psychedelic with the empathogenic.


----------



## clubcard

I THINK the time has come to ask everyone look up 'Lipinski's rule of 5'

Also, use Marvinsketch for LogP & Pka - no use unless it's unprotonated at physiological pH.


----------



## Dresden

Midnight Sun said:


> so like, has no one considered the benzofuran analogue of aMT?  I sure hope it's in the pipeline what with 5-MeO-DiBF seeing the light of day
> 
> Loved 5-APB, which if it isn't obvious this would be an isomer of; wonderful balance of the psychedelic with the empathogenic.








Seems like I saw the methcathinone benzofuran analogue of this for sale somewhere, don't remember where.






Soulfake,

The 3,4-dimethoxy phens have proved largely and surprisingly disappointing.

clubcard,

What, are you assigning us homework?  Just explain yourself.  Many of us such as myself are not in college or high school anymore.

One time I finally got to try 3-MeO-MA, but it was very, very mild and frankly quite a disappointment, and I took 500mg:


----------



## pharmakos

lipinski's rule of five was pretty easy to look up



> Lipinski's rule states that, in general, an orally active drug has no more than one violation of the following criteria:
> 
> - No more than 5 hydrogen bond donors (the total number of nitrogen–hydrogen and oxygen–hydrogen bonds)
> - Not more than 10 hydrogen bond acceptors (all nitrogen or oxygen atoms)
> - A molecular mass less than 500 daltons
> - An octanol-water partition coefficient[5] log P not greater than 5
> 
> Note that all numbers are multiples of five, which is the origin of the rule's name. As with many other rules of thumb, (such as Baldwin's rules for ring closure), there are many exceptions to Lipinski's Rule.



thanks clubcard


----------



## Midnight Sun

Dresden said:


> Seems like I saw the methcathinone benzofuran analogue of this for sale somewhere, don't remember where.



8(

now that's just weird

of all the things...


----------



## clubcard

Your welcome P - May I recommend the on-line Marvinsketch free software? Gives you the LogP AND pKa - if you medicine isn't unprotonated at physiological pH, it's not likely to work. Try methadone - now you can SEE why it's slow onset.... on the other hand, if you base it out and smoke it.... ahem.... forgive me, BAD IDEA!


----------



## roi

Only seen the 3-desoxy-MDPV (5-DBFPV) as far as cathinones go.


----------



## Nagelfar

sekio brought "NK-1145" to my attention in a PM, for whatever reason the benztropine-substituting-carbmethoxy style phenyltropanes but with isoxazoles, and changing the oxygen to a nitrogen at the linkage to the benzene as has been seen in other analogs, & voilà.






^my attempt to make the cyanotoxin "Very Fast Death Factor" (VFDF) into a cocaine like compound (seeing as cocaine can be a precursor in its synthesis, even)

Anybody know what the following compound is? Chemicalize.org says this is one in their database that matches as similar to the above one I was working on:
exo-8-Benzyloxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene

it looks like:





Why would this show up as an attested compound? Something I've overlooked in my in-depth study of such compounds or am I being foolish and it is something obvious?

EDIT:

Finally, would something like this make sense? "Cupric cocaine benzoate?" ;-p


----------



## flying-potato

Hello,

I read somewhere that the phenylethylamine is a very potent stimulant but is metabolized by the body too fast to be active. I also read that the utility of adding an alpha methyl group to the PEA to create an amphetamine structure prevent this destruction by blocking some enzyme. Is there a possibility for a non akyl group to act the same way ?


----------



## clubcard

Fluoromethyl groups HAVE been tried. truly AMAZING MAOI activity.


----------



## flying-potato




----------



## clubcard

Now - one of those really IS active. the p-N version of (meth)amphetamine is known, but the LogP is less favourable so their are more physical side-effects. Just changing the 'beta' to use non-IUPAC, trivial names, to a CH2F makes active compounds. A I have said, they have BIG MAOI issues so this is purely informational - make them and your going to kill a lot of people. Durations are also LOONNGGG!


----------



## flying-potato

Thx for all your explanation. Does this little variation of already know compound make sense ?






naphmetrazine :






MHP like :






various stuff :


----------



## Nagelfar

flying-potato said:


> Thx for all your explanation. Does this little variation of already know compound make sense ?



Wouldn't the above not work due to free rotation? Wouldn't it stabilize to something with restricted rotation or am I mistaken here?


----------



## flying-potato

Idea taken from another thread. Why no more lysine based prodrugs ?






Also i have another, maybe naive question :

It is possible to create a pro-drug metabolized by some process that will be inhibited by the drug or need time to be regenerated ? So it limit the possibility of becoming dependent because after taking too much in a too short time frame there is no more effect at all.


----------



## sekio

> various stuff :



some of these are known compounds, the methylphenidate morpholine analog has been sighted in the wild, the top 2 morpholines are known pharmacologically too

not sure about benzyl ritalinate or the thio esters but it'd be interesting to see what they would do (hey, have you heard the latest band the kids are listening to, Benzyl Ritalinate and the Phenidate Thioesters?)



> Wouldn't the above not work due to free rotation?



logically as long it can still conform to the binding pocket, it's all good, even though it may be less potent than others



> Why no more lysine based prodrugs



I think lysine-MDA has been made, maybe that was just a hallucination though. As for how useful it was, I suspect delaying release is not going to make it any more intense. I also think the latter 2 (mephedrone & MDMA) work best as bolus doses with fast administration rather than gradual slow releases over time. Methamphetamine is already long duration enough, look how unpopular stuff like benzphetamine & its analogs seem to be



> It is possible to create a pro-drug metabolized by some process that will be inhibited by the drug or need time to be regenerated ?



Sure, you could find compounds such that one of the downstream metabolites of the drug would inhibit the enzyme/process that converts inactive prodrug to active drug. You would be liable to mess up metabolism of a lot of other things in hat case though... its rare to have an enzyme in the body with an affinity for only one compoud.


----------



## flying-potato

sekio said:


> You would be liable to mess up metabolism of a lot of other things in hat case though... its rare to have an enzyme in the body with an affinity for only one compoud.



I think I will say something controversial but I think short term hardcore side effect or not necessary a bad thing, maybe a good thing. I was addicted to a few substance in the past, tobacco, weeds and benzos. I think it's very easy to fall addict to this substance because there is very few short term side affects. On the other side, when I did binge on 4-MMC, the hardcore crash that happened next prevented me from abusing the substance and taking too much of it. The ideal would be to mess up things that give uncomfortable but not dangerous side effect.


----------



## aced126

How would ether/thioether bridges fair in these analogues. Idea stolen from paroxetine












Would this resist MAO metabolism?


----------



## aced126

I know there is very little tolerance for substitution on the methylenedioxy ring but could this be active?











I know the difluoro has already been made but it is less potent I think


----------



## aced126

The distance of amine to benzene in the below molecule should be relatively the same to normal amphetamine


----------



## Nagelfar

aced126 said:


> The distance of amine to benzene in the below molecule should be relatively the same to normal amphetamine


----------



## roi

Inspired by diphenidine etc.


----------



## aced126

Nagelfar said:


>




My thinking is that this the strained cyclic part of the molecule will be metabolised into something polar very quickly due to its unstability.


----------



## pr0d1gy

Nagelfar said:


>



That's some cancer


----------



## clubcard

http://postimg.org/image/ooc55thl9/

NOT random... lazy RC chemists.....


----------



## flying-potato

clubcard said:


> http://postimg.org/image/ooc55thl9/
> 
> NOT random... lazy RC chemists.....



I have just some base in chemical and pharmacology but I would be impressed if it work.


----------



## clubcard

The lower LogP is the issue. The QSAR of cathinones is actually quite different to the amphetamines. Dimethyl analogues of cathinones are active, for example, due to lone-pair interaction. In Chemoffice they overlay so I would be quite surprised if it were inactive.

The synthesis of this one is the sticking point for RC-grade chemists, especially the lazy ones. There is a simple, 2 step route from the right precursors - I cannot give details but I presume you can see it. Now, THAT was too much like hard work!


----------



## aced126

What do you mean by dimethyl analogues for cathinones? Where are the subsequent methyls you're talking about placed? On the alpha carbon? On the nitrogen?


----------



## clubcard

aced126 said:


> What do you mean by dimethyl analogues for cathinones? Where are the subsequent methyls you're talking about placed? On the alpha carbon? On the nitrogen?



Sorry - on the nitrogen.

As for diphenidine analogues, having a flexible amine group (like the N-ethyl) gives the greatest affinity. The problem with the class is that they are generally too low-catching evidenced by the high dosages. If you make the sulfate, diphenidine works much better when snorted but the optimal compound (by a country mile) in the class is the N-isopropyl. A lot of experienced K users thought it was K. Same dosage as K and so forth. Why didn't we see it? Apparently the chemistry was too hard. I don't think I even need to describe a route, it's so simple.


----------



## roi

Diclotiazolam? Who needs phenyl rings anyway.


----------



## aced126

Are you sure n,n-dimethyl cathinones are intrinsically active, or are active due to cyp3a4? I thought it was the latter


----------



## sekio

> NOT random... lazy RC chemists.....



I don't like the look of an alpha-tosyl-amine, no sir...


----------



## adolf

> Has anyone tried making cyclohexadiene analogues of amphetamines?



Thats a great idea, the cycloalkene structure stabilizes the ring so you dont have the annoying cis or trans formationod the cyclohexane.

@clubcard 



> http://postimg.org/image/ooc55thl9/


 

How do you want to synthesize that? is TsOH the precursor ?


----------



## Dresden

aced126,



aced126 said:


> Are you sure n,n-dimethyl cathinones are intrinsically active, or are active due to cyp3a4? I thought it was the latter



I'm not entirely sure either, as N,N-dimethylamphetamine is only 1/10th the potency of methamphetamine.

As for your latest molecules, the benzylic, substituted with an an oxygen amphetamine molecule will not form.  The N and O are one carbon apart again.  Not sure if using a piperidine ring with the nitrogen spaced only one carbon from an oxygen would work or not.  I kind of think it would for some reason.

As for the phenyl-cyclobutyl-amine, it to me looks like transcyclopropylamine (its cyclopropyl homologue), which is an MAOI.

Finally, the carbonic anhydride MDxx thing won't work, as upon contact with water such as in saliva for example, the 3-Ar-O-(C=O)-O-4-Ar ring system will break apart.


----------



## clubcard

4'-Methyl-α-pyrrolidinopropiophenone is the most famous example.


----------



## Nagelfar

Methylphenmetrazidate?


----------



## neurotic

aced126 said:


> Are you sure n,n-dimethyl cathinones are intrinsically active, or are active due to cyp3a4? I thought it was the latter



I don't think they're prodrugs. Thinking of N-pyrros like MDPV and a-PHP.

Prolintane which is without the beta-keto is active too though... Maybe it's a whole different SAR for these compounds with long alkyl chains on the alpha carbon. They might cause monoamine release differently than amph and cathinones too... I think they're regarded as reuptake inhibitors instead of releasers. If they're recreational surely enough they don't just block the transporters tho, I don't know if anyone looked closely enough to know though


----------



## sekio

MDPV is known to be a reuptake inhibitor with no monoamine releasing effects, and stuff like mephedrone are mixed releasers/reuptake inhibitors. 

I think SAR of DA releasers requires a moderately basic amine residue for best efficacy, that means secondary amines are better than primary amines, and tertiary amines are at the bottom. Look up the effective dosage of something like benzphetamine compared to methamphetamine.

Conversely MDPV can get away with bulky substituents on the amine that serve to increase lipophilicity & metabolic stability at the expense of efficacy as a releasing agent. But Isuspect that by the time you get to something like alpha-propyl-phenethylamine there is going to be minimal releasing efficacy.


----------



## clubcard

S - always direct and to the point.

Prolintane is VERY mild indeed - you would be hard-pressed to get a buzz.

As for bulky substitution on the beta (trivial name) like a phenyl group (the first aromatic being a p-toluene), gives something that, is identical to pyrovalerone. The MW is higher, but so is the LogP and so, in an elegant twist, it's the same potency as pyrovalerone. Lefetamine was marketed as a stimulant, the minor NMDA and partial opiate agonist affects were discovered later. I read of it being trialled in Italy (I think) in a comparison with methadone and buprenorphine and although it helped, it wasn't seen as useful. I believe a cyclohexyl moiety will replace the benzene-ring. I have the papers on tests concerning both isomers and the (S) isomer actually has more NMDA activity but at the doses needed for analgesia, seizures occur (showing the AMPA affinity). That's why the 2-substituted were a bad idea (IMO). It interested me because it's one of the few opioids that break the rules and have the basic nitrogen in the benzyl position (like BDPC & ciramadol). Lednicer actually started with a p-toluene and 4-cyclohexanone, not the stupid, murderous super-potent agonists, this is a very useful insight into these rule-breakers. I need some software that takes a group of training compounds and finds the 3D coincidence of given moieties of said training set. Any suggestions gratefully recieved. 

I know I keep banging on about it, but Marvinsketch online is free and gives LogP & PKa. The best example I can think of is EXP-561. It's about 98% protonated in the blood so at any one time, only 2% of the amount in the blood-stream can pass into the brain so SLLLOOOWWWW onset. Just using Marvinsketch and remembering Lipinski's rules of 5 mean that people can design stuff that would reach the brain.

Oh yes, I've just remembered. Seiko, the 5-carbon amphetamines do exist. They work in a different manner. It IS a (mild) stimulant but it's effects are upstream of the monoamine releasers and so it's an insight into the next level of the cascade. I can find the patent number if you can't.

I'm afraid that my education is from an era where none of these cascades were understood.

Can someone recommend a windows or UNIX app that allows a training-set of compounds be used to find shared moities in 3D. I saw one for opioids BUT it doesn't cover the alkene on allylprodine/14-Cinnamoyloxycodeinone (for example). Another is the benzylic-nitrogen opioids BDPC, ciramadol (and Lednicer's earlier, pethidine strength opioids which just had a cycloexanone. It's like the N & O can be swapped.


----------



## aced126

Well in lefetamine you could view the nitrogen as the 1 carbon away from the phenyl, but what probably happens in the binding site is the phenyl ring 2 carbons away conforms to the positive residues rather than the alpha substituted phenyl. I think the alpha phenyl is analogous to the cyclohexene ring in morphine. Thus if it were hydrogenated potency might increase as you said. I posted a few compounds based on these ideas a couple pages back


----------



## Nagelfar

Nagelfar said:


> Methylphenmetrazidate?








Napthyl variant? Rather bulky looking.

And if you fuse the carbmethoxy:






Interesting, but probably isn't a ligand at all, haha.


----------



## Nagelfar

Inspired by the nitrogen on the 3_β_-Carbamoyl cocaine analogues being roughly where it would be on the fentanyl positioning of its similar backbone to methylphenidate with which cocaine overlays. The position of the carbmethoxy similarly inspired by MPH using that very same nitrogen group as a convenient way to host it. The phenylethyl on the tropane lines up with where fentanyl's is on its piperidine using the MPH orientation too. I actually quite like this one for those reasons.


----------



## clubcard

Adolf - sorry for slow response. I'm afraid synthesis discussion is not allowed. I think I can tell you that the 3 reagents you need are all in Aldrich - you have to destabilize Hs on the carbon you want to add to... I think that's enough for you to figure out while I'm not naming any chemicals, conditions or solvents.

I advise everyone to read Derek Lowe's pages in Science Translatable Medicine. 'Things I won't Work With' shows serious chemistry can be seriously funny as well http://blogs.sciencemag.org/pipeline/archives/category/things-i-wont-work-with FYI I've worked with 2 things in his list. I remember him writing that during the end of the 19th century, you could find out who was working with nitroso compounds by turning to the obituaries. It STILL happens. A couple of years ago, a girl was in the uni lab, unattended, while working with t-butyl lithium. Now, if your going to work with this crazy stuff - expect flames. She managed to drop the syringe & cover her body. No lab-coat, a synthetic top that turned into boiling plastic; all in all, not good. What is worse is that an emergency shower was 10 feet away. WHATEVER you are working with, work out the risks & have a plan. That she was inexperienced & not even wearing a lab-coat spelt her end. 

If you wonder WHAT crazy stuff I worked with, diethyl cadnium (OK, he said dimethyl but let's not split hairs) and Magic methyl. The latter had been used for years but after a Dutch researcher killed himself with a small spill, it was dropped. You notice this over time. You don't see periodic acid much - I seem to remember the Japanese researchers who looked at mitragynine made the 7-hydroxy using it....

Basically, a lab is a dangerous place to be and during ones education, you soon found out who the passion fingers was (fucks everything they touch) in the form of a girl who was refluxing diethyl ether in a 3-neck flask.... without the stopper being in the unused neck. Ether flames are amazing! But not from close up :-(


----------



## Dresden

2-amino-1-carbomethoxyindan






2-amino-1-carbomethoxy-5,6-methylenedioxyindan


----------



## clubcard

Why not find the overlay between RTI-55, amfonelic (and oxolinic acid) & Benocyclidine. I should add that experimentation shows that the most electron-withdrawing groups (where the I is on RT-55_ give the compounds more potent). A good excercise because as you work on it, you will see 3D relationships between moieties, so it gets easier, the longer you work on it.

As a start:

1-tertiary amine.


----------



## Dresden

clubcard said:


> Why not find the overlay between RTI-55, amfonelic (and oxolinic acid) & Benocyclidine. I should add that experimentation shows that the most electron-withdrawing groups (where the I is on RT-55_ give the compounds more potent). A good excercise because as you work on it, you will see 3D relationships between moieties, so it gets easier, the longer you work on it.
> 
> As a start:
> 
> 1-tertiary amine.



The two molecules I drew are mostly planar.


----------



## Dresden

In addition to 5-HT, melatonin, DA, NE, and glutamate etc., I think this would make an awesome addition to our current family of neurotransmitters.  No idea how to go about that one, though, unless it is through some kind of extensive natural selection following a designer gene insertion:






3,4,5-trihydroxyphenylethanamine.

This is the stuff of aliens, I believe.
Sound far fetched?  Well, sure, but then again, some kind of octopus (and many insects and, to a lesser extent, humans as a TAAR agonist) uses octopamine:






Octopamine.

(Then again, scientists who recently did some DNA study on octopuses finally reached the conclusion that they may actually be an alien life form.)

I also think it's a shame we don't produce this neurotransmitter:






N-methyl-dopamine.

N-Me-DA is the reason MDMA is so rewarding, and if you can figure that relationship out on your own, then you're smarter than most, I would say.

But, like I said last week or the week before maybe, this molecule is really all we need:






2-methylamino-1-phenylpropane.

It's a good place to start, anyway.  Notice how it has no oxygen molecules anywhere in its constitution to lower its potential energy (oxidized organic compounds are basically partly like ash, which of course always has a lower potential energy than whatever was burned ["rapidly oxidized"] to produce that ash).  Also, see how its basic form is supremely fat soluble and ready to cross into the brain at a moments notice, while its protonated N form is perfectly water soluble if I understand that right and ready to be absorbed by the acidic aqueous solution found in our stomachs.  Finally, note how sturdy the molecule is; so sturdy, in fact, that 50% of a dose in humans is excreted unchanged in our urine.  Yes, I'm on it again.


----------



## sekio

> 3,4,5-trihydroxyphenylethanamine.
> 
> This is the stuff of aliens, I believe.



given what we know about polyhydroxylated dopamine/serotonin molecules being massive neurotoxins due to redox cycling i would shy away from it


----------



## Dresden

Don't worry.  I have no intention of me or anyone else taking it.  I just think it has the potential to be an awesome NT in a species with receptors for it, metabolic pathways to synthesize it, and brains with the necessary safeguards to protect themselves from any inherent danger possibly posed by its three aromatic hydroxyl groups.  While we're on the subject, one time I saw HHMA being sold on the clear net somewhere.  Does anybody have a clue what HHMA feels like if ingested?  Don't worry in advance, mind you, as I have no intention of trying that one either.






HHMA.


----------



## sekio

I thought alpha-methyl dopamine was toxic; logically the N-methyl analog should be too.

Also, cachetols have horrible pharmacokinetics, phenols are generally bad enough to begin with, but by the time you get to drugs like dopamine they have to be administered as prodrugs or through IV infusions.


----------



## blueberries

Sorry for the late reply!



clubcard said:


> The BEST legal-lude isn't specifically mentioned - it was worked out using Intelligent Design and some time with Ames tests, affinity tests & metabolism tests.



So what is this mystery quinazolinone? 

Plus to Dresden; Etaqualone, while being fairly similar to Methaqualone, it just doesn't hold up. It's MQ light. That's why we need to work on the basic MQ structure with slight alterations. The most slight, while increasing potency is the one in my post. It's literally the only thing I can think of without getting into nutty Japanese pharmacology, altering Afloqualone and whatnot.

My other concern however is if one does create an MQ analogue with all the same affects and a lower dose; would people pick up on it and regard it as MQ 2.0, or would they see it as just another RC? The hype would still be within MQ, no matter how good a compound you made. It could even trump MQ 1000 times over and still be almost unheard of. It's a sad age we're living in when we have better compounds than their parents but no-one gives a fuck because it doesn't have the history that the parent does. Possibly with 2C-B as the exception but still; would the average user choose 2C-B or Mescaline (hoping they're not a hippy naturist!)?

People want what's known. The RC industry is a bystander to "famous" drugs. We have better drugs and better affects from them than nearly all common drugs but we never get heard. RC is associated with untested and unknown. People fear it. "At least we know the dangers of the known drugs" What the hell?! These compounds are derived from the same structures as the known drugs, the differences (and side effects) are almost exactly the same but no matter what, they'll never gain ground and the lesser, "known" drugs will always be more popular. 

In this community we can design, create and beautify these compounds but they'll never gain a foothold. That's sad. We can draw anything we like but only we can reap the benefits and we are but a tiny society. There needs to be a drastic change in our way of thinking, as a society and it will stem from us. I don't know what to do, I don't know how to start educating but if someone does then maybe, just maybe, we can have a chance at creating, cleaner, safer and overall better intoxicants that general society needs, even if they don't want it. I mean we could create a non-addictive heroin and nobody would know. That just fills me with hopelessness for modern society. I feel like a general inside a bunker before the apocalypse...and not in a good way. RANT OVER.

tl;dr: This is all fantasy. It's pointless til we turn the page in modern drug users' ideology. Find your monkey and educate them.


----------



## aced126

People fear RC for a good reason imo. Even though RC compounds are derived from parent compounds (with established safety and efficacy), we just don't know enough molecular biology to accurately predict the effects one substitution might have. For example, an RC chemist might find it reasonable to break the methylene bond on MDA to give 3,4-dimethoxyMDA. This would be metabolised to alpha-methyldopamine which is potentially neurotoxic. You're right, most RCs have similar side effects and profiles to their parents. But you never know, just one small change to the molecule could confer it several times more potency at an undesired target. Yes, the probability of this is low, but the probability is still there. That is not to say that RCs could be better and safer drugs. Many of Nichols' compounds are way less neurotoxic than MDMA. 

I guess a decent analogy would be house insurance. You pay a known price (equivalent to taking a known drug and accepting the well established risks). If you don't have house insurance, your house probably won't burn down (you probably won't experience negative effects from RCs), but in the unlikely event that it does, you are fucked. My probabilities might be out of proportion I guess but the thing is most users can't calculate the risks for themselves.

But yeah, you're right, we live in a world where people don't accept altered states of consciousness.


----------



## flying-potato

4-metoxymethyl-methcathinone :


----------



## roi

Fluoroadamantate. Or something.


----------



## clubcard

Dresden said:


> The two molecules I drew are mostly planar.



But they aren't in real life unless you make them rigid and even then, the lowest energy-state might not be planer.


----------



## aced126

clubcard said:


> But they aren't in real life unless you make them rigid and even then, the lowest energy-state might not be planer.



Where can they rotate? Guessing there will be 4 isomers for each of the molecules, one of which will probably be of the right conformation. The non substituted one (ritalindane maybe?) will probably just act like ritalin. Not so sure how effect of an SRA will the other molecule be. Will probably just inhibit reuptake of 5HT.


----------



## clubcard

an MD itself isn't totally planer - look into the bonding-angles as described by VSEPR theory. The lowest energy state is when the bonds are closer than their natural angles. Look at ammonia - the lone-pair means that the shape is a 3-sided pyramid. That's why you need software to see it in 3D. Speed isn't flat and ritalin (or it's reversed ester) are miles from being planer.


----------



## clubcard

Fluoroadamantate is an interesting idea. What about just having that methyl on the thiophene homologue of MPA? If that shows serotonin-releasing activity, an MD has a good chance of working. You would need the methylamine and optical resolution BUT you could do it.


----------



## roi

clubcard said:


> Fluoroadamantate is an interesting idea.



Inspired by bromantane, obviously. Any idea if there's more research into adamantane stimulants? Also your inbox is full, go delete old messages 

Methamadatamine






Bonus:


----------



## clubcard

Requires an aromatic (flat & binding in lipophilic pocket via Van der Waals forces.


----------



## Nagelfar

clubcard said:


> Requires an aromatic (flat & binding in lipophilic pocket via Van der Waals forces.



Would an endo-etheno bridge on a cyclohexane fit to that specification or is it not flat by its internal linkage (as rendering tools usually default it to a boat conformation if its not held in a specific way to other constitutents)?

Same molecule weight I'm assuming.

Since the double bonds rotate in benzene, is there another conformation where the same would be the case, holding a stable rotating type structure within a 2D-planar fixed molecule?


----------



## adder

> Would an endo-etheno bridge on a cyclohexane fit to that specification or is it not flat by its internal linkage (as rendering tools usually default it to a boat conformation if its not held in a specific way to other constitutents)?



It would make the structure even "more three-dimensional", besides no conformation of cyclohexane is really flat with half of the hydrogen atoms being axial while in aromatics hydrogen atoms are perfectly aligned with the plane of the ring. Aromatic rings usually interact with aromatic rings of amino acid residues (in some cases they can also interact with carboxyl groups, which are also flat, proper substitution with an electron-withdrawing group on the ring is necessary, I guess, as plain alkylbenzene moiety is not electronically predisposed for such an interaction, e.g. cocaine's ester interacting with a tyrosine residue at DAT). It's certainly the case for stimulants related to amphetamine which when bound to DAT has its aromatic ring placed in a region with a few aromatic rings to interact with. Look up propylhexedrine which has mainly adrenergic effects. Wikipedia states it has psychostimulant properties at doses much higher than therapeutic ones, but somehow I doubt it could get any better than levo-methamphetamine at any dose.



> Since the double bonds rotate in benzene, is there another conformation where the same would be the case, holding a stable rotating type structure within a 2D-planar fixed molecule?



What do you mean by that? The bonds constituting the ring can't rotate for sure, they're not really double bonds either, each carbon atom of the benzene ring has an unhybridized p orbital with one electron in it and these 6 p orbitals create a pi system in which all 6 bonds are equivalent in length.

BTW, a few weeks ago we discussed whether 1-(2,3-dihydro-1,3-benzoxazol-6-yl)propan-2-amine would be a stable compound, I've checked and it might be. Apparently benzoxazoline can be easily made in a similar manner as benzodioxole, no sophisticated methods needed. N-acylbenzoxazolines seem stable with respect to the position between N & O atoms, so plain benzoxazoline should be stable enough to survive subsequent steps in the synthesis towards the target compound.


----------



## Nagelfar

adder said:


> It would make the structure even "more three-dimensional", besides no conformation of cyclohexane is really flat with half of the hydrogen atoms being axial while in aromatics hydrogen atoms are perfectly aligned with the plane of the ring. Aromatic rings usually interact with aromatic rings of amino acid residues (in some cases they can also interact with carboxyl groups, which are also flat, proper substitution with an electron-withdrawing group on the ring is necessary, I guess, as plain alkylbenzene moiety is not electronically predisposed for such an interaction, e.g. cocaine's ester interacting with a tyrosine residue at DAT). It's certainly the case for stimulants related to amphetamine which when bound to DAT has its aromatic ring placed in a region with a few aromatic rings to interact with. Look up propylhexedrine which has mainly adrenergic effects. Wikipedia states it has psychostimulant properties at doses much higher than therapeutic ones, but somehow I doubt it could get any better than levo-methamphetamine at any dose.



Very insightful, I thank you for the time taken in this back and forth to be so clear and thorough with your response.

So as for my original curiousity: are there any other structures like benzene that are flat but even out on the atomic level to be a pure shape such as "pi" (another shape but unusual in the same manner, a idiosyncratic "default" orbit?) anywhere in the literature? Getting into mathematical "real numbers" and such e.g. a pure sphere instead of a (pi) circle? A molecular tesseract? One taking on the golden ratio to exacting dimensions or Pythagoras' theorem or a torus, a Möbius strip molecule? Any examples of eletron quantum entanglement of two places on the same molecule making interesting properties? I suppose it's a loaded and long winded inquiry I made of that. ;p I mean, for a simple answer, anything that *functionally* substitutes for a benzene in most all circumstances, would be what I'm looking for moreso than the novelty seeking I've dished out above.



adder said:


> What do you mean by that? The bonds constituting the ring can't rotate for sure, they're not really double bonds either, each carbon atom of the benzene ring has an unhybridized p orbital with one electron in it and these 6 p orbitals create a pi system in which all 6 bonds are equivalent in length.



I don't mean rotate like "freely-rotatable" (I mean, phenyls rotate the benzene on their methyl branch in 3D if I'm not mistaken). Perhaps I misunderstood how that they "are not really" double bonds (which I knew, but misconstrued?) in my reading up on that some time ago; thus why sometimes benzenes are drawn as a cyclohexane with a plain circle in the middle (to denote that they aren't truly double bonds but such is a convenient way of rendering them). I thought where the double-bonds were didn't matter because they were continually flowing from one bond to the next like a wheel; but if they're just equally bound in "a perfect Pi circle" as a static & stationary structure, that makes sense. But philosophically speaking, the particle/wave dimorphism posits that they are all undulating in perpetual minute permutations continually. (I suppose I am being, yet again, pedantic.)



adder said:


> BTW, a few weeks ago we discussed whether 1-(2,3-dihydro-1,3-benzoxazol-6-yl)propan-2-amine would be a stable compound, I've checked and it might be. Apparently benzoxazoline can be easily made in a similar manner as benzodioxole, no sophisticated methods needed. N-acylbenzoxazolines seem stable with respect to the position between N & O atoms, so plain benzoxazoline should be stable enough to survive subsequent steps in the synthesis towards the target compound.



I'm willing to stake my post count that you're getting a conversation we've had mistaken with anothers on this particular subject; phenethylamines are a class so over expounded upon within the demographic of interests on this particular forum, that I don't even think I've ever discussed any potential or attested one here in depth. (I'm more of a DRI & opioid guy than empathogen & DRA aficionado)

BUT, anybody care to draw a random molecule inspired by this beaut? -> 3-(dimethylamino)-2,2-dimethyl-1-phenylpropan-1-one (super-simple 1-step synth opioid)


----------



## pharmakos

aren't all the bonds in benzene technically 1.5pi bonds?


----------



## clubcard

Thanks for putting that up, N. I had to do U47700 and it was sheer hell. They KNEW it was important but were concerned that only PRIMARY sources were referenced. I mean - THAT IS ALL THAT'S OUT THERE!
I would strongly recommend that you also add Lednicer's parent compounds for BDPC. 4-(dimethylamino)-4-(4-methylphenyl)cyclohexan-1-one & 4-(4-bromophenyl)-4-(dimethylamino)cyclohexan-1-one were both equipotent. I asked him why he hadn't tried MDPC... and he said that he simply forgot! WHY a bromine & methyl worked equally well for the simple cyclohexanones is a mystery - but an interesting one.

I really think you should obtain a copy of Chemoffice by hook or by crook. I want us all to be able to just use SMILES to transfer compounds and the IUPAC name is generated. I don't know how much the student edition costs but it's like Word for the PC. Yes, there alternatives but even in The Ukraine, they use it, allowing me to describe compounds to them. I know it isn't cheap, but when you have it, you will wonder how the hell you managed before.

It calculates minimum-energy conformations and allows 3D overlays. The patent I posted concerning the 'reversed ester' of nortilidine has to be seen... especially when the active isomer of cypenamine overlays perfectly. I've heard Dutch, Belgian & German people say that they take tilidine before an exam because it lets you focus. No surprise when you realize it's increasing the amount of dopamine into the body via 2 different actions. OK, it's too much work but it's fun to work out a chiral synthesis. I spent a full day on it and I was pretty proud of myself... well, not pride, more like seeing what nobody else has seen, EVER within the synthesis.

Medicinal chemistry is an art AND a science. People like Adder are good examples of brains and creativity.

BTW it appears in one years 'Journal of Medicinal Chemistry', I will dig it out for you. But you have to admit, 1-step name-reaction.


----------



## Dresden

Thought I'd draw out those structures you mentioned if you don't mind.  It makes me happy.  






4-(4-bromophenyl)-4-(dimethylamino)cyclohexan-1-one






4-(dimethylamino)-4-(4-methylphenyl)cyclohexan-1-one.

This next molecule was designed so that I could draw out another cool looking new molecule; from a pharmacologically predictive standpoint here, however, it is more likely to elicit groans.  Just remember why I drew it (Because I like to draw pictures of random molecules!!!):






This is my favorite thread EVER!  Thanks roi for introducing me to http://opsin.ch.cam.ac.uk!


----------



## Nagelfar

clubcard said:


> Thanks for putting that up, N. I had to do U47700 and it was sheer hell. They KNEW it was important but were concerned that only PRIMARY sources were referenced. I mean - THAT IS ALL THAT'S OUT THERE!
> I would strongly recommend that you also add Lednicer's parent compounds for BDPC. 4-(dimethylamino)-4-(4-methylphenyl)cyclohexan-1-one & 4-(4-bromophenyl)-4-(dimethylamino)cyclohexan-1-one were both equipotent. I asked him why he hadn't tried MDPC... and he said that he simply forgot! WHY a bromine & methyl worked equally well for the simple cyclohexanones is a mystery - but an interesting one.



Put it on the BDPC page:

https://en.wikipedia.org/wiki/BDPC#Structure-activity_relationships



clubcard said:


> I really think you should obtain a copy of Chemoffice by hook or by crook. I want us all to be able to just use SMILES to transfer compounds and the IUPAC name is generated. I don't know how much the student edition costs but it's like Word for the PC. Yes, there alternatives but even in The Ukraine, they use it, allowing me to describe compounds to them. I know it isn't cheap, but when you have it, you will wonder how the hell you managed before.



My issue is that I don't have either a phone, computer, or internet connection WiFi or otherwise, I come to the library to use the computer on an almost daily basis. Five years as a street junkie took it's toll, now I got into a program where the gov't pays my rent, otherwise I'd probably be still under a bridge chasing the chemicals I am talking about. ;p


----------



## Nagelfar

Strobamine + " 7-(((1R,3r,5S)-9-Azabicyclo[3.3.1]nonan-3-yl)oxy)-2H-chromen-2-one " + C2-acetyloxy-cocaine

Some pretty good affinities, wonder if they gimp one another when put together?

Reminds me of some alternate drawings of some morphinans, e.g. 3-ethoxy-7,8-dihydro-morphinan-6-one as below:






EDIT:

So I started with the above two, hit the automatic clean up key, and got this hot mess:






As garbled lookin' as a neurotoxin

EDIT#2, also:

G-130 + 6-methyl-phenmetrazine + etc. = "2,2,3,3,5,5-hexamethyl-6-phenylmorpholine" add a crazy isomerism and get:






...as you can see I've been bored today and spending far too much time @ the library


----------



## SONN

anyone ever heard of an n-feruloylserotonin?






I wonder if you could stick a number of other tryptamines where the serotonin is? the study on n-feruloylserotonin said it had selective effects on stress in rodents, who knows what it does to humans but its in a number of preworkout supplements, including mine probably (considering theres carthamoides extract in mine)

I'd love to know if anyone finds any intriguing info on n-feruloylserotonin or related compounds


----------



## Dresden

RC fodder.






2C-SHIVA, a known stimulant but not, reportedly, a psychotomimetic.


----------



## SKL

Dresden said:


> RC fodder.



Does it have a name? Can we call it mescalone?



> 2C-SHIVA, a known stimulant but not, reportedly, a psychotomimetic.



That looks kinda interesting.


----------



## Nagelfar

SONN said:


> anyone ever heard of an n-feruloylserotonin?
> 
> 
> 
> 
> 
> 
> I wonder if you could stick a number of other tryptamines where the serotonin is? the study on n-feruloylserotonin said it had selective effects on stress in rodents, who knows what it does to humans but its in a number of preworkout supplements, including mine probably (considering theres carthamoides extract in mine)
> 
> I'd love to know if anyone finds any intriguing info on n-feruloylserotonin or related compounds



According to a quick search, it's found in safflower seed? I added a very meager stub of it to WP


----------



## neurotic

Dresden said:


>



What about an alpha methyl homologue of that??? Seems promising enough to me. The a-methyl doesn't get in the way of psychedelic activity... (Most?) DOx are even more potent than their 2-Cx counterparts, and that beta keto group doesn't seem to get in the way of 5-HT2a agonism either (thinking of BK-2C-B... It is not a very potent drug though...)





Looks sexy too...


----------



## pharmakos

SKL said:


> mescalone



lol'd


----------



## Dresden

Sure, you can call it whatever you want!


----------



## roi

Wouldn't bk-mescaline have a dose of like 3g+? lol


----------



## sekio

I suspect it's been made already.


----------



## neurotic

roi said:


> Wouldn't bk-mescaline have a dose of like 3g+? lol



the alpha-methyl could make it more potent though, if we extrapolate from the potencies of DOB (which at 1mg of the R-isomer produced a +++ according to Shulgin in PiHKAL) vs. 2C-B vs. BK-2C-B


----------



## roi

TMA is far from DOB potency, but yeah, the cathinone should definitely be much more potent than bk-mesc.


----------



## Dresden

I was thinking maybe around one gram.


----------



## Nagelfar

psychoactive (putatively) with the minty taste of camphor and vanilla.

Also comes in menthol:






Move over bromin/ketone stinky, bad taste in back of throat, chemicals. Welcome refreshing, cool breeze of that refreshing taste bud and olfactory soothing aromatically non-noxious drug. 

That &:






Like I *wasn't* going to make Dimethylaminopivalophenonebenzoylmethylecgonine.


----------



## Midnight Sun

I'm one of the minority who likes dichloromethylphenidate for what it is, a long lasting super functional stimulant... the idea with the propyl ester is to make it so big and floppy it no longer hits 5HT2b.  though if dichlororitalinic acid is the culprit this is kind of in vain


----------



## aced126

Midnight Sun said:


> I'm one of the minority who likes dichloromethylphenidate for what it is, a long lasting super functional stimulant... the idea with the propyl ester is to make it so big and floppy it no longer hits 5HT2b.  though if dichlororitalinic acid is the culprit this is kind of in vain



Very good idea indeed. I have a strong suspicion that the ring substituents play the major role in binding to 2b. So you're right, the alkyl group will likely reduce affinity for 2b. Although we need to compare that to reduction of DAT binding; if more affinity is lost at DAT than at 2b, it is futile. Can anyone suggest why 3,4-dcmph has a long half life compared to mph? I thought they would both undergo ester hydrolysis, which wouldn't be affected by the ring substituents would it?


----------



## crmt28

Here's a bizarre one. No idea what it will do. Very likely inactive, but it's a random molecule!

2'-Cl-3'-MeO-3-Oxa-PCP






It's supposed to look like a phenethylamine. But if you want to go even crazier with something like 2C-C:

3-Oxa-4'-Cl-2','5-DiMeO-PCP (it just rolls of the tongue!)


----------



## Midnight Sun

aced126 said:


> Very good idea indeed. I have a strong suspicion that the ring substituents play the major role in binding to 2b. So you're right, the alkyl group will likely reduce affinity for 2b. Although we need to compare that to reduction of DAT binding; if more affinity is lost at DAT than at 2b, it is futile. Can anyone suggest why 3,4-dcmph has a long half life compared to mph? I thought they would both undergo ester hydrolysis, which wouldn't be affected by the ring substituents would it?



Well, the general consensus for ring-unsubbed methylphenidate analogues seems to be that to a point, lengthening the ester increases affinity for DAT and decreases it for NET.  So it should work, very well actually, because 3,4 DCMP is way too fond of NET.  Furthermore the longer chain might bring potency to a more reasonable level.

as for the other question it's something I've pondered my own self... It's my guess that the 2 chlorines are interfering with hydrolysis, though I don't know how

Who was the guy who posted the MPH analogues with the piperidine ring tightened into a pyrrolidine?  I liked the idea of that one...


----------



## Nagelfar

Shortened the tropane, don't know why. I think such has been shown to be ineffective.

But I wonder if this has ever been done:






EDIT:






^Someone, does the above break any rules? Would it be stable at all?


----------



## aced126

Dresden came up with pyrrolidine subbed into mph, but I'll take credit for the idea of introducing the ring into amph

Hydrolysis into 3,4-dcmph acid would terminate all CNS effects I'm guessing, but that doesn't mean the molecule can't hit the 2b receptors in the heart which arent guarded by a BBB. Nevertheless the acid would have a short half life before it's quickly excreted I think, so I would bet that even if it did have 2b affinity, it would be short lived agonism. It's pretty interesting how a tfm group in norfenfluramine increases 2b activity several fold over amph which is pretty much negligible, as well as 5ht releasing effects. I think in terms of binding interact, once the nitrogen picks up a proton it will interact with a negative residue, but an electron rich aromatic binds weakly. Once electron density is removed from the ring, better interactions will occur (ie the electron deficient aromatic repels less) and so greater 2b affinity is the result. With that being said, could one of the chlorines in the molecule be substituted with a methoxy? The idea here is to still block the transporters, but add electron density to the ring to remove 2b affinity. It'll make the ring more prone to hydroxylation but that doesn't happen anyway, so I can't comment on the new half life. As for neurotoxicity of the o demethylated metabolite, I don't think it will enter the neuron ( I don't think ritalin does anyway, correct me if I'm wrong, maybe it just doesn't block vmat 2 and agonise taar1). I think all it's gonna do is sit on the transporter and block it, and this is going to stop say dopamine entering the 5ht cell, so I guess it's similar to how fluoxetine is hypothesised to be neuroprotective post SRA administration.


----------



## aced126

Nagelfar, your first molecule could be a pretty effective reuptake inhibitor. It looks very similar to methylphenidate/methamph and is likely to bind to dat, SERT and net with reasonable comparative affinity I'd say. I wonder if replacing the oxygen with a sulphur would increase half life.

I couldn't possibly comment on whether the last molecule will be stable or not as I don't have high enough knowledge of chemistry. All I could suggest is the possibility of the double bonds attacking something positive.


----------



## aced126

Replaced chloro with fluoro to reduce clogP to 2.43 (predicted with molinspiration.com, uncertainty around +-0.5), clubcard wil appreciate lol


----------



## Nagelfar

aced126 said:


> I couldn't possibly comment on whether the last molecule will be stable or not as I don't have high enough knowledge of chemistry. All I could suggest is the possibility of the double bonds attacking something positive.



I'm using the Benzoyl*thio*methylecgonine (sulfur instead of oxygen) but with a hydrogen (so more, instead of less, putative electronegativity) to allow a bond both like the 3β-Alkylphenyltropane analogue 224d & e together (both have better affinities than the parent cocaine, but the latter one has better uptake selectivity and the former worse, but both are better IC50s)


----------



## white55

desmethyltriazolam - likely to be slightly less potent and longer lasting






nitrazolam - likely a good and strong hypnotic (but not crazy strong), perhaps a bit euphoric







flualprazolam - stronger and more hypnotic alprazolam, somewhere between triazolam and alprazolam imo







flunitrazolam - flunitrazepam only better, really hope they make it







pynazolam - supposedly an extremely euphoric pyrazolam analog


----------



## Nagelfar

white55 said:


> desmethyltriazolam - likely to be slightly less potent and longer lasting
> 
> 
> 
> 
> 
> 
> nitrazolam - likely a good and strong hypnotic (but not crazy strong), perhaps a bit euphoric
> 
> 
> 
> 
> 
> 
> 
> flualprazolam - stronger and more hypnotic alprazolam, somewhere between triazolam and alprazolam imo
> 
> 
> 
> 
> 
> 
> 
> flunitrazolam - flunitrazepam only better, really hope they make it
> 
> 
> 
> 
> 
> 
> 
> pynazolam - supposedly an extremely euphoric pyrazolam analog



heh, a user on WP has a personal page that, is, perhaps meant to be a list made in the future at the following link. It has those you've mentioned above. It gives pIC50 & IC50s and CAS & PubChem #s. Nice resource.


----------



## Nagelfar

Nagelfar said:


> ^Someone, does the above break any rules? Would it be stable at all?








Don't know why, but I've always wanted to go the *other way* with the benzoyloxy than the phenyl/simplifying route. And there are a few analogues which make a more effective compound in that direction seem viable.


----------



## white55

Nagelfar said:


> heh, a user on WP has a personal page that, is, perhaps meant to be a list made in the future at the following link. It has those you've mentioned above. It gives pIC50 & IC50s and CAS & PubChem #s. Nice resource.



Awesome.. am I blind or are there no numbers for flunitrazolam  ?


----------



## Midnight Sun

aced126 said:


> Dresden came up with pyrrolidine subbed into mph, but I'll take credit for the idea of introducing the ring into amph
> 
> Hydrolysis into 3,4-dcmph acid would terminate all CNS effects I'm guessing, but that doesn't mean the molecule can't hit the 2b receptors in the heart which arent guarded by a BBB. Nevertheless the acid would have a short half life before it's quickly excreted I think, so I would bet that even if it did have 2b affinity, it would be short lived agonism. It's pretty interesting how a tfm group in norfenfluramine increases 2b activity several fold over amph which is pretty much negligible, as well as 5ht releasing effects. I think in terms of binding interact, once the nitrogen picks up a proton it will interact with a negative residue, but an electron rich aromatic binds weakly. Once electron density is removed from the ring, better interactions will occur (ie the electron deficient aromatic repels less) and so greater 2b affinity is the result. With that being said, could one of the chlorines in the molecule be substituted with a methoxy? The idea here is to still block the transporters, but add electron density to the ring to remove 2b affinity. It'll make the ring more prone to hydroxylation but that doesn't happen anyway, so I can't comment on the new half life. As for neurotoxicity of the o demethylated metabolite, I don't think it will enter the neuron ( I don't think ritalin does anyway, correct me if I'm wrong, maybe it just doesn't block vmat 2 and agonise taar1). I think all it's gonna do is sit on the transporter and block it, and this is going to stop say dopamine entering the 5ht cell, so I guess it's similar to how fluoxetine is hypothesised to be neuroprotective post SRA administration.



I don't think the O-demethylated metabolite would be a neurotoxic issue at all since the ester would probably be hydrolized first.  I'd be interested to see what a methoxy sub would do especially considering I can't think of any stimulant, DRI or DRA, off the top of my head that used a methoxy substitution of any kind that worked, or didn't have substantial side effects (which are already a present issue in DCMP).  That being said, I believe 3-chloro-methylphenidate is described in a patent somewhere and that might be a good place to start, at least to compare to DCMP itself.  3-chloro alone might do what you're talking about right?  removal of one of the chlorines to return electron density to the ring (this part of your post went above my head a little, sorry ) although, if fenfluramine is any indication, 2b likes electronegative things at meta SO that idea might backfire

interestingly enough, there's an abstract out there that demonstrates vanilla methylphenidate to barely tickle 5ht receptors, including 2b. 


unrelated:


----------



## Nagelfar

Nagelfar said:


>



Similar to this "constrained "proline" analog:






Only reason I believed mine wouldn't work, was because of how close the carbmethoxy was to the phenyl

...EDIT:


----------



## sekio

Nagelfar, those sulfur containing compounds don't look feasible. Sulfur acts like oxygen or selenium; it doesn't like to go hypervalent. In fact hypervalent sulfur reagents with methylene groups act to transfer the CH2 to ketones, forming epoxides (Corey-Chayovsky reagent).

The weird disulfide-sulfinic acid thing is also a bit of a head scratcher, my gut sense is that it would fall apart in acid conditions like thiosulfate does.

It's thioethers, sulfoxides, sulfones, sulfates, or nothing. No methylenes, no sulfur atoms with hypervalent oxygens plus a free hydrogen....






> Can anyone suggest why 3,4-dcmph has a long half life compared to mph?



look at logP ?


----------



## aced126

Why would it not work? The carbomethoxy is the same distance to the aromatic in mph?

Midnight, yes oxygen is electronegative and it is in the meta position, and will pull a bit of electron density via inductive effects, however the oxygen has the ability to donate a lone pair of electrons into the aromatic system (resonance effect), and I would presume this to heavily overpower the inductive withdrawing effect. Take phenol for example, the aromatic system attacks electrophiles way easier than just plain old benzene, because the oxygen lone pair is delocalised into the pi cloud.


----------



## aced126

Sorry sekio, I meant to say duration of stimulant action rather than half life. Once the carbomethoxy is hydrolysed wouldn't that kill all stimulant activity? The acid form might stay around in the body for longer but it won't cross the BBB loads?


----------



## roi




----------



## clubcard

Diclazepam was designed for a reason - duration. Anything that has x10 diazepam for ALL it's metabolites is going to be potent. Adding the triazolo reduces duration. People were sold SHITTY green diclazepam (a test batch) at first so it's reputation nose-dived. A 2mg pink diclazepam dissolved under the tongue (BID) will fix a 40mg/day diazepam habit. When the 1,4-benzos are banned - people will be buying these up ASAFP!


----------



## Nagelfar

sekio said:


> Nagelfar, those sulfur containing compounds don't look feasible. Sulfur acts like oxygen or selenium; it doesn't like to go hypervalent. In fact hypervalent sulfur reagents with methylene groups act to transfer the CH2 to ketones, forming epoxides (Corey-Chayovsky reagent).
> 
> The weird disulfide-sulfinic acid thing is also a bit of a head scratcher, my gut sense is that it would fall apart in acid conditions like thiosulfate does.
> 
> It's thioethers, sulfoxides, sulfones, sulfates, or nothing. No methylenes, no sulfur atoms with hypervalent oxygens plus a free hydrogen....
> 
> 
> 
> 
> 
> 
> look at logP ?



Would a nitrogen keep those sulfurs together? I'm just thinking a SH is more electronegative than a plain O, and thinking of benzoylTHIOmethylecgonine, and some of those 8 position sulfur substitutions, but using it on the 3 position bridge.

How's this, the styrene analogues on the 2B and the 3, the benzoyloxy and the carbmethoxy:






Simple enough?


----------



## Dresden

MXE is soon to be illegal here.  Luckily, this one is still "legal."






1-ethylamino-1-(3-methoxyphenyl)-cyclohexane


----------



## clubcard

Look, it's as simple as 8-methyl-3-(4-nitrophenyl)-8-azabicyclo[3.2.1]octane SMILES CN2C1CC(CC2CC1)c3ccc(cc3)N(=O)=O

Only 1 chiral centre, no requirement for an N-O lone-pair interaction. A compound as strong & short-acting as coke BUT with that p-nitro. I don't know if it's better or worse than levamisole-laced coke but gives identical freeze and the same potency. 30mg = 50mg of UK coke so, I'm guessing, the same potency as real coke.

FREEDOM OF SPEECH


----------



## sekio

> Sorry sekio, I meant to say duration of stimulant action rather than half life.



Maybe the greasy compounds just have less affinity for BuChE (butyrylcholinesterase) ?


----------



## Nagelfar

clubcard said:


> Look, it's as simple as 8-methyl-3-(4-nitrophenyl)-8-azabicyclo[3.2.1]octane SMILES CN2C1CC(CC2CC1)c3ccc(cc3)N(=O)=O
> 
> Only 1 chiral centre, no requirement for an N-O lone-pair interaction. A compound as strong & short-acting as coke BUT with that p-nitro. I don't know if it's better or worse than levamisole-laced coke but gives identical freeze and the same potency. 30mg = 50mg of UK coke so, I'm guessing, the same potency as real coke.
> 
> FREEDOM OF SPEECH



Gotcha, no carbmethoxy, OK.

I'm just doin' my thing though:






Checking out my "Interesting simple breakdown" thread, I noticed where it compares pethidine to a stage in the biosynthesis of morphine, and tried to take some of the steps restricting its rotation and adding them to cocaine, to get this:


----------



## aced126

Dunno how stable that peroxide would be


----------



## Nagelfar

aced126 said:


> Dunno how stable that peroxide would be



I think I could've shortened it by one, or maybe a double bond between the oxygens?

Don't know how much of a point there is to it, though forming cocaine into the closest it can get to the morphine skeleton has always been a bizarre fixation of mine. ;-p


----------



## Nagelfar

sekio said:


> Nagelfar, those sulfur containing compounds don't look feasible. Sulfur acts like oxygen or selenium; it doesn't like to go hypervalent. In fact hypervalent sulfur reagents with methylene groups act to transfer the CH2 to ketones, forming epoxides (Corey-Chayovsky reagent).
> 
> The weird disulfide-sulfinic acid thing is also a bit of a head scratcher, my gut sense is that it would fall apart in acid conditions like thiosulfate does.
> 
> It's thioethers, sulfoxides, sulfones, sulfates, or nothing. No methylenes, no sulfur atoms with hypervalent oxygens plus a free hydrogen....








^This more feasible, sek?


----------



## chatsnap

Nagelfar said:


> I think I could've shortened it by one, or maybe a double bond between the oxygens?



2 oxygens with a double bond between them is O2 and won't form any more bonds


----------



## clubcard

8-methyl-3-(4-nitrophenyl)-8-azabicyclo[3.2.1]octane SMILES CN2C1CC(CC2CC1)c3ccc(cc3)N(=O)=O

Just input the above.


----------



## Nagelfar

clubcard said:


> 8-methyl-3-(4-nitrophenyl)-8-azabicyclo[3.2.1]octane SMILES CN2C1CC(CC2CC1)c3ccc(cc3)N(=O)=O
> 
> Just input the above.



Gotcha.






More crab like? Remember bromo-dragon-FLY? Here's piperi-crustacean:






Hope it doesn't mean "cancer". I like it, 'cause it is the most artistic of anything I've done which may actually be functional, and as a DARI at that...


So I took the cocaine 6-alkyl-3-benzyltropanes benzyl type benzene linkage & the N-constrained phenyltropane "42a" (back-bridged tropane with extreme DA affinity) to make this beaut:






These are the kinds I just think would do wonders


----------



## Nagelfar

So I had this nutty idea. You can't do a front fused & a back fused tropane; the nitrogen doesn't allow the bonds, but you have things like desoxypipradrol that use two benzenes, and you have the benztropines that are sandwiched closer, why not two cycloalkane rings instead of the two benzenes, and you have the same basic structure of those desoxypipradrol-type stimulants. Since the fused tropane allows for much greater selectivity than the simple cyclohexane, why not use two *different* fused tropanes connecting to a single benzene?

Both fused rings are used from attested examples, none of my strange splicing of bonds to create weirdness, this looks weird enough all on its own:






Cleaned up:






methyl 4-{[(6R)-6-butyl-1-azatricyclo[5.4.0.0³,⁹]undecan-5-yl](phenyl)methylidene}-2-azatricyclo[4.4.1.0²,⁸]undecane-7-carboxylate

Insanity, or ingenious? (_cf_. these "constrained" PTs)

EDIT:

P.S., came back and re-entered it by name, and it drew it even funkier, hehe:






Anyhow those above three are all the same, here's another one based on a back-bridged & a front bridged (I believe the last one was two back bridged, I can't tell anymore, too turned around with it all):
(2Z)-2-{[(5R)-5-butyl-1-azatricyclo[4.4.0.0²,⁸]decan-4-yl](phenyl)methylidene}-11-methylidene-8-azatricyclo[5.4.0.0⁴,⁸]undecane






"Cleaned-Up":






Re-entered by IUPAC:


----------



## pr0d1gy

I've been looking into ester derivatives of tapentadol lately. Synthesis of tapentadol involves an ester intermediate so it's well documented, but I can't find anything at all about activity or lack thereof. With a propanoate ester the tapentadol seems to bear some similarity to prodine. I'm also interested in morpholine/piperidine derivatives of tapentadol though I think it's quite a stretch. The more I look into it the more I expect that dimethylamino is really the only viable substitution for tapentadol.

I'm more interested in esters of morpholines. I've searched quite a bit and haven't found much. Compounds somewhat similar to above seem to have been investigated as anticholinergic but not much else. Is is crazy to think esters or ethers such as these might have any activity as opioids?


----------



## sekio

This is cubism, not chemistry


----------



## Midnight Sun

is tert-butyl still futile?





this looked prettier in my head


----------



## Dresden

No, tert-butyl 2C is known to be active IIRC.


----------



## Nagelfar

sekio said:


> This is cubism, not chemistry



But taken seriously, the "constrained" variants have much better selectivity for MAT, *much*, something simple piperidines don't have, for example with methylphenidate. I think this is the real golden direction to go for DARIs from what coke can tell us:

The front-bridged (on the double-bond side to the benzene) has a SERT Ki (nM) of 0.06, with NET & DAT @ >10K, and the single bond "back-bridged" one has a DAT activity of 2.23 (nM), if I connected it to the 7 instead of the 6 of the tropane, it'd similarly lower SERT affinity to well below the DAT, but much higher DAT than coke. Being able to associate to one or the other, well, who knows how that'd work. Might have a very interesting subjective effect profile. ;-p

If you don't start from the nitrogen, but from the methyl on the nitrogen's eight position (however, the method for cyclization of the compound may be trickier) you can bridge one tropane skeleton forward & backward, as like:






They also haven't bothered to go to the trouble on the back bridge to connect to both the 6 & 7 positions at once:






if you do both of the above diagrams together, the "front-to-back" bridge has as many bonds as the tropane skeleton itself. ;-p

So...






I think there's two places the benzene can be linked, the usual 3beta and a place on the front bridge, perhaps it can have both and not have the draw-backs of the benztropines


----------



## crmt28

2C-B-DragonFLY.  (Not DOB-DragonFLY/Bromo-DragonFLY)






Why this one was never researched? 2C-B-FLY seems very safe. I don't see much reason for 2C-B-DragonFLY to be unsafe, since the toxicity from DOB-DragonFLY seems to be from the vasoconstriction due to the amphetamine structure.

Playing around with the molecule a bit, we can even see the trypamine ressemblance. So I came with this Dimemebfe/2C-B-DragonFLY hybrid. 






Plus a closed ring version, obviously without fucking around with the alpha-position to avoid potentially deadly substances.


----------



## Hammilton

A heptacyclic (did I miss any?) cycloalkane derivative with a cyclobutyl and two cyclopropyl rings.  Aside from being ridiculously bulky and unable to fit in the binding pocket, does this structure have a name?


----------



## Hammilton

pr0d1gy said:


> I've been looking into ester derivatives of tapentadol lately. Synthesis of tapentadol involves an ester intermediate so it's well documented, but I can't find anything at all about activity or lack thereof. With a propanoate ester the tapentadol seems to bear some similarity to prodine. I'm also interested in morpholine/piperidine derivatives of tapentadol though I think it's quite a stretch. The more I look into it the more I expect that dimethylamino is really the only viable substitution for tapentadol.
> 
> I'm more interested in esters of morpholines. I've searched quite a bit and haven't found much. Compounds somewhat similar to above seem to have been investigated as anticholinergic but not much else. Is is crazy to think esters or ethers such as these might have any activity as opioids?




No, not crazy.  Pretty similar to methadone type opioids of course, but yeah, also not too far removed from some anticholinergics.  I'm not sure of any key structural distinctions that push the activity definitively one way or the other, but perhaps someone can chime in on that subject as I'm sure there's extant knowledge on it.


----------



## Hammilton

Nagelfar said:


> I think I could've shortened it by one, or maybe a double bond between the oxygens?



I don't think such a molecule could form, peroxide bonds already want to spontaneously break apart and release O2.   Methoxyoxymethane does not exist so far as I can tell, and I can't imagine it forming in part of a ring, either.


----------



## clubcard




----------



## clubcard

PLEASE use this http://www.organic-chemistry.org/prog/peo/

and remember Lipinski's Rules of 5


----------



## Dresden

Without going into too much detail, I will say that the left half of this molecule is not currently hard to source at all [Hint:  Open Sesame]:






3-(3,4-methylenedioxyphenoxy)tropane.

Not for this one either, obviously, but that goes without saying:






3-phenoxytropane.


----------



## Dresden

pr0d1gy said:


> I've been looking into ester derivatives of tapentadol lately. Synthesis of tapentadol involves an ester intermediate so it's well documented, but I can't find anything at all about activity or lack thereof. With a propanoate ester the tapentadol seems to bear some similarity to prodine. I'm also interested in morpholine/piperidine derivatives of tapentadol though I think it's quite a stretch. The more I look into it the more I expect that dimethylamino is really the only viable substitution for tapentadol.
> 
> I'm more interested in esters of morpholines. I've searched quite a bit and haven't found much. Compounds somewhat similar to above seem to have been investigated as anticholinergic but not much else. Is is crazy to think esters or ethers such as these might have any activity as opioids?



It seems like to me the methyl group in the middle should be alpha to the N.  But I don't claim to know.

From what I've read, though, the following is "one of the worst drug experiences ever":






2-amino-4-phenylbutane.  
Likely a deliriant?

And when Sasha Shulgin accidentally made this next one (and took some), he wrote--summarized--that it, "Was an extremely weird trip that bore no resemblance to any currently known class of drugs that he had tried":






2-methylamino-4-(3,4-methylenedioxyphenyl)butane.

Since you're looking for tapentadol (Nucynta) like opiates, though, I see why the beta-carbon is methylated and not the alpha-carbon.  How about this one?:






Or this?:






For IV use.

Or this, lol (no, I'm not kidding):


----------



## clubcard

As I have mentioned, you need to find the pharmocore. I think Singh's paper covers many cocaine analogues. All I know for certain is that NO ester is required for activity. If you take other DRIs like amfonelic acid & nomifensine, you should get said pharmocore. Generally, binding is based on:

-lone-pair donor (usually tertiary amine)
-aromatic having an electron-withdrawing group para to the bond through to the amine.

If you remove the aromatic amine on nomifensine, you will see that it's a semi-rigid desoxypipradrol derivative.

FORGET EXP-561. The pKa means that it passes into the brain VERY slowly. It MAY still fit the pharmocore you come up with, but trust me, the pKa leaves under 2% of the compound unionized at the pH of blood.

FREEDOM OF SPEECH


----------



## Dresden

3-(4-nitrophenyl)tropane.

Aromatic nitro compounds are generally not the safest/healthiest option for a drug.  I think 4-chlorophenyl would be preferable or even 4-methoxyphenyl.  In the case of the latter, would it be the paramethoxyamphetamine, which is lethal at much lower dosages than typical amphetamines, of cocaines?  I think I don't want it to test on myself, anyway.  And, yes, I do realize that the nitro group is about as electron withdrawing as they come.

In this forum, for example, it has generally been pretty much anathema to suggest this or its nor-methyl counterpart:






Undeserved reputation or killer death drug in the making?


----------



## roi

A (shitty) attempt at increasing phenibut potency.


----------



## clubcard

Yeeyy - the right isomer, at last. As I explained, the p-nitro was the only one as potent as C & the only one with the duration of C DUE to the nitro being reduced. Reduce it and the LogP drops through the floor and it's looking for watery, not fatty material BUT it would be a very good target for gluconation.

Other analogues (like the trifluoromethyl) were almost as potent BUT didn't give a freeze so were nasty to snort and had a LOOOOOONGGGG duration. The body can remove the N-methyl but it's still going to stay in the brain.

As I have said, the pharmocore is quite simple. The amine spatially relative to the aromatic, A tertiary amine that can donate a lone-pair, the least basic, the better so tertiary amine. That is all that is required. It's finding the same things in Nomifensine & Amfonelic acid that prove this. Often, the lipophilic pocket can fit in larger groups. I guess while looking at the 2 compounds I suggested, people would do well looking at mazindol analogues. Expanding the imidazoline to a piperazine gives x10 more dopamine affinity. Again, aromatic relative to amine.

I read in Pihkal that DON is almost as long-lasting as the halides which shows that a nitro with something ortho prevents reduction. I have a pet-theory CC DON. I think separating the isomers could produce interesting results. One isomer binds to the 5HT2a while the latter is very likely a reuptake inhibitor.


----------



## Hammilton

Have any of you bothered to compare your energy  minimized structures to cocaine or other known DARI?  I don't see why bothering with these ridiculously complex structures if you can't even be added to do a simple overlay.


----------



## neurotic

clubcard said:


> FORGET EXP-561. The pKa means that it passes into the brain VERY slowly. It MAY still fit the pharmocore you come up with, but trust me, the pKa leaves under 2% of the compound unionized at the pH of blood.



Why does a molecule have to be unionized to pass into the brain? I remember reading about this but I don't know why is that so

The trifluoromethyl analogue you speaked of seems like the best option of a stimulant BTW, even if it's not the most similar to cocaine. I mean no topic anesthetic properties means less messing with the heart and longer duration makes it less addicting... Cocaine's duration is what makes it a useless and too addicting drug ime


----------



## crmt28

> And when Sasha Shulgin accidentally made this next one (and took some),  he wrote--summarized--that it, "Was an extremely weird trip that bore no  resemblance to any currently known class of drugs that he had tried":
> 
> 
> 
> 
> 
> 
> 2-methylamino-4-(3,4-methylenedioxyphenyl)butane.



That's an interesting one! That one would be a MDMA analogue of phenpropylamine! I wonder if the  bad effects could come from the alpha-methylation, or the methylenedioxy, and what receptors it hits.

Also, never heard about this one from Shulgin! Was that quote on the full version of PiHKAL?  

Here's the 2C-B analogue from that compound:


----------



## Dresden

It's somewhere in PiHKAL.  Something about piperonyl this or that being sold according to some mistaken identity nomenclature and thusly producing said compound.  Probably in the discussion of one of the MD-drugs somewhere in the second (chemical) half of the book.  I personally haven't read the thing in many years and no longer have a copy, either.

* * * 

In unrelated news, here's one that's likely not scheduled in China and which I wouldn't mind trying either:






Or even:






Though I understand that this one gives people psychotic, suicidal tendencies:






Perhaps the N-ethyl homologue of ibid. would be more forgiving?:






And, with this, I'll end with a likely winner:






I've actually always referred to this last molecule as "GREEN" for no known reason.

P.S.

However, from whisperings heard at the Hive long ago, this PMA derivative is supposed to be a first rate psychedelic.:






Therefore, I think I'll name it HEARSAY.


----------



## Nagelfar

neurotic said:


> Cocaine's duration is what makes it a useless and too addicting drug ime



Ability to repeat subjective *rush* affection from a quick onset route of administration: e.g. intravenous or smoked. I think that's something the cocaine-over-amph taste aims for.


----------



## Dresden

Well, if that feels like cocaine but lasts way longer, then sign me up.
However, I feel like this next one would be better:






DOC illegal now?  No problem!:


----------



## SKL

Somewhat but not quite in this genre is β-CFT ( WIN 35,428 ) ...

I thought of it when long acting cocaine analogs were mentioned. It's a pretty cool drug which I tasted and wrote a trip report/commentary on a ways back.


----------



## flying-potato

4-CMMC ?


----------



## Dresden

Sick of subpar fluoro and methyl phenmetrazines?  Check out this series of O-->CH2 phenmetrazines.:


----------



## Nagelfar

Dresden said:


> In unrelated news, here's one that's likely not scheduled in China and which I wouldn't mind trying either:
> 
> ....
> 
> Or even:








The para-cis-propenyl-amphetamine (lower right), seeing what the _p_-_cis_-propenyl troparil/phenyl-ecgonine does (renders it so as to not bind to NET, but still to DAT & SERT. _cf_ compound (RTI-)"11w").

Also since the cycloalkane on phenmetrazine seems to make it a subjectively more euphorgenic substance than _n_-methyl-amphetamine, but the benzylpiperidines have poor stimulation, how about just tweaking (no pun intended) the ring to a shorter, more amphetaminesque type substance (upper right). Less metabolically labile perhaps as a benefit? The double bond in the middle (lower left), simply because the 3-beta-styrene cocaine analog had such better affinity. The remaining one (upper left) just incase the QSAR requires that instead of the _para_ position.



SKL said:


> Somewhat but not quite in this genre is β-CFT ( WIN 35,428 ) ...
> 
> I thought of it when long acting cocaine analogs were mentioned. It's a pretty cool drug which I tasted and wrote a trip report/commentary on a ways back.



Thank you for that, missed it the first time through. Nice to see some colloquial input on these kind of compounds.


----------



## white55

1p-dmt... would the same trick that works for lysergamides work for tryptamines?


----------



## Solipsis

I actually thought of that right when 1P-LSD became available but I realized a problem: 1P-LSD itself cannot be active according to Nichols, it must be depropionylated. If 1P-DMT is administered, will the propionyl group be cleaved before MAO noms up the DMT? Perhaps but it does seem like a possible kinetic contraindication.

More substituted or N-bulkier tryptamines should work great though, they don't have that window of opportunity involved for DMT...

Then again IM DMT worked for nearly 45 minutes, 20 of which very psychedelic involving entities.. about double the duration of vaped for me. Maybe it could work.


----------



## roi

Solipsis said:


> I actually thought of that right when 1P-LSD became available but I realized a problem: 1P-LSD itself cannot be active according to Nichols, it must be depropionylated. If 1P-DMT is administered, will the propionyl group be cleaved before MAO noms up the DMT? Perhaps but it does seem like a possible kinetic contraindication.
> 
> More substituted or N-bulkier tryptamines should work great though, they don't have that window of opportunity involved for DMT...
> 
> Then again IM DMT worked for nearly 45 minutes, 20 of which very psychedelic involving entities.. about double the duration of vaped for me. Maybe it could work.



http://onlinelibrary.wiley.com/doi/10.1002/dta.1884/abstract

While 1P-LSD shows only 38% the potency of LSD in mice, LSD is detected via LC-MS when 1P-LSD is incubated in human serum. So it seems to act as a prodrug for LSD in humans after all?


----------



## white55

Solipsis said:


> I actually thought of that right when 1P-LSD became available but I realized a problem: 1P-LSD itself cannot be active according to Nichols, it must be depropionylated. If 1P-DMT is administered, will the propionyl group be cleaved before MAO noms up the DMT? Perhaps but it does seem like a possible kinetic contraindication.
> 
> More substituted or N-bulkier tryptamines should work great though, they don't have that window of opportunity involved for DMT...
> 
> Then again IM DMT worked for nearly 45 minutes, 20 of which very psychedelic involving entities.. about double the duration of vaped for me. Maybe it could work.



Makee it 1p-4-ho-dmt or 1p-4-ho-met then  Anyway well known vendor thought it as a good idea and said they'll look into it.


----------



## roi

Inspired by metabolites of tert-butyl-cathinones:


----------



## white55

desmethyltriazolam - longer lasting triazolam (same way as metizolam is a longer lasting etizolam)






ethoxetamine






1p-eth-lad






3-methylbutyrfent


----------



## roi

3-methylbutyrfent already exists. Supposed to be identical to butytrfentanyl, just 10x more potent.

http://www.bluelight.org/vb/threads/759536-Novel-opioid-3-Methylbutyrfentanyl


----------



## roi




----------



## Solipsis

roi said:


>



whats that modeled on?


----------



## roi

https://en.wikipedia.org/wiki/Azaprocin

With these modifications it should be ~50x morphine.


----------



## Dresden

Might be dangerous.  Nonetheless, a brilliant concept--don't get me wrong.


----------



## roi

Should be a MDMA prodrug.


----------



## SKL

4-MAR analogues anyone?

I only had access to 4-MAR once, and I have to say it was amazing, not very good for you apparently, but one of the few over-hyped drugs that lived up to the hype.

Stimulus properties of some analogues of 4-methylaminorex. - PubMed - NCBI http://www.ncbi.nlm.nih.gov/pubmed/7667356

4,4'-dimethylaminorex via EMCDDA (apparently this has circulated in Eastern Europe at least)

As suggested by another Bluelighter here, 2-flouro-methylaminorex? 

2,4-dimethylaminorex? 4-ethylaminorex? (apparently some people have tasted this one)


----------



## crmt28

I'm not a specialist, but isn't that benzyl cyanide attached to the amine? I feel like this could have some toxicity issues. According to Wikipedia, benzyl cyanide produces hydrogen cyanide when burned.

(And trust me, people will try to smoke it)


----------



## roi

Not that many people smoke MDMA!

Attemppt at a sane potency fentanyl analogue with longer duration:


----------



## neurotic

i've been thinking about fentanyl too these last few days...






here's one based on carfentanil. just tweaked it a little in an attempt to stop obvious metabolic attacks. that bridge where it was the phenethyl was daring but who knows... carfentanil is pretty potent


----------



## Dresden

roi said:


> Not that many people smoke MDMA!
> 
> Attemppt at a sane potency fentanyl analogue with longer duration:



That looks something like Zantac.


----------



## crmt28

N,N-di(trifluoromethyl)tryptamine /  N-methyl-N-trifluoromethyltryptamine
DTFMT / MTFMT. 

Is that possible? I wonder why nobody ever tried to put any halogen in there. Fluroine seems small enough to me, but I'm no chemist.


----------



## Dresden

I don't know if those can exist or not, but these two sure could:






and






These next ones probably don't do anything much, but you never know.  Possible alien neurotransmitters.

The Melatonin Series:


----------



## Midnight Sun

An effort to introduce the DET skeleton into LSD.  I guess in a way it really isn't, though.  More like EiPT if you ignore everything else.  Random molecules right?


----------



## Dresden

It's hard to say without testing it, but the synthesis looks really really hard.  It would have to be made from scratch if what I'm thinking is right.  But I don't want to discuss synthesis of course.

I think this LSD analogue looks interesting though:






12-CF3-LSD.

On second thought, this one looks much yummier:






BAM!  Note the DMT and MDMA pharmacophores in one molecule.


----------



## aced126

neurotic said:


> i've been thinking about fentanyl too these last few days...
> 
> 
> 
> 
> 
> 
> here's one based on carfentanil. just tweaked it a little in an attempt to stop obvious metabolic attacks. that bridge where it was the phenethyl was daring but who knows... carfentanil is pretty potent



If the rigidified structure is in the correct binding conformation it could increase affinity by degrees.


----------



## aced126

Dresden said:


> I don't know if those can exist or not, but these two sure could:



Why do you think so? The aromatic nitrogen won't attack anything because the lone pair is involved in aromaticity isn't it? So just trifluoromethylation of the aliphatic amine.


----------



## aced126

Dresden said:


> BAM!  Note the DMT and MDMA pharmacophores in one molecule.



Something makes me think this could block SERT really well.


----------



## crmt28

Uh, no idea what to call these tryptamine/phenethylamine hybrids. Inspired by lysergamide.


----------



## Dresden

aced126 said:


> Why do you think so? The aromatic nitrogen won't attack anything because the lone pair is involved in aromaticity isn't it? So just trifluoromethylation of the aliphatic amine.


I can't think of a reason why they couldn't exist, but I also haven't seen any before, and I've been at this for 20 years now.  Like I said, I just don't really know for sure either way.


----------



## Solipsis

Isnt it because of the same reason why 2C-D with a chloro on the para methyl isnt stable?
I forgot the mechanism of degradation reactivity unfortunately.. 
Fluoro might be exception as leaving group.. Also its only with methyls apparently cause 2C-EF is a thing..

Am i way off here?

I might be confusing this with terminal halo or chloro alks being toxic..?

Or the fact that simply chlorinating 2C-D with UV light via radicals is unfortunately not a good idea..

Sorry to confuse..

I just thought something isosteric to 2C-E but analogous to 2C-D and 2C-C was a good idea..

: (

Edit:
Forget what i said : p
Apparently primary and secondary amines can be trifluoromethylated in good yield
using this 20b reagent:
http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-6-65

Protect the indole N first though right?


----------



## pharmakos

would you want that end of the molecule to be that electronegative?


----------



## neurotic

aced126 said:


> If the rigidified structure is in the correct binding conformation it could increase affinity by degrees.



where's clubcard when you need him


----------



## aced126

N indole doesn't need protecting I don't think, because the lone pair isn't available as a nucleophile because it is participating in forming the aromatic indole cloud. Halo alks could be toxic alkylating agents however the heavily electronegative trifluoro group should shield the carbon from nucleophilic attack. Furthermore fluorine is the worst halogen leaving group because it is so small, making it less able to delocalise the negative charge it gains if it leaves.


----------



## belligerent drunk

aced126 said:


> N indole doesn't need protecting I don't think, because the lone pair isn't available as a nucleophile because it is participating in forming the aromatic indole cloud. Halo alks could be toxic alkylating agents however the heavily electronegative trifluoro group should shield the carbon from nucleophilic attack. Furthermore fluorine is the worst halogen leaving group because it is so small, making it less able to delocalise the negative charge it gains if it leaves.



You're right about the nitrogen in the indole. It usually is protected though, just as a precaution, but normally it needs activation with a strong base (hydride for example) to deprotonate it, so the nucleophilicity is greatly increased (I hope I'm not going into synthesis discussion here, if I am, I apologize) for it to participate in a reaction. AFAIK trifluoromethyl moiety does not behave as an alkylating agent, and yes fluoride is the worst leaving group. Perfluoroalkanes are an interesting class of molecules, chemically very inert and typically not keen on interacting with anything.


----------



## crmt28

Silly bonus molecule.

N,N-Diperfluroisopropyltryptamine. (Tree-ptamine)


----------



## aced126

belligerent drunk said:


> You're right about the nitrogen in the indole. It usually is protected though, just as a precaution.



As you said the only way it can be protected is by addition of a strong base first for deprotonation. Why add 2 steps when you know that the trifluoromethylation conditions doesn't require base? The only way a trifluoromethyl group will get on the indolic nitrogen is if while trifluoromethylating you add base. I just read Solipsis' link, and it seems like you don't need a strong base.

https://en.wikipedia.org/wiki/Trifluoromethylation#Electrophilic_trifluoromethylation

In one of the pictures it shows a TFM group adding onto the sulphur and not onto the nitrogen, with 97% yield. If it's selective for that then I don't think TFM will be adding onto the indolic nitrogen in DMT.


----------



## adder

If you put two TFM groups on the nitrogen's amine, then you decrease its basicity by withdrawing electron density and thus likely lower affinity.


----------



## Solipsis

Also, won't it be so polar that it has a harder time entering the brain? Vaped DMT is a fantastic flash, but to be honest I think the kinetics are way too fast. Things like 4-AcO-DMT have a much more reasonable pace, helps with having a more meaningful experience.. Then again slow acting less potent versions of DMT may not be overwhelming enough for MAO?

I have no idea if the trifluoros prevent MAO breakdown..

[Maybe this synth talk is exceeding a bit if we would keep going? ^^]

Had this morph-AMT idea but it's apparently unpromising:


----------



## crmt28

Alpha-methylated tryptamines are indeed mostly unpromising. Maybe the beta position would be a better choice?

3-(2-morpholinyl)-indole 






It actually already exists and even has a CAS number. But absolutely no papers explaining what it does. Interesting!


----------



## aced126

adder said:


> If you put two TFM groups on the nitrogen's amine, then you decrease its basicity by withdrawing electron density and thus likely lower affinity.



True that, assuming the charged nitrogen interacts with a negative residue, which is very likely. With that logic, will electron donating substituents increase potency? N-monomethyltryptamine would have a much more basic nitrogen yet it seems to have similar potency to DMT. How can those results be explained? Maybe having a hydrogen donor reduces potency by creating unfavourable interactions. Maybe it is metabolised quicker.


----------



## crmt28

That's what I'm hoping for! Orally active and equipotent to DMT. It would be simply amazing. 

In case two TFM groups end up reducing potency, we can also have the N-Trifluoromethyl version alongside.  So we have NTFMT, MTFMT and DTFMT.

If it doesn't work very well, we'll always have the 4-AcO-DMT counterpart too!


----------



## aced126

Solipsis said:


> Also, won't it be so polar that it has a harder time entering the brain?
> 
> I have no idea if the trifluoros prevent MAO breakdown..



I don't know whether it would be more or less polar. The thing is, when you add a fluorine substituent onto benzene, it gets slightly more lipophilic, but when you add it onto an aliphatic carbon chain, it gets slightly more hydrophilic. I guess one would just have to make this and experimentally determine logP. If the fluorine was a chlorine or bromine instead, then that would very likely make the molecule much more lipophilic, as chlorine or bromine substituted onto benzene or aliphatics increases lipophilicity much more than fluorine. 

Used this website to predict logP for indole, dmt and d(TFM)t. Predicted 2.16 for indole, and experimental value is 2.14 suggesting the prediction for these compounds would be relatively accurate.

For dmt it predicted 2.30
d(TFM)t was 4.12 surprisingly. Very high. As expected, it predicted 5.97 and 6.76 respectively for the chloro and bromo derivatives. Can anyone more advanced in chemistry explain why logP was increased by so much. I'm not too sure really on why fluorine increases logP slightly on benzene but decreases it slightly on an aliphatic. I'd be grateful for a nice explanation.

As for metabolism, all I could speculate was that it would increase half life. 

http://www.nature.com/nrm/journal/v13/n5/fig_tab/nrm3327_F1.html

So obviously taking a big assumption here that demethylation by MAO works in a similar way to the enzymes described above in histone demethylation. Someone studying/with a degree in biochemistry here please correct me if wrong. 
In reaction a), it seems that the molecule of oxygen gets one hydrogen from the methyl group to be removed and one from the charged nitrogen. Well if the methyl group had 3 fluorines on it, then the oxygen would have to attack the fluorine. As far as I know that would make for an unstable compound. The wiki page on dioxygen difluoride says it reacts nearly every chemical it encounters. So that would suggest dioxygen monofluoride monohydrogen is of similar reactivity and would not be likely to form as much as hydrogen peroxide when metabolising normal DMT. 

For reaction b), I would suspect the addition of a hydroxyl onto the TFM would be hard, and furthermore when that moiety leaves to form difluoroformaldehyde, well... I can't even find any information on that chemical. So yeah my gut instinct is it would really increase half life.


Just thinking about it now, this compound would have a high logP and increased resistance to MAO. So maybe it could be oral and equipotent to DMT (less affinity but hopefully increased logP makes up for it).


----------



## belligerent drunk

Solipsis said:


> Also, won't it be so polar that it has a harder time entering the brain? Vaped DMT is a fantastic flash, but to be honest I think the kinetics are way too fast. Things like 4-AcO-DMT have a much more reasonable pace, helps with having a more meaningful experience.. Then again slow acting less potent versions of DMT may not be overwhelming enough for MAO?
> 
> I have no idea if the trifluoros prevent MAO breakdown..
> 
> [Maybe this synth talk is exceeding a bit if we would keep going? ^^]
> 
> Had this morph-AMT idea but it's apparently unpromising:



What molecule do you have in mind with the polarity? Two trifluoromethyl groups won't make it more polar.

To aced, I'm not really sure why the logP increases so much for the TFM derivative. It could be because DMT can be a much more significant hydrogen bond acceptor at the tertiary nitrogen than DTFMT, because the TFM groups are quite bulky plus they lower the basicity of said nitrogen. You have to remember though that at physiological pH the nitrogen is protonated so the latter has no effect, I'm not sure if the program takes that into account. TFM groups are, I would say, on the non-polar side of things; yes, fluorine is very electronegative, but still the negative charge is quite diffuse in TFM even with fluorine atoms, so the relatively non-polar bulkiness could add to the lipophilicity? I'm not entirely sure of that, could be wrong - I don't really know how polar/non-polar TFM group is, just speculating.

I don't really have a good explanation for the difference between fluoroaryl and -alkyl logP behaviour. Maybe because the electron pair on fluorine resonates with the aromatic ring? Not an expert in chemistry, so maybe someone who knows what they're talking about could chime in.

As for the metabolism of the N substituents, C-F bond is hard to break, fluoroalkanes are very unreactive. Neither reaction would work. So yes, that would increase half-life.


----------



## Nagelfar

3β-diaryl-thiophene/furan 2β-isoxazole back-tropane-bridged phenyltropane/cocaine-analogue


----------



## Midnight Sun

Dresden said:


> It's hard to say without testing it, but the synthesis looks really really hard.  It would have to be made from scratch if what I'm thinking is right.  But I don't want to discuss synthesis of course.



Yeah no kidding, but this is the random molecules thread not the commercially viable ones  










(ignore the highlighting there)


----------



## roi

48 hour energy:


----------



## Nagelfar

roi said:


> 48 hour energy:



_p_-fluoronated desoxypipradrol?

I still think, if I had time to try out many different models in 3D, that making the cycloalkane with nitrogen in a more constrained "boat" formation would be best, since those seem to optimize binding with the cocaine analogues with which it is easiest to begin with as a starting compound for those as semi-synthetics, but what if we tried with the above, or say, MPH?

This is me shooting in the 2D dark, someone with time might want to align the below "boat" ring to a back-bridged phenyltropane, make sure the nitrogen winds up in roughly the same spot:






The way the ring is torsioned has a lot to do with it. But there's an attempt at making something more "form-fitted" like hand in glove, to MAT


----------



## Dresden

Much more activated ring system than 5-Br-DMT (which is now on the market):






Yes, this one's clever.

* * * 

In other news, 






I can almost taste it!!!  The thought of a psychedelic opiate (like pentazocine, I guess) turns me on.  Note the MMDA pharmacophore.

This is MMDA, for those of you who don't know or remember:






MMDA is very sedating and thusly is best combined with methamphetamine.  However, in an opiate that's good.  Also, note the 6-acetoxy (a la heroin) group, making this one an IV drug.  If you don't want an IV drug, then I would suggest:






This one should be good orally.


----------



## aced126

What's the rationale behind the 6-acetoxy group? It's not really necessary for opioid activity and will most likely hinder psychedelic activity so I'd say it would better be left out. Same for 6-ketone.


----------



## Dresden

Well, these structures are based on morphine, and morphine has a 6-OH but a 6-oxo or a 6-acetoxy can be derived from the hydroxy, and both make the entire molecule get into the brain much better than if morphine's 6-OH was just left there.  Since these two molecules would likely be made from scratch, I guess you're right though.  I was kind of always under the impression that they were necessary for activity or helped it somehow, but hey, my specialty is the amphetamines, not the opiates.  Amphetamines are delightful and amenable to so many structural changes.


----------



## SKL

Total noob question, I had O-chem well more than a decade ago and Pharmacology (not to any really advanced classes much less degree in either) not soon much thereafter, although I have tried to keep up on both informally, yeah, a lot escapes me, but whenever something does, I try to learn it so as to add to my fund of knowldge ... in ADD I always figure even if I grok 10% it's a good 10%, so I read ... but in terms of simple technical stuff could I just ask which chemical drawing software y'all are using to draw these molecules? 

I have tried a few different ones both online in-browser for Linux and they don't make as pretty pictures and are a bit of a pain in the ass. You all seem to be using the same thing and it's probably Googleable but I'd like to know so I could present of my thoughts (like I was saying before about 4-MAR analogs) more visually....


----------



## Dresden

Great question!  

http://opsin.ch.cam.ac.uk

You have to be able to sort of be able to name what you are trying to draw, and you will need to read the instructions I gave about 10 pages back in this thread for using it.  It just involves some copying and pasting, creating a website for your drawing, copying that url, and pasting it into here between a URL and a /URL (but with square brackets around them!) before posting it here on bluelight.

Other people prefer MarvinSketch.  YMMV.  Good luck!  Opsin is great once you get the hang of it.  If you get stuck and have questions, just ask.

Aw, shucks, let me just run down how to do it:

-go to above website
-erase 2,4,6-trinitrotoluene from the entry screen and type "2-methylamino-1-phenylpropane"
-press enter
-see your structure
-copy the name of the structure in the box above the drawing using your computer's Copy function
-in the address bar, type http://opsin.ch.cam.ac.uk/opsin/ Paste "2-methylamino-1-phenylpropane" which you just copied followed by .png immediately after the "e" in propane
-press enter, the computer will take you to a new url with just your molecule drawn on it
-copy the entire address bar of the url using the Copy function
-return to this thread in bluelight
-make a post with [ then URL then ] then Paste then [ then /URL then ] with no spaces anywhere
-press enter 
-Viola, your molecule is online for the world to see!!!


----------



## crmt28

What about this one? Both the 2-EtO and methylthio analogues are weaker than the regular 2Cs. A trifluoromethoxy group wouldn't be too big and might even produce interesting results.


But let's not get overboard with fluorine or we might contribute to ozone depletion


----------



## Dresden

How many of us have ever seen an Ar-O-CF3 (Ar-O-CH2CF3, yes) or an R-NF2?


----------



## doctordetox

lol


----------



## crmt28

Dresden said:


> How many of us have ever seen an Ar-O-CF3 (Ar-O-CH2CF3, yes) or an R-NF2?



Never seen it anywhere. I thought it would be a nearly impossible compound, but surprisingly the 2-(Trifluoromethoxy)benzaldehyde precursor seem to be widely available. 

The NF2 bond was actually an accident! I wasn't expecting the perfluoro- prefix to fluroinate the amine. 
But N,N-difluoromethanamine exists too! 

Not sure if it can be used to synthesize N,N-difluorophenethylamine. I'm still studying a bit about reactions.


----------



## Dresden

Fluorine is the most electronegative element (with oxygen being a close second), but it is about the size of a hydrogen atom and thus not as an effective electronegative atom to add to a molecule as bromine or chlorine due to the "heavy atom effect."  It's like your greatest impact on impacting the electronegativity of a molecule comes from an atom's innate electronegativity (which F is the winner of) times its atomic weight, and in this calculation, bromine and chlorine come ahead of fluorine.  That's why you'll see Br or Cl on my structures far more often than F.  They are simply more effective in influencing drug behavior because they influence the molecular orbital of the drug more than F does.  And that's all I have to say about the matter other than it's a very common and sophomoric drug design mistake.  To reiterate:






is probably going to be less of an impressive drug than






as far as entactogenesis goes because while F and Cl are both highly electronegative, the Cl is also bigger and heavier.  
I hope that makes sense because I'm not explaining it again.

I really wasn't going to take the time to try to explain why the whole "Oh, F is the most electronegative element" and "electronegativity plays a huge role in drug design" (both of which are true statements) and coming to the conclusion "so I'll just stick a F on this drug here for maximum effect"  (which is not true), but you seem earnest and clever so I did.

Even then, it's not as simple as drawing per-chloro (as opposed to per-fluoro) 2CC now and expecting anyone to take that seriously.


----------



## crmt28

I wasn't expecting anyone to take perfluoro-2C-C seriously! I was just joking around with chlorofluorocarbons and greenhouse gases 

Fluorine being smaller is exactly my point! The methylthio group is already too big and seems to decrease activity on 2C-x compounds. (see BIS-TOM on PiHKAL) 
Putting any other halogen in there would reduce activity in the same way. 

The 5-EtO analogue is a little bit larger than MeO and this increases the duration 3-fold according to Shulgin! 

I would expect a trifluoromethoxy version to be somewhere in between.


----------



## aced126

Dresden said:


> Fluorine is the most electronegative element (with oxygen being a close second), but it is about the size of a hydrogen atom and thus not as an effective electronegative atom to add to a molecule as bromine or chlorine due to the "heavy atom effect."  It's like your greatest impact on impacting the electronegativity of a molecule comes from an atom's innate electronegativity (which F is the winner of) times its atomic weight, and in this calculation, bromine and chlorine come ahead of fluorine.  That's why you'll see Br or Cl on my structures far more often than F.  They are simply more effective in influencing drug behavior because they influence the molecular orbital of the drug more than F does.  And that's all I have to say about the matter other than it's a very common and sophomoric drug design mistake.  To reiterate:
> 
> 
> 
> 
> 
> 
> is probably going to be less of an impressive drug than
> 
> 
> 
> 
> 
> 
> as far as entactogenesis goes because while F and Cl are both highly electronegative, the Cl is also bigger and heavier.
> I hope that makes sense because I'm not explaining it again.
> 
> I really wasn't going to take the time to try to explain why the whole "Oh, F is the most electronegative element" and "electronegativity plays a huge role in drug design" (both of which are true statements) and coming to the conclusion "so I'll just stick a F on this drug here for maximum effect"  (which is not true), but you seem earnest and clever so I did.
> 
> Even then, it's not as simple as drawing per-chloro (as opposed to per-fluoro) 2CC now and expecting anyone to take that seriously.



True, and you're correct in the instance of ring substituted amphetamines, however as you said since chlorines and bromines are big, they could sterically hinder the molecule from binding to the target, and in that case a fluorine which wouldn't cause this yet still increasing affinity would be a better option. Also substituted halogens on rings block enzymatic hydroxylation where they're substituted as well as other ring positions due to its electron withdrawing effects on the ring.

This molecule might've already been drawn, but I'll explain my rationale behind it. 






TFM group on amine likely reduces its basicity which will decrease potency (amine charged when interacting with its targets most likely). However the molecule will be more lipophilic which could make up for lost potency. However I think it might actually have a shorter half life than meth. I suspect trifluoromethylamine (a weaker base due to the fluorines reducing the nitrogen lone pair's nucleophilic power) is a better leaving group than methylamine itself, and thus deamination would occur quicker. Anyone who knows about deamination and these kinds of metabolic reactions in detail can correct me.


----------



## aced126

Dresden said:


> Well, these structures are based on morphine, and morphine has a 6-OH but a 6-oxo or a 6-acetoxy can be derived from the hydroxy, and both make the entire molecule get into the brain much better than if morphine's 6-OH was just left there.  Since these two molecules would likely be made from scratch, I guess you're right though.  I was kind of always under the impression that they were necessary for activity or helped it somehow, but hey, my specialty is the amphetamines, not the opiates.  Amphetamines are delightful and amenable to so many structural changes.



I get you, the acetoxy would be added because it is easier to do so to morphine rather than remove the 6 hydroxy group completely and make it saturated. This would indeed increase logP without affecting potency. In fact, I believe aliphatic chains on carbon 6 of morphine yields potent derivatives (think adder mentioned this). So yeah, the 6 position doesn't seem to play a big role in actual receptor interactions but rather just lipophilicity of the molecule.


----------



## adder

> In fact, I believe aliphatic chains on carbon 6 of morphine yields potent derivatives (think adder mentioned this). So yeah, the 6 position doesn't seem to play a big role in actual receptor interactions but rather just lipophilicity of the molecule.



It's not necessarily just about lipophilicity. In case of plain alkyl/alkoxy chains it might be true, take heterocodeine as an example, its potency doesn't correlate well with its affinity vs. morphine, but if you start putting longer alkyl chains there with heteroatoms at the end of the chain, then they actually do take part in binding (interaction with K233). There are quite a few irreversible MOP ligands that make use of it (chlornaltrexamine, beta-funaltrexamine etc.), strong binding of chloromorphide is likely due to chlorine interacting with K233 as well. However, there might also be a possibility to direct the C6 alkyl/alkoxy substituent into the region which bulky C7-substituents of orvinols bind to, it's just a matter of getting the C ring to take the right conformation.


----------



## Nagelfar

The above PTs that are meta-cis-propenyl have great SERT & DAT but low NET affinity; *all of them*, for instance the middle one's Ki for SERT is 0.05, DAT 3.45 and NET is 24

now the para-cis-propenyl of troparil is even better:






SERT= 7.1
DAT=15
NET=28,000(!!!)

So I take the amphetamine skeleton from the phenyltropane; beingthe line along the string of bonds on the top of the PT from the benzene, and wonder if, then, as a VMAT substrate releasing agent, the para-cis-propenyl'd do the same for negating norepinephrine affinity for it as it does for the DRI; since it lengthens the molecule taking off the n-methylated part and presume SERT affinity stays as good as methamp but without the NE release:






para-cis-propenyl-amphetamine, a winner? (since PCP-amphetamine would just confuse people, call it Parcip-amphetamine, since it's close to the German for Percival "Parzifal", Percival can be it's street name; the "holy grail of stims" ;-p )






taking this above example of "epibati" tropane, and thinking of the way in which desoxypipridrol binds in 360 degree rotation, and how the nitrogen works with the cycloalkane, I come up with this:






What'd you all think the benzene relation would be^ might it work with the cycloalkane being changed to a straight benzene perhaps? Triple phenyl with nitrogens a DRI?


----------



## Nagelfar

Strobamine *plus +* SoRI-20041 _*equals =*_






dopamine transporter allosteric modulators are the future of stimulants, IMHO


----------



## neurotic

Serotonin/dopamine selective stimulants... Now that's interesting. I'd love to try. These compounds have never tried by anyone I guess? Neither human not mouse?

Just a thought though: even though noradrenaline is like the shitty monoamine, I'd bet that it is necessary, to some degree, for the stimulant effects as we know them, that is, 5HT/DA selective stimulants might not be better perhaps just different or even uninteresting. Ofc just speculation.


----------



## Nagelfar

neurotic said:


> Serotonin/dopamine selective stimulants... Now that's interesting. I'd love to try. These compounds have never tried by anyone I guess? Neither human not mouse?



http://pubs.acs.org/doi/abs/10.1021/jm060641q _"In vivo study: rat, mouse, monkey & non-human primate"_

So apparently, those top meta-substituted ones have been tried in invivo in animals, I don't see why'd they bother radiolabling them if that were not the case: also check out:
https://en.wikipedia.org/wiki/RTI-83

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841478/ _"Development of 3-Phenyltropane Analogs with High Affinity for the Dopamine and Serotonin Transporters and Low Affinity for the Norepinephrine Transporter"_


----------



## Nagelfar

Nagelfar said:


> What'd you all think the benzene relation would be^ might it work with the cycloalkane being changed to a straight benzene perhaps? Triple phenyl with nitrogens a DRI?



Holy heck, here is exactly what I was talking about there.






Apparently it is quite the stimulant.

EDIT:

Throw in some more heteroatoms, and since most can visualize that, I'm mixing in the Hexapradol tail, but using the phenmetrazine of the desoxypipridrol (i.e. 3-Benzhydrylmorpholine) but giving it a benzene and a nitrogen to emulate the fentanyl skeleton, 'cause that back when still intrigues me:






Put on the naphthyls on a whim, too


----------



## roi




----------



## crmt28

2C-T-21/2C-EF analogue. 2C-EP!






Roi, about your first molecule, I was thinking of this instead, since the methoxy groups would be closer to the 2,5 positions:


----------



## SKL

neurotic said:


> Serotonin/dopamine selective stimulants...



Isn't 4-MAR one? Or at least overwhelmingly favoring S/D?

*persevering about 4-MAR


----------



## neurotic

i found this paper here - https://bitnest.netfirms.com/external.php?id=%7DbxUgXXCNAUj%7By%02%0D, check out pages 9 & 10

tested three aminorex analogues and d-amphetamine for monoamine release, "All test drugs were fully efficacious in their ability to evoke release at DAT, NET and SERT, i.e. drug effects achieved 100% of maximal release.". the aminorex's look like they are awesome stimulants btw.


----------



## Nagelfar

neurotic said:


> i found this paper here - https://bitnest.netfirms.com/external.php?id=%7DbxUgXXCNAUj%7By%02%0D, check out pages 9 & 10
> 
> tested three aminorex analogues and d-amphetamine for monoamine release, "All test drugs were fully efficacious in their ability to evoke release at DAT, NET and SERT, i.e. drug effects achieved 100% of maximal release.". the aminorex's look like they are awesome stimulants btw.



Anybody find anyone ever synthing that para-propenyl-amp, ever, at all...? I think that should be rushed to right away as top priority if not, anyone reading this? ;-p



crmt28 said:


> Alpha-methylated tryptamines are indeed mostly unpromising. Maybe the beta position would be a better choice?
> 
> 3-(2-morpholinyl)-indole
> 
> 
> 
> 
> 
> 
> It actually already exists and even has a CAS number. But absolutely no papers explaining what it does. Interesting!



Is it just me, or does the pyrrole on the indole make one of those optical illusions that makes tbe morpholine looks one bond bigger than the benzene? I think the optical illusion has something to do with the benzene having the border lining the inner pi-orbital bonds; 'cause I think I've seen that on an optical illusion website "which box is bigger" when they're exactly the same circumference but everyones eye is trained to deceive you otherwise


----------



## aced126

Nagelfar said:


> Anybody find anyone ever synthing that para-propenyl-amp, ever, at all...? I think that should be rushed to right away as top priority if not, anyone reading this? ;-p



Yeah it'd be good if it was synthesised and evaluated but amps mechanism of action is different to phenyltropanes which are reuptake inhibitors, not releasing agents, so I don't think you can fully apply the same logic to amps.


----------



## aced126

I know that barely information is available regarding the 5-HT2b SAR, but I was wondering if the design of a possible charged 2b antagonist which doesn't cross the BBB could be done? This could mean that the 2b therapeutic target could be opened up again, and that drugs like fenfluramine, aminorex and MDMA wouldn't have that issue of cardiac fibrosis. 

This probably won't result in antagonism but everyone gets the point.





*Opsin doesn't allow more than 3 bonds to nitrogen so just imagine there's another methyl on the nitrogen so it can't cross the BBB. Yeah, the 2b receptor probably is quite different to opioid receptors but at least its a start.*


----------



## Nagelfar

aced126 said:


> Yeah it'd be good if it was synthesised and evaluated but amps mechanism of action is different to phenyltropanes which are reuptake inhibitors, not releasing agents, so I don't think you can fully apply the same logic to amps.



I understand that of course, but the underlying basic shape along the top is the same ligand structure, the larger "below the boat - iceberg" of the PTs are what keep them from going all the way up  intothe pump, and anchoring on to just be a reuptake inhibitor.


----------



## aced126

Nagelfar said:


> I understand that of course, but the underlying basic shape along the top is the same ligand structure, the larger "below the boat - iceberg" of the PTs are what keep them from going all the way up  intothe pump, and anchoring on to just be a reuptake inhibitor.



I thought it wasn't only due to sterics and the carboxyl played a role electronically to hold it to the transporter.

Edit: I meant carbmethoxy.


----------



## Nagelfar

aced126 said:


> I thought it wasn't only due to sterics and the carboxyl played a role electronically to hold it to the transporter.



clubcard has gone over this numerous times just recently, the carboxyl isn't necessary, and infact just disables the ability to bind as a ligand in full if it is just a "carboxyl" and not a "carb_meth_oxy"

para-FBT is a fully functional and efficacious DAT uptake pump ligand:






tropacocaine is roughly one 58th the potency of cocaine (at inhibiting the phenyltropane "CFT" from binding to just DAT, so not a definite scale of potency in over-all terms), it has no 2-tropane branch whatsoever, but benzoylecgonine (just a carboxyl, no methyl on it) is roughly 2,191th the strength, less than one two-thousandth cocaine's inclination to displace CFT from the DAT reuptake site, which is essentially saying no affinity at all, probably has the same measure of affinity for the opioid receptor (the fact that the molecule floats around the body indiscriminately makes pretty much any site measurable for any compound, and such a number is a way of saying "not a ligand")


----------



## aced126

Nagelfar said:


> clubcard has gone over this numerous times just recently, the carboxyl isn't necessary, and infact just disables the ability to bind as a ligand in full if it is just a "carboxyl" and not a "carb_meth_oxy"
> 
> tropacocaine is roughly one 58th the potency of cocaine (at inhibiting the phenyltropane "CFT" from binding to just DAT, so not a definite scale of potency in over-all terms), it has no 2-tropane branch whatsoever, but benzoylecgonine (just a carboxyl, no methyl on it) is roughly 2,191th the strength, less than one two-thousandth cocaine's inclination to displace CFT from the DAT reuptake site, which is essentially saying no affinity at all, probably has the same measure of affinity for the opioid receptor (the fact that the molecule floats around the body indiscriminately makes pretty much any site measurable for any compound, and such a number is a way of saying "not a ligand")



Ahh I see, I meant carbmethoxy, sorry. Would a molecule like this be transported into the neuron or simply block the transporter?





Looks very amphetamine like


----------



## Dresden

I know troparil 






was a huge disappointment.  Not sure about your 3-phenyltropane






But hey, it looks great on paper.

Maybe add an electron withdrawing 3,4-methylenedioxy group?


----------



## aced126

Dresden said:


> Maybe add an electron withdrawing 3,4-methylenedioxy group?




Wouldn't the electron donating resonance outweigh the inductive withdrawing effects of the oxygens and increase the electron density of the ring? 

So if carbmethoxy plays no role in actually holding the molecule to the transporter what does it actually do then? I think I might've already posted this molecule before but I'll do it again. I don't know why no researchers have made this and found out how it works.






If that molecule shows reuptake abilities only then we know the carbmethoxy is binding to something on the transporter. However ...






If this shows reuptake abilities only then it would suggest the carbmethoxy group doesn't really do anything, although I suspect this molecule will be act like a normal substrate at DAT and dissociate from the transporter once in the presynaptic membrane, and then go on to release DA through normal amphetamine action.


----------



## Dresden

aced126 said:


> Wouldn't the electron donating resonance outweigh the inductive withdrawing effects of the oxygens and increase the electron density of the ring?



1.  Yes, you're right.  Otherwise oxygenated arenes wouldn't be ortho/para directing.  

2.  As for the carbomethoxy issue, all I know is that esters are fruity and usually smell delicious, which could possibly make them more desirable when incorporated into drugs of abuse.

3.  As for 






Idk again, but I've heard that it is one of the worst drug experiences imaginable.

But speaking of such possibly hellish ideas (since Halloween is Saturday), raspberry ketone is a widely available, cheap, unwatched compound:






Raspberry Ketone (found in red raspberries)

Which could lead to this:






First sassafras, now raspberries!!!

Finally,






alpha-methylfluoxetine (alpha-methyl-Prozac; AMProzac)


----------



## Dresden

These are my antibiotics.  This is my prior art.






2-carbomethoxy penicillin G; intended to get into the brain much better than plain penicillin G (which is identical but has a 2-carboxylic acid) when administered intravenously; for use in neurosyphilis (which only has a cure rate of 50% at the moment with the current pen G regimen) and other brain infections.






This one is identical to the above one, but with inspiration from chloramphenicol; for IV use.  For the treatment of bacterial meningitis and neuro/syphilis and other susceptible infections of the brain.

*The methoxylation of the carboxylic acid to the carbomethoxy group can be applied to any penicillin or cephalosporin antibiotic used to treat brain infections.*






The last one is for oral use and is intended for the treatment of acne vulgaris, (non-neuro)syphilis, and probably many other infections.  

*If you know anyone in the big pharma business, please show them this post.*


----------



## aced126

Good idea...but surely they would've made and tested alkyl esters?


----------



## Dresden

It may depend on which was discovered first:  most penicillin/cephalosporin antibiotics or the blood brain barrier?  To me, the bigger question is why wouldn't these carbomethoxy pro drugs work when given IV as superior brain permeating drugs?  After all, we know that the brain contains esterases.  Either way, though, the last one is still a 2-carboxylic acid.  And here's chloramphenicol's structure for easy reference:






The dichloroacetate is metabolized away IIRC.  Chloramphenicol is a natural product.

Then there's this (and the 2-CO2H analogue), which may be a stretch due to possible unwanted CNS stimulation:






And this one (and its 2-CO2H analogue), which actually looks rather promising...






A molecule can have up to two bare hydroxyls and still manage to make it into the brain well enough.


----------



## Nagelfar

aced126 said:


> Ahh I see, I meant carbmethoxy, sorry. Would a molecule like this be transported into the neuron or simply block the transporter?
> 
> 
> 
> 
> 
> Looks very amphetamine like



It is, the following is a DA releaser rather than a DAT re-uptake pump ligand:






http://www.bluelight.ru/vb/showpost.php?p=5728429&postcount=10

and check out:

exo-2-Phenyl-7-azabicyclo[2.2.1]heptane-1-carboxylic Acid: A New Constrained Proline Analogue.


----------



## Dresden

I wouldn't mind trying that.

And this:






And this:






Nifty!


----------



## aced126

Nagelfar said:


> It is, the following is a DA releaser rather than a DAT re-uptake pump ligand:



If this is the case then surely it is likely that the molecule I drew would display similar amphetaminergic releasing qualities. Surely then the addition of the carbmethoxy group will prevent it from dissociating with the receptor once presynpatic membrane bound (or dissociating to a lesser extent at least) and thus the molecule is an inhibitor rather than releaser.


----------



## aced126

Dresden said:


> It may depend on which was discovered first:  most penicillin/cephalosporin antibiotics or the blood brain barrier?  To me, the bigger question is why wouldn't these carbomethoxy pro drugs work when given IV as superior brain permeating drugs?  After all, we know that the brain contains esterases.  Either way, though, the last one is still a 2-carboxylic acid.  And here's chloramphenicol's structure for easy reference:
> 
> 
> 
> 
> 
> 
> The dichloroacetate is metabolized away IIRC.  Chloramphenicol is a natural product.
> 
> Then there's this (and the 2-CO2H analogue), which may be a stretch due to possible unwanted CNS stimulation:
> 
> 
> 
> 
> 
> 
> And this one (and its 2-CO2H analogue), which actually looks rather promising...
> 
> 
> 
> 
> 
> 
> A molecule can have up to two bare hydroxyls and still manage to make it into the brain well enough.



Doesn't most of the ester hydrolysis process happen in the liver? You don't see much ritalinic acid or benzoylecgonine being made in the brain itself. So I'd imagine an absurd dose would be needed if the intention is to hydrolyse the molecule once past the BBB. Nevertheless the methylester could be efficacious itself, but I know nothing about antibiotic SAR and couldn't possibly comment. 

In the last molecule in particular, wouldn't the increased logP due to the methylester be outweighed by the several other polar FGs in the molecule, like the p-nitro especially. Although admittedly if you had to put one substitution in to increase logP the most it would probably be esterification.

Edit: My bad, it seems nitro groups don't seem to alter logP a lot on rings. The calculated logP for the carboxylate was 1.5 and for the carbmethoxy was over 3, so yeah that molecule is probably gonna cross into the brain pretty well.


----------



## Dresden

You know, like IV heroin (diacetylmorphine) gets into the brain 3x better than morphine when IV'ed because it is more lipophilic.  As for your molecule, it doesn't have the same "amphetamine spacing" as Nagelfar's.  Of course, that doesn't mean it's not active as well.


----------



## adder

aced126 said:


> I thought it wasn't only due to sterics and the carboxyl played a role electronically to hold it to the transporter.
> 
> Edit: I meant carbmethoxy.



The fact that it isn't necessary doesn't mean it's not playing a role in binding if it's there. I suppose it dramatically increases affinity. From what I've seen the carbomethoxy in phenyltropanes binds to the same tyrosine residue that phenyl in amphetamine does. I suppose the aromatic hydroxyl is crucial here impacting the aromatic ring electronically in such a way that an ester can bind. If you look at more sophisticated phenyltropanes, you can see that many different groups bioisosteric with carbomethoxy, like aromatic isoxazolyl, were tried and seem to do well.


----------



## aced126

If this is so then what does the phenyl in phenyltropanes do? So the reason why amphetamine dissociates from DAT once inside the neuron is because the interactions between the amph pi cloud and the tyrosine pi cloud are weak? But the carbomethoxy (or bioisostere) has strong enough binding to the tyrosine pi cloud/hydroxyl itself to prevent dissociation once exposed to the presynaptic membrane? Or maybe the carbomethoxy binding instead of the phenyl means the phenyl can interfere in the conformational change the transporter undergoes when in the process of transportation of substrate from synaptic cleft to cytosol?


----------



## Dresden

If the carbomethoxy binds to the same site as the phenyl, then wouldn't this






do something good?


----------



## aced126

That's what I had in mind. Seems like that would have many other targets in the brain though and might not be selective enough. LogP seems fine for that compound as well though. Ahh, if the phenyl ring in phenyltropanes interferes with the conformational change process, and nothing is there to do that on this molecule, it might dissociate once in the presynaptic membrane. How is it then supposed to release dopamine? It might release vesicular DA via altering the proton gradient (I think only a basic nitrogen is needed for this) but how is it supposed to reverse the function of DAT? It might not bind properly to TAAR1 which is needed for DAT reversal I believe.


----------



## aced126

On a different topic, which of the lone pairs in iso-oxazole is donated into the ring? One of the 2 oxygen lone pairs or the nitrogen lone pair?


----------



## Dresden

And of course the 4-OH and 5-MeO analogues.






What would result if methamphetamine and Strattera had a baby.


----------



## Dresden

aced126 said:


> On a different topic, which of the lone pairs in iso-oxazole is donated into the ring? One of the 2 oxygen lone pairs or the nitrogen lone pair?



How do you expect anyone to know that answer?


----------



## aced126

Dunno, got some pretty high level organic chemists in this forum


----------



## Dresden

I found an instance of a carbomethoxy acting in place of benzene:






Arecoline, a mild stimulant.  It's good too; I used it once.

* * *






isoxazole

One lone pair of the oxygen and two electrons a piece from the two double bonds participate in the aromaticity of the ring.  The nitrogenous lone pair does not participate in isoxazole's aromaticity.  In fact, the N's lone pair of electrons is orthogonal to the aromatic pi ring system electrons.

2 + 2 + 2 = 6 pi electrons

Huckel's Rule

H(n) = 4n + 2
H(1) = 4(1) + 2 = 6, making isoxazole a 1st order (n=1) aromatic compound.

Sorry, that was actually an easy question once I looked at it.


----------



## aced126

Dresden said:


> I found an instance of a carbomethoxy acting in place of benzene:
> 
> 
> 
> 
> 
> 
> Arecoline, a mild stimulant.  It's good too; I used it once.
> 
> * * *
> 
> 
> 
> 
> 
> 
> isoxazole
> 
> One lone pair of the oxygen and two electrons a piece from the two double bonds participate in the aromaticity of the ring.  The nitrogenous lone pair does not participate in isoxazole's aromaticity.  In fact, the N's lone pair of electrons is orthogonal to the aromatic pi ring system electrons.
> 
> 2 + 2 + 2 = 6 pi electrons
> 
> Huckel's Rule
> 
> H(n) = 4n + 2
> H(1) = 4(1) + 2 = 6, making isoxazole a 1st order (n=1) aromatic compound.
> 
> Sorry, that was actually an easy question once I looked at it.



Thanks, is there any way of determining in a case where more than one heteroatom has lone pairs to donate into the ring, which lone pair actually delocalises? 

Is arecoline amphetamine-like in action? The wikipedia page says it's a partial muscinaric agonist.


----------



## belligerent drunk

aced126 said:


> Thanks, *is there any way of determining in a case where more than one heteroatom has lone pairs to donate into the ring, which lone pair actually delocalises?
> *
> Is arecoline amphetamine-like in action? The wikipedia page says it's a partial muscinaric agonist.



What rings do you have in mind? Anyway, if a heteroatom had a lone pair and it was not delocalized into the ring structure (and it wasn't double-bonded to a neighbor), then that would break aromaticity as there can be no atoms in the chain that don't have a pi orbital aligned with the ring's delocalized pi electron cloud. Same principle as with conjugated double bonds - if there is a sp3 carbon somewhere in the middle then it breaks conjugation. If a heteroatom is double-bonded to its neighbor, then its lone pair is free and not conjugated; if it doesn't have a double bond within the ring, then it must donate its lone pair.


----------



## aced126

belligerent drunk said:


> What rings do you have in mind? Anyway, if a heteroatom had a lone pair and it was not delocalized into the ring structure (and it wasn't double-bonded to a neighbor), then that would break aromaticity as there can be no atoms in the chain that don't have a pi orbital aligned with the ring's delocalized pi electron cloud. Same principle as with conjugated double bonds - if there is a sp3 carbon somewhere in the middle then it breaks conjugation. If a heteroatom is double-bonded to its neighbor, then its lone pair is free and not conjugated; if it doesn't have a double bond within the ring, then it must donate its lone pair.



For example, why isn't 1,4-diazepine aromatic? It has 6 pi electrons from the double bonds itself, and 2 lone pairs on the nitrogens. Why isn't pyran aromatic? Why isn't oxepine or thiepine aromatic? Can't both the oxygen lone pairs delocalise into the ring to make 10 pi electrons?


----------



## belligerent drunk

According to Pauli principle only 2 electrons can occupy the same space, so only 1 pair can be aligned with the ring electron structure; 4 electrons can't be in the same space thus the other pair/orbital has to be somewhere else, which is why p orbitals face different directions. 

1,4-diazepine isn't aromatic because it has 8 pi electrons in the ring which makes it antiaromatic (4n is antiaromatic, 4n+2 is aromatic; a general rule), same goes for oxepine and thiepine. Pyran isn't aromatic because there's one sp3 carbon in the ring which means that the conjugation is "broken", like it's missing a link. Furan on the other hand is aromatic with all carbons being sp2 giving 4 pi electrons plus oxygen's pair, totaling 6 pi electrons.


----------



## adder

> If the carbomethoxy binds to the same site as the phenyl, then wouldn't this
> 
> 
> 
> do something good?



Perhaps it would have some weak stimulant activity like this DMAA designer drug. But it's not like the carbomethoxy in phenyltropanes or cocaine interacts with the Y156 at the same angle and distance as the phenyl in amphetamine does. The fact that it helps with affinity in phenyltropanes doesn't mean that phenyltropanes could do without the phenyl ring.



aced126 said:


> If this is so then what does the phenyl in phenyltropanes do? So the reason why amphetamine dissociates from DAT once inside the neuron is because the interactions between the amph pi cloud and the tyrosine pi cloud are weak? But the carbomethoxy (or bioisostere) has strong enough binding to the tyrosine pi cloud/hydroxyl itself to prevent dissociation once exposed to the presynaptic membrane? Or maybe the carbomethoxy binding instead of the phenyl means the phenyl can interfere in the conformational change the transporter undergoes when in the process of transportation of substrate from synaptic cleft to cytosol?



The phenyl ring in phenyltropanes likely interacts with the same tyrosine residue that the carbomethoxy does. And the positioning of the phenyl ring in phenyltropanes when they're bound is certainly different from that in amphetamine, you can see that the same substituent on the phenyl ring can have different effect in phenyltropanes and amphetamines. As I imagine it, you can never judge the ability of a compound to bind to its target by considering single interactions between moieties in the compound's molecule and aminoacid residues, binding clefts in receptors can be quite tight, so all steric and electronic effects have to be taken into account. I mean even if it seems like the distance between some residue with an aromatic bit and some positively charged site in the receptor matches the distance between the aromatic ring and the amine in your compound, it doesn't automatically mean that it will bind there, what is present in the neighbourhood is important too. Compounds lacking the ester are less potent stimulants, as clubcard wrote in this thread or the other one, that 4-nitro compound is a few times weaker than cocaine, right?

I don't have article names at hand, but you can search for dopamine, CFT & amphetamine binding at DAT. There are many articles explaining how these molecules bind to DAT and they have nice graphics showing it.


----------



## Dresden

Afrin (oxymetazoline) inspired speed:






Afrin (oxymetazoline) inspired ecstasy:






I guess it's kind of obvious from my posts that two of my favorite drugs are methamphetamine and MDMA.

* * *

Yeah, chewing on betel nut (whose active ingredient is arecoline) gives a mildly stimulating, strangely rewarding yet subtle high.


----------



## roi

Opioid, inspired by dextromoramide and dipipanone.


----------



## Fruitofknowledge

Yeah there a containment in street meth when people utilize the birch reduction and add too much lithium.


----------



## Fruitofknowledge

Desdihydromethamphetamines.


----------



## Dresden

Fruitofknowledge said:


> Desdihydromethamphetamines.



Umm...do you mean a partially reduced benzene ring?


----------



## pr0d1gy

aced126 said:


> On a different topic, which of the lone pairs in iso-oxazole is donated into the ring? One of the 2 oxygen lone pairs or the nitrogen lone pair?



In isoxazoles it would be oxygen. Nitrogen is already contributing one electron to the pi system so it can't contribute the lone pair as well, among other reasons.


----------



## aced126

What would this do


----------



## Midnight Sun

aced126 said:


> What would this do



slightly less crappy version of ppa/ephedrine?

which isn't saying much either


----------



## aced126

Midnight Sun said:


> slightly less crappy version of ppa/ephedrine?
> 
> which isn't saying much either



Would me more than "slightly less crappy"; compare said structure to phenmetrazine.


----------



## Dresden

The closest thing I could come up with is beta-methoxy-2cb:






"I was in a sociopathic snit.  All in all, pretty negative."--from PiHKAL.

I've often wondered your same question myself.


----------



## Midnight Sun

aced126 said:


> Would me more than "slightly less crappy"; compare said structure to phenmetrazine.



It's far closer to ppa/ephedrine than phenmetrazine, maybe you could expect a jittery methcathinone type high

beta-methoxy = adrenergic BS

That shit will love the NET


----------



## Dresden

Re-uptake inhibitor or neurotransmitter releaser or both (is that even possible)?






This next one is the bom:











SHIVA






N-Me-SHIVA






N-Et-SHIVA

N-ethyl-SHIVA looks as silky smooth as getting fucked in the ass while lubed up with a silicone based lubricant.






PARVATI

Haha, checkmate.


----------



## aced126

I think if DAT was working in reverse it'd be blocking reuptake by definition, along with releasing free DA in cytosol.


----------



## aced126

Ketone should still provide some (although probably a lot less than carbomethoxy counterpart) interaction with tyrosine-156? Could be a more mixed reuptake inhibitor/releasing agent? Longer half life as well as higher oral bioavailability as the ester bond previously is replaced by a C-C bond preventing hydrolysis. 

Maybe probe the binding pocket more with carbons in hopes of blocking the conformational change when DAT tries to transport this molecule into the neuron. Should give more reuptake and less releasing character to the molecule as well as increase BBB penetration. 




















Maybe a charged nitrogen in place of the ketone could do even better at binding to Y156.








How about locking it into 1 of the following conformations for increased (or decreased) selectivity?


















Secondary amines should have maximum basicity as well so gets charged easily.
I expect the last 2 to perform reuptake the best due to the distance between the non-amphetaminergic amine and the ring (tyr residue likely to be close to the ring).


----------



## Dresden




----------



## roi

More THC-y cannabinoid.


----------



## pharmakos

is anyone able to overlay THC and JWH-018 arranged in the configuration in which they bind to the CB1 receptor?  i would like to see it, but i don't have the knowledge to do so.


----------



## klfiend

http://imgur.com/IwQysax

Was looking at phenylpiracetam and pemoline and was wondering if this has been researched.  Looks like it could be a stimulant but I don't know shit!


----------



## SKL

Dresden said:


>



As you may recall Shulgin made and tasted N-methyl-DOB:






He didn't explore it very much, but it didn't sound like any kind of fun at all ... he makes reference to trying some of the other halogenated versions as well ... mostly just sounds abrasive on the body, and one of the researchers had an odd experience with it potentiating psilocybin taken the day after. He doesn't say much more but it sounded like a dead end. As someone was just saying sometimes he didn't push high enough with doses but this stuff sounded physically unpleasant enough that one wouldn't want to...

Do you think that one (N-ethyl-DOC?) might be more promising?

What about using the phenmetrazine skeleton? (I bet someone has thought of this already) Too bulky?






I know methylenedioxy-phenmetrazine has been discussed, wonder if anyone ever made it, and if it were active would it be MDMAish or more of a straight stimulant a la MDPV.


----------



## aced126

If this could get into the brain it could be a potent DRA as guanidines are very strong bases; it should be taken up by DAT because when substrates bind, they do so with a charged nitrogen anyway I believe. Too polar to do so probably. In an attempt to increase permeability but still be a substrate at DAT (and still be released once inside the dopamine neuron), I'll add some ring substituents. This is going to confer a lot of SERT activity as well inevitably.






Edit: Apparently the above molecule would have a poor affinity at SERT.


----------



## white55

SKL said:


> As you may recall Shulgin made and tasted N-methyl-DOB:
> 
> 
> 
> 
> 
> 
> He didn't explore it very much, but it didn't sound like any kind of fun at all ... he makes reference to trying some of the other halogenated versions as well ... mostly just sounds abrasive on the body, and one of the researchers had an odd experience with it potentiating psilocybin taken the day after. He doesn't say much more but it sounded like a dead end. As someone was just saying sometimes he didn't push high enough with doses but this stuff sounded physically unpleasant enough that one wouldn't want to...
> 
> Do you think that one (N-ethyl-DOC?) might be more promising?
> 
> What about using the phenmetrazine skeleton? (I bet someone has thought of this already) Too bulky?
> 
> 
> 
> 
> 
> 
> I know methylenedioxy-phenmetrazine has been discussed, wonder if anyone ever made it, and if it were active would it be MDMAish or more of a straight stimulant a la MDPV.



According to Shulgin  n-methyl versions of 2c-x/dox are practically useless as psys. n-hydroxys  are however good (think hot-7  and 2c-t-7).

There's been some talk here about using the phenmetrezine skeleton for a mdma  analog.


----------



## SKL

white55 said:
			
		

> There's been some talk here about using the phenmetrezine skeleton for a mdma  analog.



So, this? 






Caught a bit of that discussion above. Possibly active? If the metabolism follows the same scheme as MDMA you might get some weird metabolites that might not be very active or might be surprising. TBH I would be surprised if this is not being explored unless there is a blatantly obvious reason why it shouldn't work ...

On thinking skeptically about the "psychedelic phenmetrazine" molecule I threw up in my prior post, I remembered this oddity:






"2CB-BZP," which did in fact circulate, but nobody much liked it, it certainly wasn't psychedelic, didnt conform appropriately to 5HT2A/SERT per what I was reading. There was MDBZP, too, it was shit. I think the most people got out of them was headaches and a little stimulation. Now of course BZP isn't nearly as amphetamine like (or as good as) phenmetrazine, but both of these molecules involve largish secondary amines which I seem to recall is part of the problem? I'm an amateur, though, maybe someone else could tell me if I'm on the right track.


----------



## roi

Few MXE analogues:


----------



## aced126

I bet someone's made this before and I really wanna know what it does:


----------



## pharmakos

klfiend said:


> http://imgur.com/IwQysax
> 
> Was looking at phenylpiracetam and pemoline and was wondering if this has been researched.  Looks like it could be a stimulant but I don't know shit!



here:





looks interesting to me


----------



## Bagseed

aced126 said:


> I bet someone's made this before and I really wanna know what it does:


turn into ephedrine at some point?


----------



## Nagelfar

Using natural flavoring & aroma compounds seems to be a good fit to cocaine's natural skeleton for hybrids






"Raspberry ketone"-caine.

Reminds me of Methylecgonine cinnamate, to-whit shorter and perhaps active therefore. I wonder what it's pyrolysis product may be.



aced126 said:


> Ketone should still provide some (although probably a lot less than carbomethoxy counterpart) interaction with tyrosine-156? Could be a more mixed reuptake inhibitor/releasing agent? Longer half life as well as higher oral bioavailability as the ester bond previously is replaced by a C-C bond preventing hydrolysis.
> 
> Maybe probe the binding pocket more with carbons in hopes of blocking the conformational change when DAT tries to transport this molecule into the neuron. Should give more reuptake and less releasing character to the molecule as well as increase BBB penetration.



The oxygen off of the carbmeth(oxy) is a good proposition, and reminds me of getting back to a MPH/fentanyl hybrid. Since there was discussion of how the benzene/phenyl can be substituted for a carbmethoxy in certain regards with specific residue binding, perhaps:





Methylcarbmethoxylidate?


----------



## aced126

Yeah bagseed, as does methylphenidate eventually turn into ritalinic acid. The compound should be decent until the liver hydrolyses the ester.


----------



## aced126

Nagelfar, could be effective at binding but seems just way too polar to be of any use once administered in vivo.


----------



## neurotic

What about this closed ring derivative of your reverse ester meth ace






Looks a lot like pemoline, very un-innovative... Looked better in my head... How are cyclic carbamates called?

There could be a morpholinone/phenmetrazine derivative of that too... As well as ring substituted ones like 3-fluoro (phenmetrazine SAR) or 4-methyl (aminorex or amph ? SAR)


----------



## Midnight Sun

SKL said:


> Do you think that one (N-ethyl-DOC?) might be more promising?
> 
> What about using the phenmetrazine skeleton? (I bet someone has thought of this already) Too bulky?



NE-DOC would hold promise only as a DOC prodrug, the tradeoff being a safer dosage (as it would be higher) for a stupidly long duration

Better idea is N-OH-DOC or N-OH-2C-X/HOT-X.  Or better yet forget that DOC ever existed because it sucked.  DOF-dragonfly would be interesting.  DOI needs to make a comeback

I would forget the idea of phenylmorpholine based psychedelics on the presumption of half-life alone (that's assuming they even fit into 2a which I doubt)


----------



## Dresden

I've heard really good and really bad things about DOC.  Never tried any DOx personally, but hey, if DOI floats your boat, wouldn't this 






be smoother and more forgiving (especially dosage wise) than DOI.  And I am not convinced N-ethyl-DOx's are prodrugs at all.

* * * 

In unrelated news,






and






I call this one LOOPY (for no good reason in particular).


----------



## pharmakos

what would happen to that bottom one metabolically?  would that ring open right away?


----------



## Dresden

No, it wouldn't.  I don't anything would happen to it metabolically.  For example, the related tetrahydrofuran (THF) is a known and stable compound:






THF (2,3,4,5-tetrahydrofuran)


----------



## Midnight Sun

pharmakos said:


> what would happen to that bottom one metabolically?  would that ring open right away?



Isobenzofuran is so unstable I don't think it could even be made 

Dresden, if n-ethyls aren't prodrugs then any N-ethyl DOx/2C-X would be a no go, based simply off what we know about simple n-methylation

Seeing as there are plenty of cases of bulky n-substituents being readily cleaved (n-benzyl, n-lysine, etc etc) I would still lean towards n-ethyl following suit


----------



## belligerent drunk

Dresden said:


> No, it wouldn't.  I don't anything would happen to it metabolically.  For example, the related tetrahydrofuran (THF) is a known and stable compound:
> 
> 
> 
> 
> 
> 
> THF (2,3,4,5-tetrahydrofuran)



THF is stable, as far as ethers go anyway, but not metabolically. It is metabolized into GBL (in two steps), albeit quite slowly, but it is metabolized nonetheless.


----------



## Dresden

Ok, so LOOPY is dead on arrival.  I get it.

IIRC N-propylamphetamine ('prop') [Schedule I]






is metabolized into this






Don't know about eth's metabolites:






As for N-ethyl-DOx's, I would be surprised if their metabolites have been studied yet by anyone at all.

As for me, I think DOAM would be fun, largely based on its effects' description in PiHKAL:






Alexander Shulgin objected to its low relative potency, but 10mg (or even 20 or 30) doesn't sound like too much material for a dose to me.  

Is DOAM a possible CB agonist?  The description in PiHKAL sounds like being stoned to me.

Speaking of amyl's, wouldn't it be great if these two beauties are active and unscheduled?






TAMMY

and






AMY 

They look like some sort of surfactant adjuvants.

And I have always wanted to try






as well.  I know that






was once a (prescription, I believe) drug in France, for all that it's worth.


----------



## pharmakos

re: DOx's with long 4-alkyl chains... the 5HT binding affinity actually goes up as the chain gets longer, even butyl and beyond... but they aren't active psychedelics, so its likely that they're either antagonists or partial agonists.


----------



## SKL

Dresden, propylamphetamine is a very nice relatively mild stimulant, used to circulate as an RC, I used a lot of it in smallish doses. It would be a good pharmaceutical for AD(H)D. Amfepentorex is definitely an interesting molecule. Was used for a bit for appetite suppression, like a hundred other weird stimulants I take it.



pharmakos said:


> re: DOx's with long 4-alkyl chains... the 5HT binding affinity actually goes up as the chain gets longer, even butyl and beyond... but they aren't active psychedelics, so its likely that they're either antagonists or partial agonists.



DOx based 5HT antagonists might actually be useful therapeutic drugs, e.g., in treatment of serotonin syndrome,  as the sometimes used cyproheptadine* is a much dirtier drug (anticholinrgic, etc.)

They may even have psychiatric uses. A lot of the new atypicals have 5HT antagonism and isolating it might be a worthwhile exercise.

* cyproheptadine, something of an interesting molecule in it's own right:


----------



## roi

tert-butyl..might work.


----------



## Dresden

bk-DMT






'Stoned' bk-DMT

And of course, all the requisite 4-OH's and 5-MeO's.


----------



## Nagelfar

Another attempt at a opioidergic-MAT reuptake inhibitor a la methylphenidate/fentanyl, using a reverse ester of the beta-carbamoyl cocaine analogue to fit the nitrogen into the proper place in the bridge for the fentanyl overlay. Keeping the MPH orientation of the carbmethoxy probably just makes it an antichlorinergic, however, like tematropium


----------



## pharmakos

SKL said:


> * cyproheptadine, something of an interesting molecule in it's own right:



interesting, never saw that stuff before.  reminds me that cyclobenzaprine is a 5HT-2A antagonist -- a fact that i learned long ago and forgot about.

it is interesting how some tricyclics have stood the test of time, while most of the rest of that class is long forgotten.


----------



## SKL

So is there anything interesting we can do with *rimonabant*, a CB1 antagonist. I have reliable reports of it's being useful in treating overdoses of synthetic cannabinoids. It was used as an appetite suppressant, like half of the other things in this thread (lol), but it's been discontinued, stateside, though, as it had some unfortunate side effects. Those of us working in clinical psych during the NYC "spice/K2 epidemic" would've liked to have a parenteral formulation of this stuff on hand, believe me.






Novel 3-substituted rimonabant analogues lack Δ(9) -tetrahydrocannabinol-like abuse-related behavioural effects in mice, but have some "cannabimetric" effects, claimed that they are suggested to lack abuse potential, whatever that means . The first two "... neither substituted for nor antagonized THC's discriminative stimulus [in mice.]" 





Exploring the binding features of rimonabant analogues and acyclic CB1 antagonists: docking studies and QSAR analysis, other interesting stuff, with a bunch of other CB antagonists.


----------



## belligerent drunk

Dresden said:


> Ok, so LOOPY is dead on arrival.  I get it.



Not necessarily. THF is quite different from "LOOPY" just by size. LOOPY may not fit into the enzyme which oxidizes THF. I mean, just because simple alcohols get destroyed by ADH doesn't mean any compound containing a hydroxyl group would have the same fate. But then again there's always the possibility.

Anyway, I actually just commented on THF. It's mostly stable on a shelf if stabilized, but not so in the body. I actually tried to get off on THF a few times just out of pure curiosity because an article described a metabolic pathway leading to GBL/GHB. As far as I'm concerned it worked (5ml of THF), but it was disgusting to drink even in like 5% dilution and my stomach didn't like it. Now I stick to dissolving things with it, it's an excellent solvent.


----------



## Dresden

No, I said LOOPY was DOA b/c Midnight Sun stated that isobenzofuran is super unstable, not because of anything having to do with the THF discussion.


----------



## aced126

Midnight Sun said:


> Isobenzofuran is so unstable I don't think it could even be made
> 
> Dresden, if n-ethyls aren't prodrugs then any N-ethyl DOx/2C-X would be a no go, based simply off what we know about simple n-methylation
> 
> Seeing as there are plenty of cases of bulky n-substituents being readily cleaved (n-benzyl, n-lysine, etc etc) I would still lean towards n-ethyl following suit



What's an example of n-benzyl being cleaved? You referring to benzphetamine? Couldn't find any pharmacokinetic for said compound. I think cleavage of n-lysine is a different process (if you are referring to cleavage of lysine from vynase to give dexamph) as a peptide bond is being broken rather than just a N-C bond. Mechanism will be somewhat similar to how chymotrypsin breaks down peptides I think. 

https://en.wikipedia.org/wiki/Catalytic_triad

However I do think n-ethyl will be cleaved.


----------



## Dresden

Dresden said:


> bk-DMT
> 
> 
> 
> 
> 
> 
> 'Stoned' bk-DMT
> 
> And of course, all the requisite 4-OH's and 5-MeO's.



I really think that bk-DMT is a good idea.  Its carbonyl group is borrowed from the now infamous JWH's.  The pentyl and the carbonyl in 'Stoned' bk-DMT are too; however, out of these 6 new molecules, bk-DMT piques my interest the most.


----------



## aced126

Dresden said:


> I know that
> 
> 
> 
> 
> 
> 
> was once a (prescription, I believe) drug in France, for all that it's worth.



What's this one called?


----------



## SKL

^ Amfepentorex. Yet another market withdrawn anorectic.


----------



## SKL

Ancient alt.drugs post archived on Erowid, on caffeine analogs

Probably not really viable recreational drugs (where does the methylenedioxy go? ), but interesting and underlooked chemistry.

Some of the more interesting ones:

Allegedly these two are CNS depressants:










Super-caffiene, ~100x potency at A1/A2:






This guy is used as a pesticide:






There are loads more, and a good bit of research since then on the subject which I'm just sort of delving into now for shits and giggles. I'm snagging a few papers. Could post more if I find interesting stuff and people are interested.


----------



## Midnight Sun

Dresden said:


> No, I said LOOPY was DOA b/c Midnight Sun stated that isobenzofuran is super unstable, not because of anything having to do with the THF discussion.



It likes to polymerize... per wiki apparently if you chill the fuck out of it, it'll stabilize enough to work with, so maybe someone out there dedicated enough could figure something out, but the Chinese are so lazy they don't even like synthesizing 6-xapb so I wouldn't get my hopes up.  The MDxx derivative clock is kind of starting to run out, I'm curious as to what they'll push out next

Maybe they'll try to unload the rest of their postban APB stock as N-OH-5-MAPB, that wouldn't surprise me a bit



aced126 said:


> What's an example of n-benzyl being cleaved? You referring to benzphetamine? Couldn't find any pharmacokinetic for said compound. I think cleavage of n-lysine is a different process (if you are referring to cleavage of lysine from vynase to give dexamph) as a peptide bond is being broken rather than just a N-C bond. Mechanism will be somewhat similar to how chymotrypsin breaks down peptides I think.
> 
> https://en.wikipedia.org/wiki/Catalytic_triad
> 
> However I do think n-ethyl will be cleaved.



Yeah I was referring to benzphetamine or that atrocity benzedrone, but matter of fact I'll even lump NBOMes in with them.  you are right about lysine coming off in a different manner, isn't that done in the bloodstream?


----------



## pharmakos

i'm definitely interested in caffeine analogues, Mr. K. Love.  caffeine is arguably the greatest drug their is when looked at in terms of cost vs. benefit.  improving on it would be wonderful.


----------



## aced126

Midnight Sun said:


> It likes to polymerize... per wiki apparently if you chill the fuck out of it, it'll stabilize enough to work with, so maybe someone out there dedicated enough could figure something out, but the Chinese are so lazy they don't even like synthesizing 6-xapb so I wouldn't get my hopes up.  The MDxx derivative clock is kind of starting to run out, I'm curious as to what they'll push out next
> 
> Maybe they'll try to unload the rest of their postban APB stock as N-OH-5-MAPB, that wouldn't surprise me a bit
> 
> 
> 
> Yeah I was referring to benzphetamine or that atrocity benzedrone, but matter of fact I'll even lump NBOMes in with them.  you are right about lysine coming off in a different manner, isn't that done in the bloodstream?



About the stability of isobenzofuran, I suspect keeping in base might lend some stability. I would think that pyrrole polymerises in a similar manner to how isobenzofuran does; pyrrole cannot be used in any reaction requiring a strong acid of pH<-4 or it will polymerise. It seems isobenzofuran is a lot more reactive than benzofuran and pyrrole (maybe because the benzene ring isn't really intact so it doesn't benefit in stability as much as it normally would) but removing any protons which could possibly catalyse (as well as react in) polymerisation might mean it is stable enough for reactions.

When Vynase is administered, lysine is cleaved off in the red blood cells to give dextroamphetamine. I'm not too sure why it happens in rbcs and why it couldn't just happen in the stomach itself; maybe because the stomach enzymes catalyse the breakdown of long chain peptides way faster and have much more selectively for them so that small molecule peptide bonds which require cission occurs elsewhere.


----------



## aced126

SKL said:


> Ancient alt.drugs post archived on Erowid, on caffeine analogs
> 
> Probably not really viable recreational drugs (where does the methylenedioxy go? ), but interesting and underlooked chemistry.
> 
> There are loads more, and a good bit of research since then on the subject which I'm just sort of delving into now for shits and giggles. I'm snagging a few papers. Could post more if I find interesting stuff and people are interested.



I don't think anyone here minds what kind of molecule it is, even if it doesn't cross the BBB, probably as long as it has a biological action will it remain interesting to me at least.


----------



## Nagelfar

SKL said:


> Ancient alt.drugs post archived on Erowid, on caffeine analogs
> 
> There are loads more, and a good bit of research since then on the subject which I'm just sort of delving into now for shits and giggles. I'm snagging a few papers. Could post more if I find interesting stuff and people are interested.



Hey, if any other such old gems you know where to dig for over there at erowid exist that don't have sufficient proper academic-chemistry-field coverage, please let me know, I just added that link in due course to the shamefully sparse 'analogs' section of the WP "caffeine" page (whose sole prior contribution, was also given by yours truly)


----------



## Midnight Sun

aced126 said:


> About the stability of isobenzofuran, I suspect keeping in base might lend some stability. I would think that pyrrole polymerises in a similar manner to how isobenzofuran does; pyrrole cannot be used in any reaction requiring a strong acid of pH<-4 or it will polymerise. It seems isobenzofuran is a lot more reactive than benzofuran and pyrrole (maybe because the benzene ring isn't really intact so it doesn't benefit in stability as much as it normally would) but removing any protons which could possibly catalyse (as well as react in) polymerisation might mean it is stable enough for reactions.



would the finished product not still have reactivity issues?

Looking at existing drugs that include isobenzofuran or pthalane -- https://en.wikipedia.org/wiki/Category:Isobenzofurans -- it looks like the big issue lies in the 1 and/or 3 position, on the benzofuran ring, as every example has a substitution sitting on there in some form or another... which in and of itself might be interesting.  I wonder how VMAT would tolerate that if at all:


----------



## aced126

If we're taking about hydrogenating isobenzufuran I think it would undergo this reaction pretty easily; I suspect the hydrogenated molecule is a lot lower in energy because now the benzene ring is stabilised. Ether bridges are normally strong. Maybe a substituent on the carbon next to the ether hinders electrophilicity at that carbon. The molecules above might not work at SERT (applies to bottom 2 more so), because a change in angle difference between the aromatic and the ring substituent appears to reduce SERT affinity. Top 2 are flat but then again there seems to be a lot of steric hindrance in the binding cleft. For DAT these molecules would be a lot better. 

One hypothesis about how monoamine releasers release monoamines from vesicles is simply by altering the proton gradient simply because they are a base, and as such all of these molecules would act in this respect. Not too sure about how they could interact with VMAT.


----------



## Dresden

Well the anhydride will be broken open by water (or saliva, as the case may be) upon contact into the following, and the lactone will be metabolized into the same thing:






which is uber electron withdrawing.


----------



## aced126

Lactone would get hydrolysed to this wouldn't it? Maybe further oxidised once in the liver.




Still would be too polar probably, and yeah a poor ring as well.


----------



## Dresden

Yes, then






then the phthalate.  

It might be active along the way, though.


----------



## Midnight Sun

Yeah, sucks, ah well

Could do benzothiophene derivatives I suppose but I bet your sweat would smell like utter ass

On a random note I'm still curious as to what MDPV metabolite it was that turned my skin oompa loompa orange after a hearty binge.  Maybe I was just tripping out but it happened every time


----------



## aced126

Midnight Sun said:


> Yeah, sucks, ah well
> 
> Could do benzothiophene derivatives I suppose but I bet your sweat would smell like utter ass
> 
> On a random note I'm still curious as to what MDPV metabolite it was that turned my skin oompa loompa orange after a hearty binge.  Maybe I was just tripping out but it happened every time



Hmm, don't know a lot about sulphur chemistry but the compound should be bioactive most like the benzofuran series. Because sulphur is hypervalent it can be oxidised; when this happens it should lose all SERT affinity; that's if it even gets into the brain in fair amounts which I don't think it will.


----------



## Dresden

2CT7 certainly gets into the brain:






It also killed a few people when it was making the rounds as one of the first modern day research chemicals, especially those unlucky enough to have combined it with MDMA.


----------



## aced126

I'm not disputing the fact that thioethers are lipophilic, but S-oxide thioethers are way less so however.


----------



## Dresden

Speaking of S, 






and






I sure would like to get stoned.






I kind of outdid myself with that last one; note the structural skeleton of a classical dissociative afforded by the addition of the 10a-ethylamino substituent to plain ole THC.

Finally,


----------



## pharmakos

i think those would all get past analogue laws, too!  too bad we have no idea if they'll work, lol.


----------



## aced126

What's the first molecule based on?


----------



## Dresden

The first molecule is based on CP-(can't remember the numbers), thought to be the simplest active cannabinoid:


----------



## clubcard

Class used, now illegal.


----------



## Dresden

pharmakos said:


> i think those would all get past analogue laws, too!  too bad we have no idea if they'll work, lol.



And their salts (the ones with the ethylamino side chains) are water soluble and, therefore, injectable.


----------



## Nexus_Tripper

R-3C-TIP


----------



## pharmakos

some 4-thioalkyl phenethylamines are thought to be MAOIs.... i wonder if its just one of the enatiomers that is an MAOI?  interesting idea there^.


----------



## Nexus_Tripper

pharmakos said:


> some 4-thioalkyl phenethylamines are thought to be MAOIs.... i wonder if its just one of the enatiomers that is an MAOI?  interesting idea there^.


2C-Ts are not chiral and are still MAOIs.


----------



## klfiend




----------



## pharmakos

Nexus_Tripper said:


> 2C-Ts are not chiral and are still MAOIs.



yeah i realized i left it ambiguous, didn't change it due to laziness... figured it would be apparent that i was referring to chirality of the alpha-methyl-phenethylamines.

the fact that 2C-Ts are not chiral and are MAOIs does not allow us to predict whether or not the R- and S- enatiomers of the 3carbon ones are both MAOIs.  imagine it like a skeleton key that fits every lock, and its not til you start adding extra pegs to the shaft that it starts being specific to certain locks...


----------



## SKL

pharmakos said:


> i'm definitely interested in caffeine analogues, Mr. K. Love.  caffeine is arguably the greatest drug their is when looked at in terms of cost vs. benefit.  improving on it would be wonderful.



Good lord, there are a lot of them. Here using the term "caffeine analogue" a little loosely, but there is a whole pretty wild and interesting world around xanthine adenosine antagonists that I wasn't at all aware of ...

First up and very cool, some SAR stuff:






From here. Lots of other good stuff.

Here's a good and more recent (looks like there was a lot of work done on this in the 80s) review:

*Müller C, Jacobson KA.* Xanthines as Adenosine Receptor Antagonists. Handb Exp Pharmacol. 2011; (200): 10.1007/978-3-642-13443-2_6. doi:  10.1007/978-3-642-13443-2_6

This paper is a tour de force if you're interested in exotic xanthine derivatives (tricyclic xanthines! see spoiler below), has a shocking number of analogues, affinities for all of them, and has sort of a "everything you wanted to know but were afraid to ask" vibe, even discussion about some applications. I was thinking about trying to draw my own caffeine analogue but all of them are probably there already.



Spoiler: Some pretty fancy molecules



Tricyclic xanthines a/k/a so that's where the MDIO goes  ...








*Daly JW.* Caffeine analogs: biomedical impact. Cell Mol Life Sci. 2007 Aug;64(16):2153-69.



> Caffeine, widely consumed in beverages, and many xanthine analogs have had a major impact on biomedical research. Caffeine and various analogs, the latter designed to enhance potency and selectivity toward specific biological targets, have played key roles in defining the nature and role of adenosine receptors, phosphodiesterases, and calcium release channels in physiological processes. Such xanthines and other caffeine-inspired heterocycles now provide important research tools and potential therapeutic agents for intervention in Alzheimer's disease, asthma, cancer, diabetes, and Parkinson's disease. Such compounds also have activity as analgesics, antiinflammatories, antitussives, behavioral stimulants, diuretics/natriuretics, and lipolytics. Adverse effects can include anxiety, hypertension, certain drug interactions, and withdrawal symptoms.



*Bruns RF, Daly JW, Synder SH.* Adenosine receptor binding: structure-activity analysis generates extremely potent xanthine antagonists. Proc Natl Acad Sci U S A. 1983 Apr; 80(7): 2077–2080.

Highlight: Meet 1,3-dipropyl-8-(2-amino-4-chlorophenyl) xanthine, "a compound of extraordinary receptor affinity, with a Ki for adenosine A1 receptors of 22 pM. _*It is 4,000,000 times more potent than xanthine itself and 70,000 times more potent than theophylline*_."






So basically, the ohmefentanyl of adenosine antagonists. Impressive. It's quite a receptor probe but as a drug who knows. I'm going to study this one further.

Maybe back with more later.


----------



## aced126

Can see these compounds being used widely in medicine and don't really know why there isn't more research going into this.


----------



## SKL

This is an interesting one. Potent, very high selectivity for A1. This could be useful in the NICU and maybe in treating hypoperfusion, shock?  Water soluble.

*8-(2-amino-4-chlorophenyl)-1,3-dipropylxanthine (ACPDPX)*






This is another potent highly A1-selective xanthine but it is probably less useful to medicine by way of not being water soluble so not suitable for IV drip, etc.

*1,3-Dipropyl-8-cyclopentylxanthine (DCPCX)*






But now it gets weird, and Bluelightish ... it has been researched as *potentiating MDMA and DOI* (inb4 it winds up in pressed pills...is the caffeine in pressed pills already doing this?)


----------



## SKL

And, on the other side, this rather baroque molecule ..

*1,3,7-Trimethyl-8-[(3-carboxy-1-oxopropyl)amino] styryl)]xanthine* 






Potent, A2 selective. Water soluble.

Good for asthma/bronchospasm?


----------



## Midnight Sun

Fuck I'm stoned

*stumbles away*


----------



## roi

Maybe 100000x Morphine?


----------



## Nagelfar

Dresden said:


> The first molecule is based on CP-(can't remember the numbers), thought to be the simplest active cannabinoid:



Dres, find the name of this one?


----------



## Midnight Sun

Nagelfar said:


> Dres, find the name of this one?



cp-47497?

edit: guess not


----------



## Dresden

Beats me.

* ** 

I bomb atomically.  Socrates' philosophy and hypotheses couldn't stop these lyrical armed robberies...


----------



## SKL

When researching some unrelated things I came across this oddity:






Azacyclonol is a positional isomer of pipradrol. Rather than being yet another NDRI or something that would inspire f&b to invade Poland, it is a mild sedative that has the peculiar quality of attenuating psychedelic experiences, although it's not a tranquilizer or an anti-psychotic. Was tried with schizophrenics in Europe with limited success and sailed into the sunset.

Perhaps something that could go in the druggie's emergency bag (I used to have one when I was actively experimenting with stuff: it started like this - Narcan, flumazenil, Thorazine, Ativan, Haldol ...)


----------



## un kle fukka

and you're proud of that now?


----------



## Dresden

Looks like an antihistamine.


----------



## clubcard

klfiend said:


>



Interesting but the S in the 2 oxidation state tends to get oxidized. I also remember the ring being a different shape but never tried, nobody knows.


----------



## Nagelfar

Dresden said:


> Beats me.








Not far from phenmetrazine-like stimulants, here it is with all the substitutions of both.


----------



## aced126

SKL said:


> ^ Amfepentorex. Yet another market withdrawn anorectic.



Does this one release or reuptake DA?


----------



## klfiend

Dresden said:


> Beats me.
> 
> * **
> 
> I bomb atomically.  Socrates' philosophy and hypotheses couldn't stop these lyrical armed robberies...



reminds me of Benocyclidine. https://en.wikipedia.org/wiki/Benocyclidine


----------



## SKL

aced126 said:


> SKL said:
> 
> 
> 
> 
> 
> 
> 
> Dresden said:
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> Amfepentorex. Yet another market withdrawn anorectic.
> 
> Click to expand...
> 
> Does this one release or reuptake DA?
Click to expand...


Boy, that sent me a bit down the rabbit-hole, and I'm a bit intrigued. I knew the soundbite, and it's available on Wiki, but trying to dig deeper, I can find next to nothing about amfepentorex and it's pharmacology via the usual venues, but haven't found much.

There's not a lot of useful information I could readily find about it, except for the basics, it was marketed in France as an appetite suppressant, etc., save a few references that I think I'd have to track down in print (fortunately I have access to a wonderful public library here in the City that stocks 1960s era _Chimica Therapeutica_, Vol. 2, Pg. 260, 196, if that will help at all ....)

Now, this is a pretty interesting chemical, actually. Question being, how far can we take single ring substituted amphetamines? A lot of us will be familiar with 4-methyl-AMP, which by all accounts wasn't very impressive, and is more serotonergic than anything else, I've actually seen some contradictory reports as to whether it's a serotonin/dopamine releaser or an S(N?)DRI. The EMCDDA has a pretty solid report about it. This of course, is without the N-methyl. 4-methyl-MA is a metabolite of mephedrone, and has some role in it's activity I figure, but sounds kind of toxic. So I guess the question is, what do we get by the N-methyl and particularly elongating the chain at the 4 position? If I can only hazard a guess I think this molecule might have some significant serotonergic activity which might well have to do with it's utility as an appetite suppressant, _a la_ locaserin (which see, is an also interesting molecule ...), but evidently retains some dopaminergic/amphetamine type actions as well. I've really had some trouble locating specific information about this molecule, it seems rather forgotten, although the time I've spent is limited. My interest is a bit piqued though. More later maybe. I'd love to know any sort of subjective account of this experience or of course more details about it's pharmacology/SAR (which as far as my limited knowledge goes suggests it may be a bit serotonergic, maybe more towards being a reuptake inhibitor?)



Spoiler: *locaserin








not related but interesting in it's own right
this is primarily serotonergic 
and a controlled substance in the USA
allegedly has some psychedelic-ish effects in high doses
but who would really want to?


----------



## Dresden

I have a hunch this one would be better due to greater ring activation afforded by the added methoxy group:






However, I was completely wrong about 3-MeO-MA, which is almost devoid of psychoactivity (I actually tried it.).






However, this one is known to be active:






* * *

We can dance if we want it.  We can go to a place they'll never find.  Because your friends don't dance, and if they don't dance, well they're no friends of mine.  As long as we have music, everything will work out fine.

* * *

This






is probably a safer bet, as N-methylation makes these compounds weaker and smoother.

And I seriously doubt that






is a reuptake inhibitor.

This






might be one though.

* * *

Bad seed from bad sperm.
Herb got my wig fried like a bad perm.


----------



## Bagseed

Dresden said:


> Beats me.
> 
> * **
> 
> I bomb atomically.  Socrates' philosophy and hypotheses couldn't stop these lyrical armed robberies...


could you technically call this a tryptamine?


----------



## Dresden

Indole.  But tryptamines are a subset of indoles.  That is, all tryptamines are indoles, but not all indoles are tryptamines.  To illustrate, here are the basic hydrocarbon skeletons of each:






Tryptamine






Indole (JENKEM)

My compound 






has its N in the wrong place to technically be called a tryptamine but is definitely an indole and possibly a wicked good trip!!!


----------



## aced126

Is it possible to see the source stating 4-MA is a metabolite of mephedrone. I simply cannot see how this could happen. Reducing the alpha ketone would make the molecule more lipophilic and harder to excrete.


----------



## Dresden

I'm pretty sure the benzylic keto of mephedrone is simply reduced to the corresponding alcohol but not any further for that C.  In other words, I don't think 4-MA is a metabolite of mephedrone.  If it were, then (pseudo)ephedrine ought to be metabolized to methamphetamine!  

Of course, not all metabolic reactions of drugs are sensical or necessarily make the subject less high.  For example, about 10% of an oral dose of MDMA gets converted to MDA, which is even more potent per mg than MDMA in most respects.


----------



## aced126

SKL said:


> Boy, that sent me a bit down the rabbit-hole, and I'm a bit intrigued. I knew the soundbite, and it's available on Wiki, but trying to dig deeper, I can find next to nothing about amfepentorex and it's pharmacology via the usual venues, but haven't found much.
> 
> There's not a lot of useful information I could readily find about it, except for the basics, it was marketed in France as an appetite suppressant, etc., save a few references that I think I'd have to track down in print (fortunately I have access to a wonderful public library here in the City that stocks 1960s era _Chimica Therapeutica_, Vol. 2, Pg. 260, 196, if that will help at all ....)
> 
> Now, this is a pretty interesting chemical, actually. Question being, how far can we take single ring substituted amphetamines? A lot of us will be familiar with 4-methyl-AMP, which by all accounts wasn't very impressive, and is more serotonergic than anything else, I've actually seen some contradictory reports as to whether it's a serotonin/dopamine releaser or an S(N?)DRI. The EMCDDA has a pretty solid report about it. This of course, is without the N-methyl. 4-methyl-MA is a metabolite of mephedrone, and has some role in it's activity I figure, but sounds kind of toxic. So I guess the question is, what do we get by the N-methyl and particularly elongating the chain at the 4 position? If I can only hazard a guess I think this molecule might have some significant serotonergic activity which might well have to do with it's utility as an appetite suppressant, _a la_ locaserin (which see, is an also interesting molecule ...), but evidently retains some dopaminergic/amphetamine type actions as well. I've really had some trouble locating specific information about this molecule, it seems rather forgotten, although the time I've spent is limited. My interest is a bit piqued though. More later maybe. I'd love to know any sort of subjective account of this experience or of course more details about it's pharmacology/SAR (which as far as my limited knowledge goes suggests it may be a bit serotonergic, maybe more towards being a reuptake inhibitor?)
> 
> 
> 
> Spoiler: *locaserin
> 
> 
> 
> 
> 
> 
> 
> 
> not related but interesting in it's own right
> this is primarily serotonergic
> and a controlled substance in the USA
> allegedly has some psychedelic-ish effects in high doses
> but who would really want to?



I don't think it would have much SERT action if my reasoning is correct.

http://onlinelibrary.wiley.com/doi/1....201300013/pdf
http://www.ncbi.nlm.nih.gov/pubmed/2623014

The active site of SERT seems to be very tight. The second link shows that ethylidenedioxymethamphetamine (methyl group on methylene carbon) is half the potency MDMA. Isopropylidene derivative (2 methyl groups on methylene carbon) has no activity at all. I don't think a long chain like that is going to fit.


----------



## Dresden

I wonder why they took it off the market?


----------



## aced126

All metabolic reactions are "sensical" in that they all ease excretion of the new metabolite. That doesn't necessarily mean the metabolite might have more or less action at its target.


----------



## Dresden

"All" can be a tricky word when taken literally.  Of course, I can't think of any counter-examples.


----------



## Bagseed

Dresden said:


> has its N in the wrong place to technically be called a tryptamine but is definitely an indole and possibly a wicked good trip!!!


ah I overlooked the missing carbon in there. do you think it would be active / psychedelic with a CH2 group squeezed in between the indole and the cyclohexane? (or between N and cyclohexane) ^^


----------



## Dresden

Possibly.  I was trying to propose a PCP like molecule with tryptamine like psychoactive properties.

The Infamous PCP:






What I proposed:






What you proposed:






Now that is, arguably, sort of a tryptamine.  I know this one is supposed to be a doosey:






And you won't see me volunteering to take this:






But maybe that's because I hate AMT, which other people love, and which kills people with some regularity.

AMT:






5-MeO-AMT is even more nefarious:






But, for some reason, I would like to try 4-OH-AMT:






And this little potentially stoning spunion (a spunion is a spun youngin'):






But would rather opt for this:






And no, I am not on






today.  Only the highly legal






propylhexedrine!


----------



## Bagseed

yeah I always wondered why other AMT analogues never really were explored...


----------



## Nagelfar

start with cocaine (my favorite for some reason, not my DOC but in QSAR I can't get it out of my mind)






Back-bridge the nitrogen on the tropane + bridge the carbmethoxy and remove the oxygens to where the bridge on the nitrogen splits off, and make that styrene into a triple bond instead of double, and...


----------



## Nagelfar

Dresden said:


> And this little potentially stoning spunion (a spunion is a spun youngin'):



I thought a spunion would be an onion cross bred with khat.


----------



## pharmakos

actually its an onion crossed with mormon tea


----------



## Dresden

It's still a 17 year old boy on a thumbprint of LSD.  Here's another one I want to try.






Sasha left virtually wide open the field of ring substituted tryptamines.


----------



## pharmakos

fuzzy psychedelic pseudoempathogen, or auditory mindfuck?  or both?  neither?   who knows!


----------



## crmt28

Let's try the same with phenethylamines:

Adding 3'-aza to the cylcohexyl ring: 

1-phenyl(3-azacyclohexyl)amine






With 2-keto: 1-phenyl(2-keto-3-azacyclohexyl)amine






Now let's have some fun:

Amphetamine versions instead:

1-phenyl(2-methyl-3-azacyclohexyl)amine
1-phenyl(2,3-dimethyl-3-azacyclohexyl)amine












Norbane mostruosities in the cyclohexyl ring:

6-phenyl-2-azabicyclo[2.2.1]heptan-6-amine
2-methyl-6-phenyl-2-azabicyclo[2.2.1]heptan-6-amine











Now some "psychedelics"

2C-C / DOC version (Chlorine just because ketamine, bromine and alkylated versions welcome)

1-(4-chloro-2,5-dimethoxyphenyl)-(3-azacyclohexyl)amine / 1-(4-chloro-2,5-dimethoxyphenyl)-(2-keto-3-azacyclohexyl)amine / 1-(4-chloro-2,5-dimethoxyphenyl)-(2-methyl-3-azacyclohexyl)amine















(Now just add a subtitutent to the amine as you like)


----------



## crmt28

Here are some interesting examples:

3-MeO-PCP / 2C-B Hybrid

3-(4-bromo-2,5-dimethoxyphenyl)-3-(piperidin-1-yl)piperidine







Let's switch around the methoxies and make something closer to ketamine:


3-(2-chloro-3,4-dimethoxyphenyl)-3-(methylamino)piperidin-2-one






We can also switch the keto group around:

3-(2-chloro-3,4-dimethoxyphenyl)-3-(methylamino)piperidin-4-one






Here's the 2-FMA norborane / PCP one

6-(2-fluorophenyl)-2-methyl-6-(piperidin-1-yl)-2-azabicyclo[2.2.1]heptane






The possibilities are pretty much endless!


----------



## roi




----------



## Nagelfar

^simple m-amp + MPH. But it begs the question, is β-Phenylmethamphetamine and related a DRI or a DRA? Anyone know?






phenmetrazine + the tropanesque cyclohexane






^just silliness. The "dimerization"-type product of that _chromen-2-one_ functional cocaine analog with strobamine on the other side, because it's somewhat formed as it's inverse.


----------



## Nagelfar

I was thinking the thiambutenes may be a better match for a methylphenidate styled opioid than the fentanyl's, esp. after looking at that simple opioid dimethylaminopivalophenone:






^Are we getting closer? Any input/feedback on the above?


----------



## Dresden

Just because.  And






PMEA

^--Hopefully/presumably less deadly than PM(M)A and, hopefully again, possibly bestowing a unique, smacky feeling.






^--Can't vouch for it first-hand, but heard second-hand (hearsay, I know) at the Hive to be a highly visual and rewarding psychedelic.  N-methyl, N-ethyl, 3-chloro, and 3-iodo variations can be made as well.  The same OP referred to the often deadly






PMA as a "crappy, ecstasy type drug."






Thinking 2,4-di-MeO-amphetamine is at least about as active as TMA-6, which isn't necessarily saying much of anything.  Possibly stoning.






Can't read 2,6-di-MeO-amphetamine either way.






Would be surprised if 3,5-di-MeO-amphetamine did anything.






I have very low expectations for 2,3-di-MeO-amphetamine.






3,4-di-MeO-amphetamine has always looked great to me, but apparently you have to ingest half a gram or more to get many desirable effects such as visuals.

The trimethoxy amphetamines are well covered in PiHKAL.  The dimethoxy amphetamines, not so much.  Unfortunately, however, all methoxylated amphetamines are illegal here in the U.S. per the Controlled Substances Act (CSA).






Lidocaine inspired amphetamine.


----------



## aced126

Nagelfar, I posted your mph/amphetamine molecule a while a go. I expect it to have DRI properties only; it seems the carbomethoxy binding to a tyrosine residue in DAT gives DRI activity.


----------



## Dresden

Yeah, I did too.  As for beta-carbomethoxy(meth)amphetamine's properties, it's impossible to be sure without making and testing it, which applies, I know, to pretty much all the molecules in this mega sticky thread.


* * * 






I used to have high hopes for this one, a eugenol derived MDMA metabolite, but then heard somewhere it is only like 1/50th as good a neurotransmitter releaser as MDMA.  Plus, I lost interest in it somewhat after trying and being disappointed in 3-MeO-MA.  Come to find out today, it's an oxytocin and vasopressin releaser, so all hope is not necessarily lost on it after all.






I'm just calling this thing THE BEAST and the next one






THE BEAST, JUNIOR.

These last two are great research chemical fodder to skirt the new law in the U.S. anyway.


----------



## roi




----------



## SKL

^i'd try that, well, as long as someone else tried it first


----------



## Dresden

This has elements of both a dopamine reuptake inhibitor (a beta carbomethoxy group is present) and a 5-HT and DA releaser (mephedrone does both to the extreme), so I don't know which it would be.  However, according to ebola?, all NT releasers are also reuptake inhibitors, but tbh, I don't know if that's true and, if so, if it means anything important.  Aced126, a penny for your thoughts on that?






MEPHEDRATE

Since the carbomethoxy group is hydrolyzed to the carboxylic acid fairly quickly, the duration of this little gem is most likely (and probably thankfully) relatively short.  I would expect it to last no longer than between 1 and 3 hours.

* * * 






ENIGMA






ESTER-METH

Aspartame inspired (+)-N-methylacphetamine (the m for methyl immediately after the a for alpha has been replaced with a c for carbomethoxy).  Cannot be easily made from L-phenylalanine, the naturally occurring isomer of phenylalanine!

 * * *

"dizzy like this, dizzy like this, dizzy like this, dizzy like this, dizzy like this, dizzy like this, dizzy like this, dizzy like this"


----------



## aced126

It's going to be a releaser if 1) it is a substrate of the respective transporter, 2) it can dissociate from the transporter once inside the neuron, 3) it can release neurotransmitters from their vesicles and 4) it can trigger the transporter to reverse its function and transport neurotransmitters from the cytosol to the synaptic cleft. 

All releasers will be reuptake inhibitors to an extent, because it will occupy the transporter for an amount of time, in which the endogenous neurotransmitter can't bind and be reuptaken. However, if the exogenous drug is reuptaken quickly, this time will be very short and so reuptake won't be blocked as much (given the transporter hasn't been reversed in function). Releasers also block reuptake by the fact that they make reuptaking transporters work in reverse, which in essence is blocking reuptake of the transporter as well as releasing more cytosolic neurotransmitters.

Good specific reuptake inhibitors will be substrates of the transporter but either 1) block the conformational change taking place in the transporter, or 2) dissociate to a lesser extent than releasers once exposed to the cytosol. I'd guess they satisfy 1) by causing sterice and/or electric hindrance and 2) by stronger binding interactions. 

For the molecule above, is it likely to be a substrate of DAT and SERT? Yes.

Is it likely to cause much steric hindrance preventing the transporter from transporting? Maybe, like ritalin does

Is it likely to have problems dissociating from the transporter once exposed to the cytosol? Yes, like ritalin, because of the stronger interactions with TYR156 in DAT and TYR163 in SERT.

What role will the methyl group play? It will increase SERT affinity by causing stronger VDW binding interactions with the very lipophilic part of the active site of SERT. Overall though, not much cytosolic 5HT will be released and more will be released from natural vesicle release. SERT is likely to be blocked however. This might give the molecule SSRI properties. 

Compare the molecule to 4-methylmethylphenidate. Not much acute serotonin activity at all. If you take it similar to an SSRI regime, one might expect antidepressant effects to start after a couple of weeks. 

It should however be a good dopamine reuptaking inhibitor, the effects of which are much more easily observed acutely.

Tldr; like ritalin, a pure reuptaking inhibitor with maybe some SSRI properties as a result of this


----------



## dopamimetic

I'm thinking about the possibility of a fusion between an arylcyclohexylamine and an oxazoline-like stimulant e.g. MXE & 4-MAR. 

I know that there have been proposed PCP analogues with a 5 instead of 6 chain ring -> now take this and combine... probability for it to actually work is next to none, but it would make some super-maniac-roflcoptr-rolling-neuroprotective RC in one molecule


----------



## aced126

Just take both at once?

On a different note, does anyone know that effect of a beta carbomethoxy group on binding to and interacting with different 5HT receptors?


----------



## aced126

Dresden, your ester meth molecule is very similar to O-methylphenylalanine and might well have been documented. Anyone know if this analogue of said amino acid has been made?


----------



## Dresden

Is O-methyl-phenyalanine active as a stimulant?  Thanks for the info on mephedrate, too.






What about ENIGMA's projected pharmacology?


----------



## aced126

From what I know about the alpha methyl group, it is increases logP and may play a role in binding interactions but its main role is blocking oxidation at the alpha carbon. Phenethylamine is a very potent releaser of dopamine but its very short half life (~30 seconds) blunts its action. Now, about this compound, it is unlikely to be a good substrate at MAO, but it might be prone to demethylation at the ester which will terminate activity, and also it may lead to different electronic effects at the receptor. It might even cause a steric clash but then again prolintane is a good reuptake inhibitor.


----------



## Dresden

aced126 said:


> On a different note, does anyone know that effect of a beta carbomethoxy group on binding to and interacting with different 5HT receptors?


 
Looks like we have the same question.  But yeah, the beta carbomethoxy will shorten enigma's half life dramatically in comparison to mescaline in all likelihood.  I would expect its half life to be in the 1 to 2 hour range, but that's just an estimate.  Possible DRI properties as well?  Who knows.


----------



## Nagelfar

Dresden said:


> Lidocaine inspired amphetamine.



This'd be interesting in showing whether a sodium channel blocker that is a DRA (and not a DRI) has any enhanced euphoric (action potential electron resonance playing a factor) faculties; the old idea of that being one of the oft overlooked potential areas of cocaine's efficacy.



aced126 said:


> Nagelfar, I posted your mph/amphetamine molecule a while a go. I expect it to have DRI properties only; it seems the carbomethoxy binding to a tyrosine residue in DAT gives DRI activity.



but we've been around in circles with the non-ecgonine tropane (para-NO2 according to clubcard) and tropacocaine being capable DRIs having little to do with that. Whether it stabilizes that affinity specifically to a larger or smaller degree, well, I just wonder what beta-phenyl-amphetamine and some of the desoxypipridrols are DR I or As


----------



## aced126

Crap I just realised I commented on ester meth rather than enigma. About enigma, I don't really know the 5HT pharmacophore well and so I couldn't really comment on the effect of the carbomethoxy binding. As you already said, in terms of pharmacokinetics, this will probably be a short acting psychedelic due to ester hydrolysis terminating activity.


----------



## Midnight Sun

aced126 said:


> Crap I just realised I commented on ester meth rather than enigma. About enigma, I don't really know the 5HT pharmacophore well and so I couldn't really comment on the effect of the carbomethoxy binding. As you already said, in terms of pharmacokinetics,* this will probably be a short acting psychedelic due to ester hydrolysis terminating activity*.



might be a good way to mitigate DOx/dragonfly duration?

either that or it'd make the residual sides worse, hmm


----------



## aced126

Yeah alright then, the carbomethoxy might not be essential. However compare methylphenidate to its counterpart with a saturated beta carbon (I drew it a while ago, was apparently an already documented releasing agent which caused seizures at low doses). The removal of the carbomethoxy group confers releasing qualities.


----------



## aced126

Yeah good idea Midnight, presuming the molecule pharmacodynamics aren't significantly altered due to the new moiety.


----------



## Nagelfar

aced126 said:


> Yeah alright then, the carbomethoxy might not be essential. However compare methylphenidate to its counterpart with a saturated beta carbon (I drew it a while ago, was apparently an already documented releasing agent which caused seizures at low doses). The removal of the carbomethoxy group confers releasing qualities.



Perhaps in some occasions but 4'-NO2-phenyltropane (non-ecgonine i.e. sans the carbmethoxy) seems to have been vouched for as not emulating the stimulation conducive to observing phosphorylation compromised life-cycle of MAT (quickly flushed from BBB i.e. cocaine comparable duration)


----------



## Midnight Sun

aced126 said:


> Yeah good idea Midnight, presuming the molecule pharmacodynamics aren't significantly altered due to the new moiety.



I'm sure it would still fit in the binding pocket however the obvious metabolic result concerns me: would it be, let's say, 5 hours of tripping then a sharp dropoff to residual stimulation that won't dissipate for 20 hours?

I dunno, relocating the acetoxy to the most unimportant position of 3,4,5 TMA (3 I think) might be better 

I made this weird sort of hemifly thing:





I'll just stop lol


----------



## aced126

I'd actually say the half life would be similar to methylphenidate (1-2 hours) as both molecules would get hydrolysed at the same rate by the esterase enzymes.


----------



## roi

Phenobarbital/PCP hybrid:


----------



## Midnight Sun

aced126 said:


> I'd actually say the half life would be similar to methylphenidate (1-2 hours) as both molecules would get hydrolysed at the same rate by the esterase enzymes.



was this directed at me?

if so the metabolite half life itself is what concerns me as it's more than capable of peripheral stimulation for hours...and hours... basically until MAO can deaminate it

***

any bourbon drinkers ITT?  someone recommend me something <20$ to drink tonight


----------



## aced126

Midnight Sun said:


> was this directed at me?
> 
> if so the metabolite half life itself is what concerns me as it's more than capable of peripheral stimulation for hours...and hours... basically until MAO can deaminate it
> 
> ***
> 
> any bourbon drinkers ITT?  someone recommend me something <20$ to drink tonight



The carboxylic acid metabolite wouldn't cross the BBB much so I don't think peripheral stimulation would occur. And yeah, it should mostly be hydrolysed outside the brain, in the liver.


----------



## Dresden

Note the similarity of ester meth






ESTER METH

to mexedrone, a new 4-MMC substitute research chemical.






MEXEDRONE

I have come to the tentative conclusion that R-(C=O)-OCH3, R-(C=O)CH2CH3, and R-CH2OCH3 are largely bioisosteric.  Comparing sufentanil to fentanyl led me to formulate this hypothesis.


----------



## aced126

They are not bioisosteric... they have different chemical properties and thus have different pharmacodynamic and pharmacokinetic effects. Here is a hypothetical situation:

Say your first compound was able to bind to the active site of an enzyme where the ketone formed 2 hydrogen bonds with serine residues and the single bonded oxygen also formed 2 hydrogen bonds with say a tyrosine and threonine residue. Your second compound would only form the first 2 interactions described. Your third molecule would only form the 2 latter interactions described. The first molecule would bind strongly to the enzyme and inhibit it the most. Likewise if R is aromatic there will greatly differing ring density changes. The first 2 compounds will withdraw electron density by conjugation (the first compound doing so more) and the final compound will actually increases electron density (or maybe decrease it slightly, but much less so than the first 2 examples; there are 2 competing factors: the electron pushing effect of the methyl group and the inductive electron pull of the electronegative oxygen. This is going to have effects on pi stacking etc, so again it might change pharmacodynamics at the biological target.

Furthermore, there will be pharmacokinetic differences. The ether will have the longest half life. The ketone can be reduced to an alcohol and conjugated for easy excretion. The first molecule can be cleaved by enzymes to give a very polar and easily excretable carboxylic acid. 

If 2 drugs with different structures work, that does not imply the 2 structures are bioisosteric, but rather that both the molecules just fit the pharmacophore. There are different pharmacophores for different biological targets. This may work for opioid receptors or MATs, but you can't generalise that to the vast array of proteins and DNA which exist as biological targets. I'll try dig up some counter examples where your hypothesis is contradicted.


----------



## Dresden

Maybe so, maybe not.

I'm aware they have wildly differing pharmacokinetics.





















Actually, a couple of those look too similar to poison hemlock's active ingredient, coniine, for comfort.






CONIINE

Safety testing (not on yourself, either) is again of paramount importance!!!

* * *

In other news,






TRYPTACAINE


----------



## Nagelfar

Dresden said:


> Actually, a couple of those look too similar to poison hemlock's active ingredient, coniine, for comfort.
> 
> 
> 
> 
> 
> 
> CONIINE



Well, you have those coca alkaloids like ferruginine:






Which look like toxins, one named for instance "Very Fast Death Factor" (VFDF):


----------



## Nagelfar

Doxpicomine 
	

	
	
		
		

		
		
	


	




 8 times morphine.

chemicalize.org has been on the fritz for me lately, I have some compounds I want to draw related to the above, and chemicalize.org keeps giving me a 503 temp service unavail. msg. (and has for the last three days from the library) anybody have any other html online chem programs? I know clubcard told me about one that rendered in 3D also to compare structures and I lost in which post he told me about it. Could someone PM me with a couple of different sites so that I may keep churning out the random molecular madness?)

EDIT: got it to work for a second:

coniine + VFDF ( ;-p ) 
	

	
	
		
		

		
		
	


	




EDIT:

Really wanted to post this other one but chemicalize.org is going on the fritz again. Did it get too popular for its server to handle or something?

EDIT:

2 minutes left on lib. comp. got this to work:






Peroxides make it unstable? I like how the carbmethoxy shares the 3 position with the benzoyloxy if at the least. V. high electronegativity though. ;-p


----------



## aced126

Just use opsin if you know the nomenclature.


----------



## Dresden

Too many oxygens in too close a vicinity for that last one to happen.

But yeah, opsin or MarvinSketch.
















ISONICOTINE


----------



## neurotic

isonicotine, that's a sexy molecule with a sexy name... how different from benzene is pyridine? i.e. could one expect that molecule to behave like amphetamine? please chemistry, please


----------



## aced126

Kinda similar, kinda not...

In pyridine, there is a basic nitrogen with a lone pair in a plane perpendicular to the pi cloud; I'd imagine it could form H bonds with suitable amino acid residues like serine. It could also become protonated and form ionic interactions with negatively charged amino acid residues like aspartate. The electronegative N will withdraw sigma electron density from its nearest surrounding 2 carbons the most but I'm not completely sure what biological effect this could have. Not sure on the effect of possible pi stacking interactions a pyridine will have. I'll do some research and expand this post.


----------



## roi




----------



## Nagelfar

Dresden said:


> But yeah, opsin or MarvinSketch.



MarvinSketch is chemicalize.org, damn thing still isn't working right.

There was a 3D one clubcard mentioned somewhere, back in this thread I believe, that I can't find now.

opsin:






I found the shotty pubchem one:






caffeicaine


----------



## aced126

Roi, rationale for trifluoroethyl moiety? Why can't it just be a tertbutyl group if you're looking for steric hindrance of carbonyl carbon?


----------



## roi

random != rationale


----------



## SKL

Find mephedrone too short-acting and compulsive? Mephedrone ER, anyone?

Captadrone. 






Mephevanse.






(_edited to remove some things I realized need a little work..._)


----------



## Nagelfar

Well chemicalize.org is still crapping out on me. Anyone else have this problem? Is it my location? (my library's connection?) I used that Osiris program, but it hangs whenever I input by SMILES or CAS reg. #., and after I get to a size of a drug roughly a few atoms bigger than cocaine it totally freezes on me (no pun intended: due to all the extra calculations of drug-likeness I am assuming)


----------



## Poelster

Dresden said:


> Lidocaine inspired amphetamine.



Put a para-hydroxy on there and you might have yourself a nice opioid.


----------



## aced126

Mephevanse would require a really high dosage though, like 500mg I'd say, and also wouldn't it be short lasting as well?


----------



## SKL

aced126 said:


> Mephevanse would require a really high dosage though, like 500mg I'd say, and also wouldn't it be short lasting as well?



Modeling it on Vyvanse (lisdexamfetamine), it should have probably twice to three times the duration of mephedrone? I suspect it would require a similar adjustment in dosage. Also since the enzymes responsible for the metabolism are in the red blood cells it would be longer acting regardless of RoA unlike, I think, "Captadrone." It'd be a bitch of a synth though.


----------



## SKL

Running with the Vyvanse theme, what if we replaced the amino acid with a biologically active tryptamine?

Somewhat fancifully ... Shroomphetamine.


----------



## aced126

Right, how would that molecule cleave; Also why are there a few out of place amino groups?

Off-topic: why does vyvanse even work? I mean, what advantages does it have over say N,N-dimethylamphetamine as a prodrug to (meth)amphetamine. Is it just that the lysine moiety is easily cleavable? Why does cleavage occur in the RBCs? Why can't it get cleaved in the stomach by peptidases? This guy seems to prove my point (not very scientific but we have grounds to believe this is true).http://www.bluelight.org/vb/threads...ersion-update-The-trypsin-method-is-confirmed


----------



## aced126

http://www.bluelight.org/vb/threads/405660-Paper-I-wrote-about-LisDex-to-D-Amp

There's this as well which is intriguing...lol

Furthermore, the half life of lisdexamphetamine itself is only 1 hour; that means that whatever amphetamine is going to be released is going to be released within that first couple of hours before the concentration of lisdexamphetamine becomes negligible. Having said that, I don't really understand how lisdexamphetamine is claimed to be a sustained release source of dextroamphetamine.


----------



## aced126

Right, I actually just got a potentially good idea; any comments and expansions are appreciated:

N-(1-(benzo[1,3]dioxol-5-yl)-propan-2-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide






Right, that was for fun, but the idea still holds; could a homeostatic equilibrium be maintained by administration of a selective monoamine releaser which releases the monoamine itself? I've definitely heard of anecdotal reports of people being able to abuse MDMA way longer than they should be able to and at much higher sustained frequencies by integrating 5-HTP into their use.

More derivatives:










How about a really selective serotonin releasing agent? Could this be a potential antidepressant when coupled along with a built-in dose dependant 5-HT releasing mechanism?

N-(5,6-methylenedioxyindan-2-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide





Off topic: does anyone know any brain enzymes which are specific to the brain and not really found anywhere else?






And finally: this should be the most selective of all I'd say:

N-(1,3-dihydrocyclopenta[f] indan-2-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide


----------



## SKL

aced126 said:


> Right, how would that molecule cleave;



If I am wrong about this, that's why I called it "fanciful" 

If I'm right, like so:

*Sharman J and Pennick *. Lisdexamfetamine prodrug activation by peptidase-mediated hydrolysis in the cytosol of red blood cells. _Neuropsychiatr Dis Treat_ 2014; 10: 2275–2280. 

Whether the psilocybin would remain intact, I'm not sure, that's where the "fanciful" part comes in again.



> also why are there a few out of place amino groups?



I goofed. Fixed the original post above, I think.



> Off-topic: why does vyvanse even work? I mean, what advantages does it have over say N,N-dimethylamphetamine as a prodrug to (meth)amphetamine. Is it just that the lysine moiety is easily cleavable? Why does cleavage occur in the RBCs? Why can't it get cleaved in the stomach by   ? This guy seems to prove my point (not very scientific but we have grounds to believe this is true).http://www.bluelight.org/vb/threads...ersion-update-The-trypsin-method-is-confirmed



From *Pennick M.* Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine. Neuropsychiatr Dis Treat. 2010;6:317–327 (cited in _ibid_.)


> LDX was not metabolized in vitro by SGF, SIF, or trypsin, supporting our view that any conversion of LDX to d-amphetamine in the GI tract in vivo is likely to be minimal.


----------



## aced126

How would this idea now compare if SSRIs were used instead? Desmethylsertraline is 50 times weaker than the N-methylated metabolite, yes, but it still has a Ki constant of 76nM and negligible constants at the other 2 transporters. So how about this:

Tryptaline

N-((1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide






Not sure whether this will be a substrate of the enzymes but the N-methylated version to hopefully yield sertraline itself:






Tryptoxetine

N-methyl-N-(3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide






Norfluoxetine is still very selective in its own right, just a slight dosage increase might be needed. 






In fact this would probably be better as for everyone one molecule of norfluoxetine released, only one molecule of 5-HTP is released as well. And with the low SSRI dosage, little 5-HTP will be released anyway. So any increase in dosage helps. In fact (since all these drugs and 5-HTP have a MR of about 200), maybe 50-200mg of the molecule would be ideal each dosage as roughly this amount of 5-HTP would be released.


----------



## aced126

Now for the dopamine series:


----------



## SKL

aced126 said:
			
		

> various interesting molecules



The 5-HTP one is definitely of interest, I'm quite familiar with the same anecdotal reports although off hand I don't know of hard evidence. 

The MDAI derivative similarly sounds interesting, if it works the way we're assuming it does, I think it would be kind of sedating, dreamy, and euphoric? As an antidepressant I don't know, as a recreational drug, it might be to the taste of some.

We all know that SSRIs attenuate the effects of MDMA, so dose might need to go up, which is potentially problematic, although allegedly SSRIs have some protective effects against MDMA neurotoxicity. With all the MDMA derivatives I'd worry about potential serotonin syndrom lurking somewhere in the background.


----------



## sekio

I think part of why you don't see prodrug-and-releaser combinations in one molecule very much is because you need a lot more of the monoamine precursor to have a useful effect than 1 mol equivalent. For e.g. MDMA, with a molecular weight of 193 g/mol and 5HTP m.w. 220 g/mol  that means a ~100mg MDMA dose would only produce about 114mg of 5HTP). I was under the impression 5HTP doses needed to be at least twice that for pre-loading.

I believe that focusing instead on high-protien (make sure its balanced in all the amino acids you need, or even better use multiple sources of protien...) snacks and meals is probably more useful all-around than focusing on any single neurotransmitter precursors. A snack of dried fruit, mixed nuts, and some pepperoni is much better tasting than a fistful of gelatin capsules full of broad beans, anyway. As a bonus, you are likely to get a bunch of other food based nutrients along for the ride, which is always good for recovery - and health in general.

I also have suspicions that stapling a rather quite polar 5HTP amino acid onto otherwise active compounds will affect PK and distribution, maybe negatively. The unmasked phenolic OH is especially concerning because it will probably be ionized in the duodenum - where drugs would normally otherwise assume an uncharged form. A charged drug cannot diffuse throguh the fatty cell membranes and as a result, will not be absorbed into the hepatitic portal vein. This means oral BA can be expected to be quite low. (c.f. morphine, 5-OH-DMT)

L-DOPA is even worse in terms of pharmacokinetics due to polarity. The double aromatic hydroxide aka catechol arrangement is super duper water soluble. The only reason L-DOPA can make it into the brain is through active transport. Peripherally administered IV dopamine is actually used in cases of... uh, something to do with the heart, I'm not a cardiologist. But it's used, all right. However, dopamine itself won't cross the BBB so pure DA injecions outside the brain don't have a reinforcing effect.

On the topic of "why lysine in lisdexamphetamine" - I can hear the audience asking that question 
I suspect that lisdexamphetamine was the most promising amphetamine prodrug selected after a quick screening effort; there are after all only 20-some amino acids that are common. Having some lab guy plug dexedrine on a Merrifield resin and whack it a few times with all the amino acids they have in their storeroom, and feeding the resulting compounds to rats to see how they behave, seems to me exactly the sort of primary research that gets your name on a patent, and puts smiles on the executives who sign your paycheck. (That's just a guess, though... it would be nice, however, to read a story straight from the farm - so to speak...)


----------



## Midnight Sun

aced126 said:


> Mephevanse would require a really high dosage though, like 500mg I'd say, and also wouldn't it be short lasting as well?



The chinese tried something like this with n-benzyl mephedrone, it was a flop for the exact reasons you stated (if meph was an order of magnitude more potent there might have been potential though)



aced126 said:


> N-(5,6-methylenedioxyindan-2-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide



I really like this

The potential of MDAI as an antidepressant has always intrigued me despite my never having used the drug.  I'd still be concerned about serotonin depletion though...  Even with something as weak as MDAI it's still a pertinent concern... would a halogenated indanyl (remember 5-IAI?) be better?


----------



## Dresden

I like these, but shouldn't the hydroxyl be in position #4 instead of #5?  (or else a methoxy at 5)

Nevermind, I think I see your rationale.  You're trying to get it to release 5-HTP.


----------



## aced126

Sekio, I don't think the phenolic OH (pKa ≈10) would be deprotonated in the duodenum (pH 7-8.5). Anyway, I was meaning for pancreatic enzymes to break the amide bond. Once broken they follow respective pharmacokinetics of their parents.

Sekio, couple another molecule of 5HTP onto the protein chain if you want to release 2 molecules of HTP instead of 1 for every molecule of SRA? 

I know you could just eat proteins, but I think it could be used as an anti abuse or sustainable mechanism.


----------



## aced126

Dresden, I double checked Wikipedia and the hydroxyl moiety is in the correct position for 5HTP release.


----------



## Pomzazed

There are random, yet not so random molecules...
(which means synthetically not too far-fetched^, there are many other commerciallized meds with synth step harder than this)
This forum has keen eyes, i think ones like (eg. sekio) should be able to guess what these should be, they fit in some "requirements"*

(*in 2-D like plus my "imaginary" molecule simulation , I havnt tried 3D structure and minimize energy yet)


----------



## aced126

Pomzazed said:


> There are random, yet not so random molecules...
> (which means synthetically not too far-fetched^, there are many other commerciallized meds with synth step harder than this)
> This forum has keen eyes, i think ones like (eg. sekio) should be able to guess what these should be, they fit in some "requirements"*
> 
> (*in 2-D like plus my "imaginary" molecule simulation , I havnt tried 3D structure and minimize energy yet)



What are these molecules meant to do?


----------



## Nagelfar

Trying to just heighten the electronegativity of cocaine by adding oxygens, but wonder why the likes of these two bonded tropane-3 position substituents aren't to be found (by me, at least) in the literature:

carbmethoxy:





acetoxy:





cyclopentane dioxy:





cubism:





possible threat to the O-zone layer:





EDIT:

Since there was a study that said co-ingestion of capsaicin containing foods with cocaine could be contraindicated and even fatal, I wonder if the opposite TRPM8 receptors, the cold sensitive ones that respond to menthol and the like, might be protective? Probably just absurd childlike reasoning on that one, but none the less, here's cocapulegone:


----------



## aced126

Why do you want to increase electronegativity?

These compounds might struggle to get past the BBB.


----------



## Nagelfar

aced126 said:


> Why do you want to increase electronegativity?
> 
> These compounds might struggle to get past the BBB.



The acetoxy, at least, should have better BBB penetration. Electronegativity is supposedly a catch-all for meaning better @ MAT ligand affinity, speed of onset, etc. ask clubcard. I dunno the exact mechanism.






















1-(3-Chlorophenyl)-4-(2-phenylethyl)piperazine (3C-PEP) _**PLUS**_ delta-9-tetrahydrocannabinol (THC) :






Beside the phenylethyl tail, there's only the chloro and the two nitrogens difference


----------



## Dresden




----------



## roi




----------



## belligerent drunk

Nagelfar said:


>



I like that. Now go and make me some!


----------



## Nagelfar

belligerent drunk said:


> I like that. Now go and make me some!



Get the precursors together and some academically learned lab-certified assistants with product handling licensing and you've got it


----------



## Dresden




----------



## aced126

Dresden said:


>



What's the idea of this?


----------



## Dresden

It's the phenyl to indole analogue of one of the most potent selective dopamine releasers found yet, which was first posted by Nagelfar.


----------



## aced126

I see, neat idea.


----------



## roi

Benzo prodrug:


----------



## Nagelfar

Doodles I made at my Intensive Outpatient group (IOP) from today.


----------



## Nagelfar

Forskolin + Salvinorin A = intermediate:






Carnosol had an interest center cyclohexane formation, it twists into a chair formation and I aligned it to the critical elements of butyltolylquinuclidine:


----------



## Dresden

(S)-p-METHYL-NICOTINE


----------



## Nagelfar

Dresden said:


> p-METHYL-NICOTINE



I like it. I think a lot more use could be made of the nitrogen heteroatom for drug-like compounds.


----------



## Dresden

Nagelfar said:


> I like it. I think a lot more use could be made of the nitrogen heteroatom for drug-like compounds.



Thanks.


----------



## SKL

methylenedioxypethidine. 4-fluropethidine and 3,4-dichloropethidine are apparently more potent as DRIs while retaining opioid analgesic effects so I wonder what we'd have here. could be a risk of nastiness, seizures, serotonin syndrome though ...






If MDPV and U-47700 had a bastard child ...


----------



## Cristall1672

Forgive me those of you who have read this question on two other threads, but I'm looking to gain knowledge before I proceed in vein.  ( Like I've done before)
I'm wondering if anyone knows what brings about the variety of colors of mdp2p. My first batch was the ideal yellow. Realizing that I forgot to pour off the NaOh layer after the mdp2p distilled I did something kind of dumb without thinking. I know realize how senseless it was but I added hcl thinking it would cancel it out. Dumb Dumb Dumb. When I added the acid, it changed colors and turned blue! Of course, I freaked. So I added a little NaOh to cancel that one out. (Honestly looking back, I'm certain my adderal fix had a lot to do with my panic attack) Anyhow, it changed colors again, but not back to the color I was hoping. It's Red.  . I'm wondering what the different colors mean for a molecule. Is it ruined??


----------



## Dresden

"Is it ruined?"

Probably, but we don't discuss chemistry on bluelight.


----------



## aced126

A free phenolic group is important for activity; ethers show very little mu affinity and as such only function as prodrugs (like codeine). The above molecules might eventually get metabolised to reveal the free phenolic group but probably not at great concentrations as other metabolites will likely result first like the cleavage of the ester.


----------



## Nagelfar

^is this all that's required to make a possible pethidine/cocaine intermediate, or would the phenyltropane variant be more viable?






^Is there any rules that would make a sulfur-(when benzene is substituted)-heteroatom untenable? (perhaps another sulfur on the benzoyloxy connecting "C1" benzene position to top it off?)






^I just think this would make a good analogue. The 3β-styrene in place of the 3β-benzoyloxy makes it longer like the 3β-carbamoyl; but since the styrene alkylphenyltropane already has great affinity, and the unsubstituted 3β-carbamoyl does so much better with the meta-nitro despite how gimped it is when alone (and clubcard's raving review of the para-nitro on the shorter phenyl linkage), I think this would be a wonderful addition. The cis-propenyl can be removed, I just had it there to make it a probable SDRI.


----------



## Dresden

aced126 said:


> A free phenolic group is important for activity; ethers show very little mu affinity and as such only function as prodrugs (like codeine). The above molecules might eventually get metabolised to reveal the free phenolic group but probably not at great concentrations as other metabolites will likely result first like the cleavage of the ester.



I'm really sorry if this is a stupid question, but what molecules are you referencing here?


----------



## aced126

The opioid/sndras SKL posted.


----------



## SKL

Thanks aced good feedback if anyone can't tell I'm the rankest sort of amateur just an ex-druggie clinical guy who likes to think up fanciful stuff  so negligible opioid activity and probably too complicated to be decent stimulants yeah?


----------



## Soulfake

2,9-bis(2H-1,3-benzodioxol-5-ylmethyl)-6,13-bis(2H-1,3-benzodioxole-5-carbonyl)-3,5,10,12-tetramethyl-1,7-dioxa-3,5,10,12-tetraazacyclotetradecane-4,11-dione

2x Methylone + 2x MDMA in one molecule (or double-dimerized (bk-&)MDMA)

edit: why haven´t dimerized drugs been made? Like putting two molecules like amphetamine or morphine via a simple linker atom together which would be hydrolized in the body.


----------



## SKL

Soulfake said:


>



Quite a structure.

_Baroque_ is a word that comes to mind ...

This (OPSIN) rendering more resembles a sort of _mandala_ ...






Mandalamine?

Will it break down to the appropriate constituents?


----------



## Dresden

(S)-2-methylamino-1-phenylpropane is a much more elegant name for this than methamphetamine.


----------



## belligerent drunk

Soulfake said:


> edit: why haven´t dimerized drugs been made? Like putting two molecules like amphetamine or morphine via a simple linker atom together which would be hydrolized in the body.



What would be the point?


----------



## aced126

Possibly better pharmacokinetic properties.


----------



## SKL

trifluoromephedrone

It has been made at least academically, I can find next to nothing about it but here, compared to methcathinone (not mephedrone), relatively selective for serotonin ... 

Has this been made or tasted in our world though? yet another serotonin realising warm cuddly mdai type drug?


----------



## Soulfake

belligerent drunk said:


> What would be the point?



I thought about circumventing law´s, maybe some molecules (if they would correctly hydrolize) could give interesting opportunities for "cocktails" like an oxycodone molecule linked together with methamphetamine. Similar to how picamilon works where Gaba is hydrolized from Niacine which are simply linked together on the ketone via oxygen. 
The only downside I could imagine is that it could take some time for the molecule to hydrolize, so it may not be useful for iv consumption and effects would take longer to be felt (which could make for safer drugs or alternatives for stuff like methadone, imagine a type of heroin with the same effects but if used i.v. it would take almost the same time to get a rush as if was swallowed.

There wouldn´t be so many exotic research chemicals if this would be a possible way to go and at least some kind of such drugs would have appeared somewhere though, I think.


----------



## SKL

Soulfake said:


> imagine a type of heroin with the same effects but if used i.v. it would take almost the same time to get a rush as if was swallowed.



Vyvanse does this with dexedrine as the breakdown occurs in the red blood cells (not the stomach acids as some assume and is often the case for XR products...)


----------



## adder

SKL said:


> trifluoromephedrone



How about trifludrone?


----------



## SKL

adder said:


> How about trifludrone?



trifludrone. I like it.

triflephedrone?
trifledrone?
trifle-drone?

it is probably sort of a trifle. I'd try it though TBH.


----------



## Midnight Sun

all this talk of fluoro-drone...


----------



## roi




----------



## roi




----------



## Nagelfar

^I had dreams about hornets and wasps last night after drawing this one.






^MAT torpedo?


----------



## SKL

So this this came into my mind ...








			
				Wiki said:
			
		

> *8-OH-DPAT* is a research chemical of the aminotetralin chemical class which was developed in the 1980s and has been widely used to study the function of the 5-HT1A receptor. It was one of the first major 5-HT1A receptor full agonists to be discovered.
> 
> Originally believed to be selective for the 5-HT1A receptor, 8-OH-DPAT was later found to act as a 5-HT7 receptor agonist and serotonin reuptake inhibitor/releasing agent as well.
> 
> In animal studies, 8-OH-DPAT has been shown to possess antidepressant, anxiolytic, serenic, anorectic, antiemetic, hypothermic, hypotensive, bradycardic, hyperventilative, and analgesic effects.



What can we play with?

A cousin to mephedrone? (7-OH-DPAT is more D2-selective and substitutes for cocaine[?] in rats)






The cliché mentioned in the very first post of this thread?






From thence, a rather baroque TMAish elaboration on the three most interesting positional isomers:






although _n.b._ I found only one very obscure reference to 4,5,6-TMA which says, in keeping with the general trend of the series, it is inactive.

And this doesn't look fun ...






But here is RDS-127, which seems to have some promising properties:






What else?

Following the above (and perhaps reinventing a wheel somewhere), and more mescaline-ish version of TMA-ish thing above:






There are a bunch of interesting things in this genre ...


----------



## Nexus_Tripper

Uniteed Kingoms Legal M.X.E analog


----------



## sekio

> 2x Methylone + 2x MDMA in one molecule (or double-dimerized (bk-&)MDMA)



if you look closely, it's alpha-hydroxymethyl analog of MDMA and alpha-hydroxymethyl analog of bkMDMA ...


----------



## neurotic

your last molecule reminds me of Jimscaline, SKL. IIRC it is a putative potent psychedelic and has high affinity for 5HT2 receptors.

i was looking at 8-OH-DPAT a few weeks ago too and wondering what could be tweaked in there. though, the one derivative that i found that seemed to have the most potential was plain 2-aminotetralin: it substitutes for amphetamine and supposedly is a 5HT and NE releasing agent. though one article reported it caused hypothermia in rodents... very weird (5HT1A agonism may be? i think 8-OH-DPAT does that. anyway it's the opposite one would expect from an entactogen). does anybody know anything about it? i wasn't able to find much literature and zero anedoctal reports of experience with it or the N-methyl homologue...

MDMAT was around but it was barely active. the MD fn group in MDMA is exceptional and never does anything good to other molecules, so there could be a good stimulant hiding behind MDMAT...

anybody knows anything about 2-AT or 2-MAT? may be i'm missing something and it's just boring.


----------



## roi

Flunitrazolam/Pynazolam/Zapizolam hybrid.


----------



## Nexus_Tripper

SKL said:


> trifluoromephedrone
> 
> It has been made at least academically, I can find next to nothing about it but here, compared to methcathinone (not mephedrone), relatively selective for serotonin ...
> 
> Has this been made or tasted in our world though? yet another serotonin realising warm cuddly mdai type drug?



Looks similar to Flephedrone.


----------



## belligerent drunk

roi said:


> Flunitrazolam/Pynazolam/Zapizolam hybrid.



I don't think there's enough nitrogens on that one.


----------



## klfiend

prolly super duper bad for the ole circulatory system...

Is there any information on pyridine analogs of amphetamine?


----------



## adder

SKL said:


> trifludrone. I like it.
> 
> triflephedrone?
> trifledrone?
> trifle-drone?
> 
> it is probably sort of a trifle. I'd try it though TBH.



Well, might not be so safe. I've recently found out that 5-trifluoro-2-AI is 50% as neurotoxic as norfenfluramine, 5-iodo-2-AI has some neurotoxicity as well while 2-AI is non-neurotoxic. So it looks like putting a halogen or a trifluoromethyl group on the ring may be risky no matter how safe the parent compound is. Cathinones are not solely reuptake inhibitors, they act as releasers too, so 4-CMC & 4-BMC might be neurotoxic too to an unknown extent. Something to look into for some researchers.


----------



## klfiend




----------



## Dresden

There's that possibly not probably possible (I've been told, not possible actually) aliphatic N-C-O group again.


----------



## SKL

Nexus_Tripper said:


> Looks similar to Flephedrone.



it does, but should be significantly more selective for serotonin



adder said:


> Well, might not be so safe. I've recently found out that 5-trifluoro-2-AI is 50% as neurotoxic as norfenfluramine, 5-iodo-2-AI has some neurotoxicity as well while 2-AI is non-neurotoxic. So it looks like putting a halogen or a trifluoromethyl group on the ring may be risky no matter how safe the parent compound is. Cathinones are not solely reuptake inhibitors, they act as releasers too, so 4-CMC & 4-BMC might be neurotoxic too to an unknown extent. Something to look into for some researchers.



This is interesting. Was not aware of this wrt halo-substitutions. Some people were touting flephedrone to be less toxic than mephedrone.

The trifluoro molecule I posted is mostly 5htergic and is indeed both a releaser and a reuptake inhibitor


----------



## roi

Possibly the most potent benzo/thieno possible?


----------



## Dresden

Because I miss MXE.


----------



## roi

More ultra potent ones:

Flutriazolam






Fluclotizolam


----------



## Dresden

SWEET.  Good luck synthesizing that, though, although I'm sure it's far from impossible.


----------



## Dresden

N-ETHYL-MMDA

Probably supersedating for an amphetamine and requiring heroic dosages, but also probably largely "legal" in the US and China (but not in the UK as I understand it).  It might even turn out to be a sedative-hypnotic!!!  It probably gives great nystagmus (horizontal eye wiggles indicating extreme rolling statuses; vertical eye wiggles for PCP) and, hopefully, massive mydriasis (pupil dilation) if it even works.  A cinch to make compared to many research chemicals.  Might not do anything.


----------



## Dresden

DI-CARBOMETHOXY-METHYLPHENIDATE

Not even sure if that can exist.


----------



## roi

Something like a methylphenidate/pipradrol hybrid is certainly possible, not sure how potency would compare to MPH though.


----------



## Solipsis

Interesting ^

I wish we would see 3C-MAL...

http://isomerdesign.com/PiHKAL/explore.php?domain=pk&id=2195

Mescaline is beautiful, then to escaline it seems to get a little less interesting - also with proscaline and allylescaline somewhat lackluster (though all of them may be excellent for a museum level or zen-like enhancement / augmentation if not really psychedelic - unless, as always, you take a lot of it -), then with MAL it sounds quite wild and psychedelic again...

Then also take that 3C-P sounds like it is considered better than 3C-E...

Combine ideas. Profit!


----------



## Nagelfar

^cocaine skeleton attempted as an opioid via fentanyl overlay






^would this do anything? or would it be completely unstable?


----------



## neurotic

that oxygen benzene just won't happen, and if it did i don't think it'd be similar enough to a benzoyl group


----------



## belligerent drunk

Completely unstable.


----------



## Dresden

I wouldn't take this.


----------



## pharmakos

Looks pretty explosive


----------



## Dresden

^--One of my dream molecules, along with:






SHIVA and






HEAVEN.






OLE DIRTY BASTARD


----------



## perpetualdawn

No drawing but..

6-vinyl-6-nor-LSD? Like AL-LAD but with a vinyl instead of allyl..


----------



## Solipsis

Unfortunately N-vinyls don't appear to be stable, I don't see any N-vinyl tryptamines either alas 

I think they might actually polymerize if you try to make them.. Well that goes for N-vinylamides, but possibly also for other compounds that can conjugate (tautomerize?).
If not, it will still tautomerize to the enamine.


----------



## SKL




----------



## Dresden

Nobody seems to have noticed my ibuprofen structure thrown in to see if anybody's paying attention, lol.






SAINT NIC

More nicotine analogue wickedness.


----------



## aced126

I did think it had no relevance to your molecules of interest, just didn't realise it was ibuprofen lol


----------



## SKL

_a la_ ibuprofen, wasn't there an alleged research chemical that was alleged to circulate that looked something like this, i.e. probably a totally bullshit structure made up by a none too bright vendor to try to look vaguely recreational and UK legal to the uninformed reader? 
or perhaps a joke? a troll molecule?
something like this...


----------



## belligerent drunk

SKL said:


> _a la_ ibuprofen, wasn't there an alleged research chemical that was alleged to circulate that looked something like this, i.e. probably a totally bullshit structure made up by a none too bright vendor to try to look vaguely recreational and UK legal to the uninformed reader?
> or perhaps a joke? a troll molecule?
> something like this...



But it looks almost like methamphetamine! Oh wait.


----------



## SKL

^ exactly. I remember seeing something like that on another site and doing a double take. I forget what they were selling it as but it wasn't "ibudrone"


----------



## belligerent drunk

SKL said:


> ^ exactly. I remember seeing something like that on another site and doing a double take. I forget what they were selling it as but it wasn't *"ibudrone"*



Lol.


----------



## roi

@SKL that was






http://www.bluelight.org/vb/threads/775413-2-NMC-(not-a-cathinone)


----------



## SKL

^yes, that

and somebody i.v.'d the better part of a gram of it?

8)


----------



## perpetualdawn

Solipsis said:


> Unfortunately N-vinyls don't appear to be stable, I don't see any N-vinyl tryptamines either alas
> 
> I think they might actually polymerize if you try to make them.. Well that goes for N-vinylamides, but possibly also for other compounds that can conjugate (tautomerize?).
> If not, it will still tautomerize to the enamine.



I had to look up tautomerize and enamine in order to barely understand your answer  That's what I love about this forum, always learn a lot.

What about halogens in the 6 position? 6-bromo-6-nor-LSD etc.. Or alkyls with halogens on the end? Flouro-meth-lad, Flouro-eth-lad etc..


----------



## belligerent drunk

Solipsis, you mean tautomerize into the imine right? That couldn't really happen because that nitrogen is tertiary, much like R'O-vinyl compounds are "stable" where R' =/= hydrogen. That is not to say they wouldn't most likely be unnecessarily reactive.

perpretualdawn, do you mean an N-bromo analog? I don't think that'd be stable. Halogeno-alkyl analogs could work on the other hand I guess, although that could pose a problem because such compounds can behave as alkylating agents (fluoroalkyls don't) and that's not cool.


----------



## perpetualdawn

belligerent drunk said:


> perpretualdawn, do you mean an N-bromo analog? .



I mean this:






Something tells me you can't do that... 

Otherwise, these would be cool:

Flouro-meth-lad (?):






Flouro-eth-lad (?):






I don't know enough about chemistry to know how difficult those would be, but I assume very or we'd probably have heard of them already.


----------



## Solipsis

I stand corrected on the imine and tertiary N-vinyl..

Also I fantasized before not only about 2C-chloromethyl but also 6-haloalkyl-LADs. Unfortunately my digging through chemistry came up with haloalkylamines being reactive in a way..

But fluoros being relatively bad leaving groups could possibly be an exception to this problem? Plus, IIRC the length of the alkyl may be pretty relevant as there seem to be intramolecular mechanisms the proximity (of the halo vs the amine I guess) seems to matter. It was either that only methyls / short chains are susceptible due to direct interactions, or rather - and I apprehensively bet my money on this - if the length of the N-alkyl chain is long enough and the halo is terminal, it circles back and reacts with itself. Probably the longer the chain the less constrained the ring of the intermediate would have to be, and the more self-reacting it should be.

Oh! Think I found it.. look up the cyclization of mustard nitrogens into e.g. aziridines - possibly nice and toxic 
But this could be relatively specific. I have no idea how many compounds act like this with regard to alkyl chain length and if bulky substitutions on the N (let's not forget the lysergamide lol) totally prevent all this..

I'm interested to look it up again, to check the reaction mechs.


----------



## belligerent drunk

Yeah terminal other-than-fluoro N-alkyls of 4-6 (even less or more) carbon length could react intramolecularly to form cycles. 

To perpetualdawn, your first molecule, an N-bromo, is most likely very unstable and too reactive. I don't know about the N-fluoromethyl without some experimental data, but N-fluoroethyl at the terminal end should be okay. Now whether they would be pharmacologically viable is another question.


----------



## DotChem

Indovalerone .. 




does that exist?? cathinones Cross tryptamines


----------



## Solipsis

Well not sure about beta-keto tryptamines, but this compound below sounds like it's terrible..

Alpha alkylating that would seem like an even fancier way to make it more sketchy, if it'd be more like aET.

https://www.erowid.org/library/books_online/tihkal/tihkal43.shtml






Also, you cannot just 'cross' any drug - only the ones that already act in similar ways pharmacodynamically. If you try to cross other drugs, you can mainly expect the modifications messing up the ability to bind and act in both ways.


----------



## perpetualdawn

belligerent drunk said:


> N-fluoroethyl at the terminal end should be okay.



I just remembered where I read about "flouro-eth-lad" - at the bottom of the TIHKAL entry for PRO-LAD, in the Extensions and Commentary section Shulgin imagines it, but with radio-labelled F: https://www.erowid.org/library/books_online/tihkal/tihkal51.shtml

So seems like at least Shulgin thought it would be pretty viable.


----------



## Dresden

DotChem said:


> Indovalerone ..
> 
> 
> 
> 
> does that exist?? cathinones Cross tryptamines



Yes, it can exist.  And while I realize that mixing and matching various functional groups from among wildly disparate drug classes is not usually a recipe for success, in this case I bet your "indovalerone" is active, just not in a good way due to similarity with 5-MeO-AMT.  Switch the 5-MeO for a 5-H or 4-OH, and I think you will be in business.











But I agree with Solipsis that these, too, may be all out nightmares on Elm Street like Shulgin's pyr-T's reportedly are.

As for the LSD variants, I don't think LSD is going to be beaten in terms of potency or profundity of the psychedelic experience, but nevertheless, I won't let that stop me from proposing one:






whose theoretical ideation was inspired by the purported endogenous cannabinoid ligand in mammals, anandamide.






ANANDAMIDE

Adding a 1-pentyl group might be a nifty addition as well:


----------



## Nagelfar

So might anyone lend a suggestion to help me make a structure that would heighten the innate electronegativity of cocaine (as much as could be actually tenable) without too drastically / likely changing its pharmacokinetics?






Is there an online program that tells the electronegativity of a compound by entering it's IUPAC? I couldn't find where it'd say on chemicalize.org (maybe using nomenclature for it with which I am unfamiliar). ^Would adding bonds (such as, on the tropane) greater or lessen it?


----------



## Dresden

F, Cl, Br, I, O, and N are all highly electronegative.  Adding any one of these to cocaine will increase electronegativity in that vicinity of the molecule.


----------



## DotChem

Dresden said:


> Yes, it can exist.  And while I realize that mixing and matching various functional groups from among wildly disparate drug classes is not usually a recipe for success, in this case I bet your "indovalerone" is active, just not in a good way due to similarity with 5-MeO-AMT.  Switch the 5-MeO for a 5-H or 4-OH, and I think you will be in business.
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> But I agree with Solipsis that these, too, may be all out nightmares on Elm Street like Shulgin's pyr-T's reportedly are.
> 
> As for the LSD variants, I don't think LSD is going to be beaten in terms of potency or profundity of the psychedelic experience, but nevertheless, I won't let that stop me from proposing one:
> 
> 
> 
> 
> 
> 
> whose theoretical ideation was inspired by the purported endogenous cannabinoid ligand in mammals, anandamide.
> 
> 
> 
> 
> 
> 
> ANANDAMIDE
> 
> Adding a 1-pentyl group might be a nifty addition as well:





Dresden said:


> Yes, it can exist. And while I realize that mixing and matching various functional groups from among wildly disparate drug classes is not usually a recipe for success, in this case I bet your "indovalerone" is active, just not in a good way due to similarity with 5-MeO-AMT. Switch the 5-MeO for a 5-H or 4-OH, and I think you will be in business.


I was actually thinking about this here on this:





the MD doesn't really do anything except may be altering PK. So why not put an indole. But then again, you end up with a bkDMT skeleton like this among others:





Which is why I thought it could be a mdpv-dmt cross. Or bk-AMT (kind of!) if you substituted on alfa. Now, since for some reasons I have always been fascinated by a "5-methoxy" on indoles so I put in on. But you're right, without the 5-methoxy, it would probably behave more like mdpv


----------



## neurotic

i don't think it's correct to say electronegativity of cocaine... it's a property of atoms, not molecules.

like Dresden said adding a more electronegative atom somewhere in the molecule will change electron density in that particular region, if that's desirable or not will depend. but the overall distribution of electron density of a molecule is just polarity.

anyway here's one i've thought about a while ago. i was always interested by aMT and how it could be improved... even though it probably is a dead end scaffold.






whoa, just found this has a CAS number even. there's a paper who references it but only as a synthesis intermediate for some other compounds... i guess it's never been looked at by the right eyes.


----------



## Solipsis

Not a far cry from this, oh wait lol it is that exact compound:

http://www.bluelight.org/vb/threads/723326-3-amino-1-2-3-4-tetrahydrocarbazole-Worth-giving-a-go






MAOI, anti-depressant, putative antipsychotic sekio says..


----------



## Dresden

DotChem said:


> I was actually thinking about this here on this:
> 
> 
> 
> 
> 
> the MD doesn't really do anything except may be altering PK. So why not put an indole. But then again, you end up with a bkDMT skeleton like this among others:
> 
> 
> 
> 
> 
> Which is why I thought it could be a mdpv-dmt cross. Or bk-AMT (kind of!) if you substituted on alfa. Now, since for some reasons I have always been fascinated by a "5-methoxy" on indoles so I put in on. But you're right, without the 5-methoxy, it would probably behave more like mdpv



Somebody said (hearsay, yes, I know) that bk-AMT is really good:






Personally, I did not enjoy AMT and consider it rather dangerous.  Adding bk's to tryptamines makes their structures overlap with the JWH's too.


----------



## Solipsis

bk-AMT will dimerize into the 2,5-dihydropyrazine... 

But yeah if you store it properly and consume it on an empty stomach and compensate for the loss, it might very well make it, a la bk-2C-B.. Anyway why don't we have bk-MDA if apparently bk-2C-B does something (yeah sometimes it does crap out into purple goo lol)


----------



## roi

Azaindazoles? Why not.


----------



## Dresden

"Why don't we have bk-MDA?"

I think it's because fastandbulbous or nuke or Hammilton or vecktor or maybe a chorus of them erroneously convinced the world that it and similar compounds would dimerize early on (although they later retracted that assertion, with some qualifications).

I have read the synthesis of bk-MDA aka MDC (methylenedioxycathinone) on erowid, and it requires a hydrogenation unit, so maybe that's why we've never seen them on the research chemical market.  

However, MDAI also requires a hydrogenation unit to synthesize, but it has popped up now and then, so it really just beats me.  It's a shame in my opinion.






MDC






MMDC






TMC





















I'm sure you get the idea...the possibilities that open up with this one are nearly limitless.


----------



## DotChem

hit "manage calcultations" menu on chemicalize results. then choose charge then "orbital electronegativity"  is that what you looking?


----------



## DotChem

Then you would expect same thing to happen with cathinone:





or does it dimerize too;




I  guess it would probably be reversible even if it does (the  dihydropyrazine getting hydrolyzed back) and so depending on conditions  (acidic or basic..) or form (salt, freebase) one or the other will  predominate


----------



## Dresden

Imines are not stable to aqueous media such as saliva or other gastric secretions.  And the protonated salt form is not going anywhere.

As I understand it, the bigger issue with cathinone's stability is degradation from the benzyl ketone (cathinone) to the benzyl hydroxy (i.e., cathine):






CATHINE.

Maybe that's a problem with the others such as MDC, too?  I dunno.


----------



## DotChem

or






compare to this:


----------



## Solipsis

I do think cathinones are similarly unstable, khat appears to be of decent quality only for up to about 48 hours apparently...

The dimerization is not the only issue, oxidation may be as well. Plus I wonder about alternative degradation routes from the dihydropyrazines? Also the dimerization (or polymerization for that matter?) is acid-catalyzed / pH dependent so you might imagine there being absorption issues, or just the unpredictability that we do observe with bk-2C-B. Best may still be snorting or IVing a weakly base-buffered solution? : p

And synthesis / storage issues aren't even considered... although apparently it was surmountable for bk-2C-B.

But even secondary amines appear to be able to react with ketones to yield enamines and we don't seem to have much trouble with that happening with our N-methylamine drugs... so could be much ado about nothing.
Well not *nothing*, bk-2C-B does (reversibly) degrade to purple stuff as I've seen myself and experimented a bit with acid and base conditions... but the significance may be overstated a bit..

@dotchem: Is that lorcanserin? They don't really look similar enough IMO..


----------



## SKL

Solipsis said:


> lorcanserin



Yeah it is, to but in, moderately interesting drug
not very effective at weight loss IMCE, weird that it's scheduled
maybe massive overdoses would be trippy
but would have inordinate side effect burden almost certainly






This is vabicaserin, abandoned by Big Pharma, but to me a more interesting drug:



			
				wiki said:
			
		

> Vabicaserin (SCA-136) was a novel antipsychotic and anorectic under development by Wyeth. As of 2010 it is no longer in clinical trials for the treatment of psychosis. It was also under investigation as an antidepressant but this indication appears to have been dropped as well.
> 
> Vabicaserin acts as a selective 5-HT2C receptor full agonist (Ki = 3 nM; EC50 = 8 nM; IA = 100% (relative to 5-HT)) and 5-HT2B receptor antagonist (IC50 = 29 nM). It is also a very weak antagonist at the 5-HT2A receptor (IC50 = 1,650 nM), though this action is not clinically significant. By activating 5-HT2C receptors, vabicaserin inhibits dopamine release in the mesolimbic pathway, likely underlying its efficacy in alleviating positive symptoms of schizophrenia, and increases acetylcholine and glutamate levels in the prefrontal cortex, suggesting benefits against cognitive symptoms as well.



maybe it shat the bed in clincial trials 
but that sounds to me like a lot of potential
worth a 2nd look

the much touted of late flibanserin is another failed antidepressant
locarserin probably is too
but reading about vabicaserin makes me feel some potential tbh
I think we are limiting ourselves in terms of what kinds of meds we can use as antipsychotics
maybe my next contribution to this thread ought to be in that genre
but it would take a lot of research on my part to make it non trivial


----------



## DotChem

Solipsis said:


> I do think cathinones are similarly unstable, khat appears to be of decent quality only for up to about 48 hours apparently...
> The dimerization is not the only issue, oxidation may be as well.



Yes I agree. In my opinion the most serious issue with Khat storage may be oxidation. Amines in general (free base) and especially primary amines tend to get oxidized easily and give you all kind of crap on storage. That's why banana peel turns crappy after a while (the amines such dopamine present getting oxidized). But not so much for the salt though (eg cathinone HCl). So it wouldn't be surprising that Khat becomes useless after few days.  



Solipsis said:


> Plus I wonder about alternative degradation routes from the dihydropyrazines?


Not sure but one would probably be getting oxidized to fully aromatic pyrazines driven by aromaticity energy gain. But hard to tell really.. 






Solipsis said:


> And synthesis / storage issues aren't even considered... although apparently it was surmountable for bk-2C-B.
> But even secondary amines appear to be able to react with ketones to yield enamines and we don't seem to have much trouble with that happening with our N-methylamine drugs... so could be much ado about nothing.



I think pretty much so: much ado about nothing. The reaction between the amine and the ketone yields imines w/primary amines and enamines w/secondary amines AND Water. It is reversible ie water will react with the imine or enamine to give back the amine and ketone. Presence of Water will drive the equilibrium to amine and ketone. Or conversely removing water will drive it to imine/enamine. But since we're dealing mostly with water (tons of it) in the human body, I think it's really non issue here. But always caution absent rigourous studies.



Solipsis said:


> @dotchem: Is that lorcanserin? They don't really look similar enough IMO..



Yes it is Locarserin. I was thinking about the cyclized AMT you mentioned.





thought about alternative cyclization so the nitrogen forms part of the cycle to give Thikal analog of Pikhal locareserin (which actually is just ring-constrained MDA). 

Now one question: I thought talking chemistry is a NO NO on this forum. Let me know.  






Indodrone


----------



## Nagelfar

SKL said:


>



Reminds me of my "restricted rotational analog" of methylnaphthidate:






...

...

...

InstaTardiveDyskinesamine?:






^Well might the acetyloxy get it to cross the BBB, and where on dopamine does it bind? covalent binding dopamine, would it at least have stimulant properties before (or at least wreaking less havoc than) going the way of oxidopamine?

Fentanyl + Diphenyl-2-pyridylmethane / (Desoxypipradrol)


----------



## aced126

A few words on the topic of dimerisation:

First, I think Sollipsis meant to post the following image (he posted the pyrazine derivative instead of the dihydropyrazine one). 





As another example, here is the following dimerisation of cathinone:





Imine formation is reversible and also requires acid or base catalyst to reach equilibrium fast. If it is stored in neutrality, or in an excess of water, I don't think dimerization would be a problem. The problem is when the compound reaches the stomach, and its acidic conditions. As Sollipsis said, this can be circumvented by dosing on an empty stomach. Even better, administering it via rectal, nasal or intravenous routes would do the job. Once in the blood (neutral pH of around 7.4), dimerisation will reach equilibrium very slowly.

Even with this, I still don't think dimerisation should pose that much of a problem; in the stomach there is still quite a large excess of water in comparison to the concentration of the drug so even if equilibrium is fully reached, the concentration of the dimerized compound should be low. Also it wouldn't be entropically favourable.

Furthermore, if this was a problem then even secondary beta ketone amines (like methcathinone, methylone, mephedrone, bupropion even) would face this problem, only to form the enamine derivative instead. To illustrate:
Methcathinone dimerisation:





Meph dimerisation:





M1 dimerisation:





On a final note, take a look at this link: http://www.rxlist.com/wellbutrin-xl-drug/clinical-pharmacology.htm
*"Absorption*

Following single oral administration of WELLBUTRIN XL tablets to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion."
This would be dimerised Wellbutrin in the stomach supposedly:





Having said this, there is evidence to suggest dimerisation (of secondary amines at least, and likely primary amines) does not take place to a significant extent in the acidic environment of the stomach, probably because water is in excess. But then again, in bupropion there might be slightly more steric hindrance preventing enamine dimerisation.


I guess the only way of really testing all these hypotheses is leaving a beta keto phenethylamine in acidic aqueous solution for a while and measuring the equilibrium concentration of the original and dimerised compounds. If a significant amount of dimerised compound concentration is observed, then measure the rate at which it is formed in acidic conditions. If the rate is fast, then I guess another route of administration avoiding the stomach must be sought. 

Sadly for me it'll be at least 5 years before I'll ever even have a possibility using a LCMS and NMR...

EDIT: Having thought about this, I'm now tending to think that primary bk-amines could actually dimerize (reversible) but then oxidize to aromatic pyrazines (irreversible) as DotChem mentioned. This would be less likely with secondary bk-amines because the 2 nitrogens would both have to form salts.


----------



## roi




----------



## aced126

DotChem said:


> Now one question: I thought talking chemistry is a NO NO on this forum. Let me know.



As long as it's not explicit synthesis I think it's fine.


----------



## roi

Not mine, from https://youtu.be/cmKo0_N7TJQ?t=1825. Looks like a piracetam analogue?


----------



## sekio

looks like a peptide... e.g. you are going to see oral PK problems

aced, those dimer molecules look like they would trivially lose H2 and aromatize given any sort of e.g. metal catalyst... more accurately the imine won't form if there is any water present because it's an equilibrium process.


----------



## Friman1987




----------



## clubcard

The alkenes are interesting. Anyone considered taking bk_2CB and replacing the -Br with a CH≡C- ?


----------



## Solipsis

Alkynes? Hmm idk has DOCN ever been considered?


----------



## pharmakos

DOCN sounds like "dosin'" if you try to say it out loud =p


----------



## aced126

I wouldn't be happy taking 2C-VI. Look at the methoxy group ortho to the vinyl moiety. That's gonna conjugate and increase the alkene's nucleophilicity loads. Could maybe alkylate cysteine and to a much lesser extent serine residues.


----------



## DotChem

was it a thread I missed on this:


----------



## Solipsis

aced126 said:


> I wouldn't be happy taking 2C-VI. Look at the methoxy group ortho to the vinyl moiety. That's gonna conjugate and increase the alkene's nucleophilicity loads. Could maybe alkylate cysteine and to a much lesser extent serine residues.



Styrenes have mutagenic epoxide metabolism anyway... but your suggested conjugation I am not following... you just mean the methoxy (methoxies) are ring activating? Or if you mean " O-methyl hexadienone "+ type conjugation products, isn't the para the most stable of all?

_Also:_






*bridgheadket*

^ Could you go all LSZ-style on the K structure? Apparently arylcyclopentylamines aren't even active while N-substitutions are pretty flexible. So if that position which overlays the alpha-carboxyl group of NMDA is so strict, why not constrict arylcyclohexylamines? Although technically I think that bicyclooctanes aren't even that constricting, still checking it vs. the norbornane might prove interesting... and it would certainly circumvent present laws right?
I suppose one could calculate the bond angles and tell you upfront that this is very similar to an arylcyclopentylamine and therefore a worthless endeavor..

^^ About the pyridinyl stims... I do wonder about pyridinyl dissociatives... but as far as phenylic bioisosteres go tiletamine seems pretty crude as a dissociative.

And finally: what about a lactone with the ring-opened version being rather lifelike cf. the NMDA carboxyl?


----------



## Friman1987

> Styrenes have mutagenic epoxide metabolism anyway... but your suggested conjugation I am not following... you just mean the methoxy (methoxies) are ring activating? Or if you mean " O-methyl hexadienone "+ type conjugation products, isn't the para the most stable of all?



Epoxide metabolism of Styrenes can pass the cell membrane and reach the cell nucleus. Can the same thing happen with 2C-VI? The epoxide metabolism should make 2C-VI more polar.





----------------------------------------------------------------


----------



## sekio

2c-vi will probabkly polymerize in the flask


----------



## Dresden

I think I really finally fried my brain on methamphetamine tonight.  The hyperthermia!


----------



## aced126

I mean this kinda conjugation; idk it probably won't happen after thinking about it more but then again caution first. About the polarity of the epoxide compound itself: yeah it is more polar than simply styrene but it would still enter the cell in lesser quantities regardless. Can't seem to find any quantitative data on styrene toxicity.


----------



## Solipsis

Oh yeah so indeed the O-methyl hexadienone cation intermediate. It would probably react well with all kinds of residues in your tissue wouldn't it.. And like sekio said, that is, if you don't manage to polymerize it first by allowing radicals to initiate it.
You can't vitamin C that stuff straight ;p No thanks I'll pass on the psychedelic polystyrene foam forming in my tracts. Or I'd need to take a shitload of GBL to dissolve it all again.


----------



## Friman1987

Thanks for all answers. Like many mentions 2C-VI seems to have many things to be concerned about.


----------



## Friman1987

I tried to draw some N-substituted tryptamines that containing not more than 6 C atoms. Some of these molecules seem interesting, like PiPT or ETBT, MTBT. The 4 HO version of those can be interesting. 






*.....and Some random structure: *


----------



## Solipsis

I am honestly wondering why we are not seeing 5,N,N-TMT as it should be close to DMT and 5-MeO-DMT in effect (but you could also say that of the 5-halo's.)


----------



## clubcard

Ever tried smoking the freebase or snorting the salt? - THAT!


----------



## aced126

Very nice structures Friman; do you work in drug discovery?

This has very probably popped up before but if it hasn't:







Just found out Dresden posted this molecule about 5 pages ago. Has this been documented ever?


----------



## DotChem

Interesting.. would the aza-indole derivatives cross the BBB? too polar, are they not? DMT already threshold


----------



## DotChem

aced126 said:


> Very nice structures Friman; do you work in drug discovery?
> 
> This has very probably popped up before but if it hasn't:



the 5-MeO seems like a horrible compound..


Solipsis said:


> Well not sure about beta-keto tryptamines, but this compound below sounds like it's terrible..
> 
> Alpha alkylating that would seem like an even fancier way to make it more sketchy, if it'd be more like aET.
> 
> https://www.erowid.org/library/books_online/tihkal/tihkal43.shtml


----------



## aced126

DMT is threshold because it is so similar to an endogenous molecule (tryptamine, and serotonin) that it is pretty much the perfect substrate for MAO metabolism in the stomach. Similar thing going on with phenethylamine. Add a methyl group on the alpha carbon of both molecules (and remove the N-methyls on DMT I guess) and you get 2 very long lasting molecules: aMT and amphetamine. All because that methyl group significantly reduces substrate affinity for their respective enzymes.


----------



## aced126

DotChem said:


> Interesting.. would the aza-indole derivatives cross the BBB? too polar, are they not? DMT already threshold



How do you name the top 2 compounds?


----------



## Friman1987

aced126 said:


> Very nice structures Friman; do you work in drug discovery?



Thank you, very kind of you. I'm still a student.



DotChem said:


> Interesting.. would the aza-indole derivatives cross the BBB? too polar, are they not? DMT already threshold


To know that you can look at polar surface area and log-P. 




The AZA-O-Methylbufotenine Looks interesting, good PSA and good LogP. Most known psychedelic has a PSA of less than 50. PSA is dependent on how many N, O you have. OH is more polar then MeO, NH3 is more polar then NH2, NH2 is more polar than N. 





RH-34 have a PSA of 70,67. It should not cross the BBB so well.


There are also other variables that you can look at for example determining drug absorption by pKa. 
Someone else might have different method to look at the polarity.


----------



## aced126

Hmm, not looking too good for the aza compounds, especially the ones having a logP of under 1. I had never considered polar surface area as a determining factor in the molecule's ability to penetrate the BBB. I also think size itself would play a big factor; oxygen can cross membranes simply because it's pretty small (and would be in quite large concentrations obviously). 

What program are you using to calculate logP and polar surface area?


----------



## Friman1987

aced126 said:


> Hmm, not looking too good for the aza compounds, especially the ones having a logP of under 1. I had never considered polar surface area as a determining factor in the molecule's ability to penetrate the BBB. I also think size itself would play a big factor; oxygen can cross membranes simply because it's pretty small (and would be in quite large concentrations obviously).
> 
> What program are you using to calculate logP and polar surface area?



I use Chemdraw-ultra 12. 

*You can also use:* http://www.molinspiration.com/cgi-bin/properties


----------



## aced126

Ahh, I never knew that program calculated polar surface area. I do use it to calculate logPs however.


----------



## Nagelfar

^intermediate of Doxpicomine (opioid 8× morphine) + Methylphenidate


----------



## sekio

the N-O-CH2-O in a ring gives me the shivers... a cyclic hydroxylamine formaldehyde acetal. That's a mouthful, and again, not very stable around water...

Throw in a nitro group just to please the CYP enzymes and, well, you should design tool compounds for a living Nagelfar. Have you considered volunteer work at Tocris?


----------



## Dresden

The signal to noise ratio on this thread is pretty bad.  There are too many structures to sift through them all and only focus on the (few) winners.


----------



## aced126

Dresden said:


> The signal to noise ratio on this thread is pretty bad.  There are too many structures to sift through them all and only focus on the (few) winners.



At least it's better when people at least have a rationale in mind (in my opinion)


----------



## Solipsis

This is the 'I like to draw random molecules' thread and it did start with ADD eminences c.s. drawing MD groups on silly rubbish. I personally like it as well when there is enough rationale behind a drawing to tickle your fancy or funny bone, but if we start considering this the thread where new RCs are invented for shady labs to try and make or whatever else you call strictly winning, then it is your own problem if people don't 'deliver', and it also would head into very dubious directions.
Sometimes it is truly amateur hour, without trying to sound arrogant it is tragic when people almost seem delusional about the whole thing (eg a certain Mr Fin). While not sure whether to laugh or cry, it _is_ pretty entertaining.


----------



## aced126

Solipsis said:


> This is the 'I like to draw random molecules' thread and it did start with ADD eminences c.s. drawing MD groups on silly rubbish. I personally like it as well when there is enough rationale behind a drawing to tickle your fancy or funny bone, but if we start considering this the thread where new RCs are invented for shady labs to try and make or whatever else you call strictly winning, then it is your own problem if people don't 'deliver', and it also would head into very dubious directions.
> Sometimes it is truly amateur hour, without trying to sound arrogant it is tragic when people almost seem delusional about the whole thing (eg a certain Mr Fin). While not sure whether to laugh or cry, it _is_ pretty entertaining.



Tbh people do comment if there is an obvious toxicity a new compound poses to health, like the one a while ago (2C-VI). I'd prefer it the RCs which came through had a thorough safety analysis done on them by proper pharmacologists.


----------



## Solipsis

Sure the theory is taken for quite a ride sometimes for hypothetical compounds, but I would be a little pissed if it became frowned upon if structural drawings made here do not go accompanied by a tox analysis. Nice chemistry ideas and even checking pharmacology, is fine... but if we start accepting responsibility too much then we start playing an active role consciously in something this forum is not meant for.
That is not to say I don't feel a calling to help point out potential flaws in ideas. Still that is not the same as really thinking of this as a development and production line, that is way too serious. Regardless of the tox analysis there are also silly and dangerous ideas passing through here, so quality control is hardly possible anyway even if we wanted to. The randomness and silliness should be welcome as ever.

Abusing this thread to sometimes vent a longing for a certain compound or family of chems is a mistake I have made as well, the important point of that is still emphasizing what interests and fascinates and not much else.

@RC safety analysis: we cannot really pretend to have enough of a real grip on the RC market anyway, although I agree that pharmacological or toxicological concerns should definitely be posted asap - but that should be done in a separate NSP thread for each, where actual RC developments are commented on. imho


----------



## roi

Meprylcaine/Dimethocaine hybrid. Certainly a shitty stim.


----------



## Solipsis

Haha gee thanks, can you make any other drugs more cardiotoxic roi? 8)


----------



## Bagseed

Solipsis said:


> Sometimes it is truly amateur hour, without trying to sound arrogant it is tragic when people almost seem delusional about the whole thing (eg a certain Mr Fin). While not sure whether to laugh or cry, it _is_ pretty entertaining.


yeah shaggyfin was one to remember. I still wonder whether he was a troll or just really stupid^^


----------



## belligerent drunk

Solipsis said:


> Haha gee thanks, can you make any other drugs more cardiotoxic roi? 8)



Heart is over-rated anyway, brain is where it's at!


----------



## roi

Solipsis said:


> Haha gee thanks, can you make any other drugs more cardiotoxic roi? 8)



Uhmm what about


----------



## SKL

roi said:


> Solipsis said:
> 
> 
> 
> Haha gee thanks, can you make any other drugs more cardiotoxic roi? 8)
> 
> 
> 
> Uhmm what about
Click to expand...


is there a contest?


----------



## Dresden

Yeah, I love this thread despite its shortcomings.  I don't publish my rationale for many compounds, as that would be difficult to explain my reasoning and would open up my own personal thought processes to possible (probable even) ridicule, but I do have rationale for every compound I've ever posted here.  The proof is in the pudding.

Oh, btw I'm on day three of no sleep meth binge now and I somewhat doubt sleep will come easily tonight even.


----------



## Friman1987

Some phenethylamines and tryptamines that you can find in the LSA / LSD structure.


----------



## Friman1987

.......


----------



## Solipsis

Thanks hehe, why didn't anyone ever tell me about the meth in my acid??

Also the O-methyl THC (why methyl) was a nice find, good easteregg : P


----------



## DotChem

aced126 said:


> How do you name the top 2 compounds?


 





Aza-DragonFly


and 







Buddhanamide


----------



## DotChem

Friman1987 said:


> There are also other variables that you can look at for example determining drug absorption by pKa.
> Someone else might have different method to look at the polarity.



But to predict BBB transport shouldnt we be looking at logD rather than intrinsic lopP that is the logP at a given pH in that case at 7.4. Take 
LSD LogP= 2.28 and LogD(7.4)= 1.60
DMT LogP=2.3 and LogD (7.4)= 0.17
4-azaDMT LogP = 1.47 LogD(7.4)= -0.59

What I meant to say is that DMT logP at pH7.4 is right about ok to pass BBB by passive diffusion. LSD is close to perfect and so is cocaine btw (2.5 and 0.82).  But then again beeing relatively small the lipophilicity of the compound wouldn't matter much. d-amphetamine logP is 1.80 and logD(7.4)= -0.67.  So I guess the Aza-indoles would probably make it


----------



## Solipsis

That bottom one... with the sulfurs it would be almost like a dioxolobenzodioxole instead of a -FLY type compound in the sense that it would be like a constricted version of a phen with not two but four methoxies!

I am personally very curious though, if it is even known what the difference is - even just in potency - between -FLY and -Dragonfly compounds, as the dragonfly pretty much always comes with a kinda unrelated alpha-methyl. That has always been pretty strange to me..
Would a lot of the trickiness of Bromo-Dragonfly be averted if it the wings were saturated, yielding DOB-FLY?


----------



## Dresden

Mathematics does a particularly poor job of modeling the behavior of molecular reactions and pretty much every other chemical application.  Just sayin'.


----------



## DotChem

Solipsis said:


> That bottom one... with the sulfurs it would be  almost like a dioxolobenzodioxole instead of a -FLY type compound in  the sense that it would be like a constricted version of a phen with not  two but four methoxies!


that's right!.. problem I guess the 2  sulfurs will give a pretty bulky compound..may make it more active  than the FLY though. or not!  no SAR as far as I know



Solipsis said:


> I am personally very curious though, if it is  even known what the difference is - even just in potency - between -FLY  and -Dragonfly compounds, as the dragonfly pretty much always comes with  a kinda unrelated alpha-methyl. That has always been pretty strange to  me..
> Would a lot of the trickiness of Bromo-Dragonfly be averted if it the wings were saturated, yielding DOB-FLY?


the saturated bis-dioxanes are about an order of magnitude less potent at 5HT2a not if I remember. so about 2% LSD activity since FLY is about 20% acid.

Now  reason i thought of a bis-thiazole or bis-indolyl is the protracted  incredibly long half life of FLY (couple of days at least) which you do  not want to go through especially if you were freakin out having bad  trip. is it possible tweaking the FLY to make it more like acid? I mean in terms of PK. Making  it more polar may be without killin much activity??

Oh I forgot this one






 closer still to FLY but is it stable??


----------



## Nagelfar

sekio said:


> the N-O-CH2-O in a ring gives me the shivers... a cyclic hydroxylamine formaldehyde acetal. That's a mouthful, and again, not very stable around water...
> 
> Throw in a nitro group just to please the CYP enzymes and, well, you should design tool compounds for a living Nagelfar. Have you considered volunteer work at Tocris?



I have now.


----------



## aced126

DotChem said:


> Aza-DragonFly
> 
> 
> and
> 
> 
> 
> 
> 
> 
> 
> Buddhanamide



Sorry, I meant in opsin lol


----------



## Dresden

Structurally, those just look like the beckoning call of death incarnate.  I would feel safer taking PMMA than those, and that is not saying anything positive about them at all.


----------



## neurotic

Solipsis, i just took a look at the studies sekio references in the thread about the cyclic aMT molecule (nice find), and i think there's still hope for that molecule.

one of the articles is actually about it N,N-dimethyl homologue and this molecule might even do something. it prevented reserpine induced ptosis which according to a  quick look at wiki is due to irreservible binding to VMAT, so it probably is a VMAT ligand at least. that's something. and it's a MAOI only at huge concentrations if i'm reading IC50 values correctly (10^-4 M?).

too bad the OP from the thread never returned...






here's Jim-aMT, the nemesis of Jim-TMA... now that looks unpromising


----------



## aced126

neurotic said:


> Solipsis, i just took a look at the studies sekio references in the thread about the cyclic aMT molecule (nice find), and i think there's still hope for that molecule.
> 
> one of the articles is actually about it N,N-dimethyl homologue and this molecule might even do something. it prevented reserpine induced ptosis which according to a  quick look at wiki is due to irreservible binding to VMAT, so it probably is a VMAT ligand at least. that's something. and it's a MAOI only at huge concentrations if i'm reading IC50 values correctly (10^-4 M?).
> 
> too bad the OP from the thread never returned...
> 
> 
> 
> 
> 
> 
> here's Jim-aMT, the nemesis of Jim-TMA... now that looks unpromising



Link the thread?


----------



## Friman1987

*Solipsis:* Thanks :D 
*DotChem: *Yes, You are right. I wrote LogP because that is what I can look up by the program that I'm using. Where can I find the logD and if possible pKa for different structures, What program do you use?

*2 New images (edit):*

*NSFW*: 











*NSFW*:


----------



## Solipsis

Would you mind using the following code in your post though, if you use such huge images:



		PHP:
	

[nsfw] IMAGE [/nsfw]


About the 4-HO tryptamine pro-drugs:
actually I have been meaning to go for that... but it first requires analytical preparations to track and confirm the reaction progress.
will be a while before thats possible.

@Aced: http://www.bluelight.org/vb/threads/723326-3-amino-1-2-3-4-tetrahydrocarbazole-Worth-giving-a-go


----------



## Nagelfar

3β-styrene + tricyclic tropane + 2β-isoxazoline w/vinylogous stem

logP: 5.61
Polar surface area: 51.13
Fraction of SP³: 0.39

=






^I just like how it looks, correct me if I'm wrong, but an FSP³ of 0.39 isn't shabby, or am I off-base? (EDIT: just noticed I forgot to put the _p_-nitro/NO2 on the 3 beta terminating phenyl that I had on my sketch of the above compound)






^Since the IC50 (nM) of cocaine for DA uptake is 209, and the 3β-styrene analog is 5(!), the 3β-carbamoyls have a nitrogen on the bridge, so something azido-esque was my thinking for this one.


----------



## Friman1987

Solipsis said:


> Would you mind using the following code in your post though, if you use such huge images:
> 
> 
> 
> PHP:
> 
> 
> [nsfw] IMAGE [/nsfw]



yes, sir 


It would be interesting with some new tryptamines.


----------



## DotChem

DotChem said:


> Aza-DragonFly
> 
> 
> and
> 
> 
> 
> 
> 
> 
> 
> Buddhanamide



Oh sorry I thought you meant what I would name them.

IUPAC






1-{8-bromo-1H,5H-pyrrolo[2,3-f]indol-4-yl}propan-2-amine







1-{8-bromo-4,10-dithia-6,12-diazatricyclo[7.3.0.0³,7]dodeca-1,3(7),5,8,11-pentaen-2-yl}propan-2-amine

I like Buddhanamide better though even it doesnt have an amide sounds like Anandamide (name coming from Ananda who was the Buddha assiatant and Ananda mean GreatBliss in hindu!)


----------



## DotChem

Try here : http://isciencesearch.com/iss/default.aspx go to Structure to  generate your molecule then "Tools" then "Chemicalize" it wil give a  bunch of parameters "Manage Calculations" then choose whatever you want  pKa LogP LogD PSA Polarizability....blabla (play around ) I found it  predict good chemical parameters but the "Predict Biological Activity"  kind of suck. 

here is LogD of one the aza-indoles you talk about











full data here:

http://www.chemicalize.org/structure/#!mol=CN%28C%29CCc1c[nH]c2cccnc12

good luck


----------



## sekio

with a logD in the negatives at physiological pH that is a death sentence for central activity...

4-Me-5-MeO DMT would be neat


----------



## Friman1987

*DotChem:* Thank you very much for this information.
*






New images: 

NSFW: 










NSFW: 










NSFW: 










NSFW: 










Physostigmine: https://en.wikipedia.org/wiki/Physostigmine
Ibogaine: https://en.wikipedia.org/wiki/Ibogaine
Some indole-alkaloids: https://uwm.edu/chemistry/people/cook-james/
PHA-57378
1. https://en.wikipedia.org/wiki/PHA-57378
2. https://patentscope.wipo.int/search...=&sortOption=&queryString=&tab=PCTDescription






Edit: 

NSFW: 















PNU-181731: 
https://en.wikipedia.org/wiki/PNU-181731

Many of these molecules are enzyme inhibitors (ex MAO-I)*


----------



## DotChem

sekio said:


> with a logD in the negatives at physiological pH that is a death sentence for central activity...


that's what I thought.. a bit too polar but it could use active transport system of small molecules like pyridoxin to sneak in past BBB!


sekio said:


> ...
> 4-Me-5-MeO DMT would be neat


how about the methylenedioxyDMT??

like this:






or the aAMT analog

like this


----------



## DotChem

did I see Ibogaine mentioned by @Friman1987?  my favorite psychedelic of all times..I thought about this sometime ago:







I wont touch the middle compound: 







 would probably be scopopalmine-like central M1 agonist nighmarish zombie visuals..  but it looks neat like BZP!


----------



## DotChem

read: scopolamine i.e. witchbrew https://en.wikipedia.org/wiki/Hyoscine_hydrobromide


----------



## Friman1987

*Dotchem: *Scopolamine is scary stuff. 








---------------------------------------------------------------

*32 different ways to draw a phenethylamine (ex 2C-B):*

*NSFW*: 









Those 32 differences should be the basic structure for drawing other phenethylamines. you can apply same thing on tryptamines. The effect should not be so predictable.


----------



## Friman1987

*NSFW*:


----------



## aced126

Friman1987 said:


> *Dotchem: *Scopolamine is scary stuff.
> 
> 
> 
> 
> 
> 
> 
> 
> ---------------------------------------------------------------
> 
> *32 different ways to draw a phenethylamine (ex 2C-B):*
> 
> *NSFW*:
> 
> 
> 
> 
> 
> 
> 
> 
> 
> Those 32 differences should be the basic structure for drawing other phenethylamines. you can apply same thing on tryptamines. The effect should not be so predictable.



Not so sure about some of those prodrugs lol, you might wanna recheck those structures. Good phenethylamine structures tho, it seems not all of those have been synthesised and doing so would be a good step in understanding the phenethylamine SAR further.


----------



## Friman1987

aced126 said:


> Not so sure about some of those prodrugs lol, you might wanna recheck those structures. Good phenethylamine structures tho, it seems not all of those have been synthesised and doing so would be a good step in understanding the phenethylamine SAR further.



The last one is prodrug for DOB. Which one do you think will not work?
I know that N-MEO is not so good pro-drug for MDMA. But I do not know if the same think can apply for 2C-B, which is a bit more potent.
N-AC on mescaline dont work at all. But how about N-O-AC? I think N-O-AC should work.


----------



## aced126

What enzyme is meant to metabolise R-N-O-(C=O)-R?


----------



## Friman1987

*(1) 2C-B-OH: * N-OH on MDMA and several 2C-T (X) acts as a prodrug. 

*(2) N-MeO-2CB: * I know that N-MEO is not so good pro-drug for MDMA. But I do not know if the same think can apply for 2C-B, which is a bit more potent. 2C-B have also not α-methyl and that maybe makes the demethylation more easier? That may not create steric hindrance for some enzymes.
I'm thinking about something like that:






*(3) N-O-AC-2CB:* I think something similar happens here too so you get 2CB-OH. I do not know what enzyme would do this so I understand what you saying haha. I have absolutely not any source on this one so there is no reliable facts behind those R-(N-O-AC)-R. 


*(4) Lis-2CB(Lysine+2CB): *If the body recognizes it as peptides then it should metabolized by Proteases/peptidases otherwise by the hydrolytic activity of the red blood cells.

*(5)*





*(6) α-C(O)OH-2CB: * Should metabolized by decarboxylase as a normal amino acid, L-DOPA working in this way. Something that is interesting is that L-DOPA can cross the BBB while dopamine can not do this. It May happen something similar with α-C (O) OH 2CB. It should metabolize in both the CNS and PNS. 




*(7) α-C(O)OH-DOB:* The last one is prodrug for DOB, Should metabolized the same way as Methyldopa, by decarboxylase.


----------



## Incunabula

Lisdexamphetamine inspired prodrugs seems to pop up with regularity in this thread. I doubt they'll ever make great psychedelics, but could they be used with a different intentl?






This is basically Shulgins "Eternity" or 2CE-5-EtO, which already has a very long duration, with a lysine attached to make the release longer and slower, so to be used as a nootropic. Lys-2CE-5EtO.

"The 5-EtO-homologue of 2C-E is 5-ethoxy-4-ethyl-2-methoxyphenethylamine, or 2CE-5ETO. The effective level of 2CE-5ETO is in the 10 to 15 milligram range. It is gentle, forgiving, and extremely long lived. Some 3 to 4 hours were needed to achieve plateau, and on occasion experiments were interrupted with Valium or Halcion at the 16 hour point. After a night's sleep, there were still some effects evident the next day. Thus, the dose is comparable to the parent compound 2C-E, but the duration is 2 to 3 times longer. It was given the nickname "Eternity" by one subject."

I'm not sure if alpha-methyl phenethylamines react similarly to 5-EtO substitution (more gentle, and a lot longer duration) but if they do, Lys-DOPr-5EtO might be even better suited as a nootropic.


----------



## Solipsis

That's pretty interesting... obviously made me curious about the release, onset delay, bioavailability... so seems relevant to quote this bit on the (animal) kinetics of vyvanse:



> Oral administration of lisdexamfetamine dimesylate in comparison to d-amphetamine sulfate demonstrated that the bioavailability (AUC) of d-amphetamine from the prodrug was approximately equivalent near therapeutic human equivalent doses (HEDs). At high doses well above the therapeutic range, however, both AUC and Cmax of d-amphetamine from lisdexamfetamine dimesylate were substantially decreased in comparison to AUC and Cmax of d-amphetamine from d-amphetamine sulfate.
> 
> Absorption of lisdexamfetamine dimesylate orally administered increased non-linearly with increasing dose. The clearance of lisdexamfetamine dimesylate was greater than that of d-amphetamine following oral administration. When lisdexamfetamine dimesylate is administered via parenteral routes, there is delayed and gradual release of d-amphetamine with substantially attenuated peak concentrations when compared to immediate-release d-amphetamine.
> Oral administration of lisdexamfetamine dimesylate demonstrated that lisdexamfetamine dimesylate was not detected in rat brain tissue. The major metabolites of lisdexamfetamine dimesylate following oral administration were glucuronidated amphetamine and amphetamine.
> These two moieties comprised >90% of the total metabolites in plasma after oral dosing. Following intravenous administration, small amounts of hydroxylated lisdexamfetamine dimesylate were observed in plasma. As in the case of oral administration, the major metabolites from intravenous administration of lisdexamfetamine dimesylate were similar, glucuronidated amphetamine and amphetamine. In vitro experiments demonstrated that incubation of lisdexamfetamine dimesylate in human hepatic microsomal suspensions resulted in no significant inhibition of a panel of CYP450 isoforms that included CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, nor induction of CYP1A2, CYP2B6 or CYP3A4/5.
> Lisdexamfetamine dimesylate is also unlikely to be involved in interactions with drugs
> transported by the P-gp pump.
> yada yada yada.



So this could produce a ceiling effect if someone were to 'lysinate' psychedelic amines? Could be very HR-y and helpful, but could also ruin it?


----------



## DotChem

Friman1987 said:


> *
> 
> 
> 
> 
> 
> 
> New images:
> 
> NSFW:
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> NSFW:
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> NSFW:
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> NSFW:
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> Edit:
> 
> NSFW:
> 
> 
> 
> 
> 
> 
> 
> 
> 
> PNU-181731:
> https://en.wikipedia.org/wiki/PNU-181731
> 
> Many of these molecules are enzyme inhibitors (ex MAO-I)*


*

Why the images you post are not being displayed on my screen? "show" or "hide" just give blank page. Am I missing something?*


----------



## aced126

DotChem said:


> Why the images you post are not being displayed on my screen? "show" or "hide" just give blank page. Am I missing something?



It works for me, you probably just need to update your browser.


----------



## roi

Hosted on imgur, do you somehow block the site?


----------



## DotChem

roi said:


> Hosted on imgur, do you somehow block the site?





aced126 said:


> It works for me, you probably just need to update your browser.



Thanks guys: it works now.. My security settings seem to block it for some reasons. 

now on phenethylamines prodrugs, the lysinates conjugates .. how do they compare to phenethylline (captagon)?






or the captagon-like DOBs. is there is any literature on those??


----------



## sekio

while we're on a captagon tip





phenmetrazine linked with theobromine is actually _unknown in reaxys, pubmed and pubchem!_ I claim prior art 

those "skilled in the art" should be able to derive a synthesis plan in about 10 minutes.


----------



## Incunabula

Solipsis said:


> ....So this could produce a ceiling effect if someone were to 'lysinate' psychedelic amines? Could be very HR-y and helpful, but could also ruin it?


Hhmm, yes, I see  Thanks.

I don't think a ceiling effect will be a problem, because my prodrugs were meant for microdosing. Depends were the ceiling is of cause. As you say, it might even be a good harm reduction precaution.


----------



## SKL

I posted "captadrone" a few pages back ...






loads of potential here tbh assuming same activity in skirting at least some analog acts (seems like the exotic N-substitution might even be UK legal at least under the original cathinone law at a cursory reading?)

but would(?) be only active orally thus taking a lot of the fun out of mephedrone

I also postulated "mephevanse" 






which would work by other routes but as someone pointed out might require high doses

more generally what if we put amino acids other than lysine in a vyvanse-like structure?


----------



## Incunabula

I think the reason we aren't seeing prodrugs like these used to skirt the laws, is the same reason that no one prefers captagon or lisdexamphetamine to real amphetamine. Same goes for psychedelics.

Extended release prodrug = not so fun.


----------



## sekio

i think captagon would probably be more popular than you'd expect were it availiable in the US


----------



## Dresden

aced126 said:


> What enzyme is meant to metabolise R-N-O-(C=O)-R?



I've heard of carbamates (i.e., R-N-(C=O)-O-R'), but 'reverse carbamates,' R-N-O-(C=O)-R', no.  I could be wrong again, but then again, impossible structures are a pet peeve of mine.


----------



## Dresden

Incunabula said:


> I think the reason we aren't seeing prodrugs like these used to skirt the laws, is the same reason that no one prefers captagon or lisdexamphetamine to real amphetamine. Same goes for psychedelics.
> 
> Extended release prodrug = not so fun.



Or perhaps the new RC laws in the UK, US, and China are working and/or maybe the darknet shut down the clearnet RC business enough that many fewer people are looking for new molecular leads.  At any rate, it used to be that you would mention a novel drug compound, and bam, somebody in China was looking into producing it and selling it on the clearnet.


----------



## Dresden

sekio said:


> i think captagon would probably be more popular than you'd expect were it availiable in the US



I'd definitely like to try it someday.


----------



## Incunabula

sekio said:


> i think captagon would probably be more popular than you'd expect were it availiable in the US



Yes, it wouldn't surprise me at all 

Wouldn't it be safe to assume that if it was easy to get, it would probably be as popular as vyvanse?


----------



## roi

Most likely yes. The problem is: Captagon has not been spotted for years (even in the middle east), it's just amphetamine + caffeine pills (basically street amph pressed in pills).


----------



## SKL

roi said:


> Most likely yes. The problem is: Captagon has not been spotted for years (even in the middle east), it's just amphetamine + caffeine pills (basically street amph pressed in pills).



This is important to note and often overlooked. 

Detailed study from Saudi drug agency


----------



## TheBlackPirate

DotChem said:


> or the captagon-like DOBs. is there is any literature on those??



This was discused in an older PD thread. The verdict was DOX drugs last extremely long durations, cause vasoconstriction, and have resulted in fatalities. The captagon DOXs should create longer durations, worse vasoconstriction, and increased health risks. This is the thread here:

http://www.bluelight.org/vb/threads/764190-Caffinated-DOx?


----------



## Dresden

It seems like these black market producers of 'Captagon' would at least be pressing methamphetamine plus caffeine pills rather than amphetamine plus caffeine ones, as methamphetamine is much stronger, much longer lasting, not much harder or easier either really to make than amphetamine, and has been shown to cause tolerance much, much more slowly than plain AMP.  But I guess ISIS knows what they like already.


----------



## Friman1987

> It seems like these black market producers of 'Captagon' would at least be pressing methamphetamine plus caffeine pills rather than amphetamine plus caffeine ones, as methamphetamine is much stronger, much longer lasting, not much harder or easier either really to make than amphetamine, and has been shown to cause tolerance much, much more slowly than plain AMP. But I guess ISIS knows what they like already.



I think those ISIS terrorists taking Captagon so they not bleeding to death if they get shot during the battles, and also increasing focus. 

*Captagon metabolism: *







> 1. Metabolic fate of 7-[2-(α-methylphenylethylamino)ethyl]theophylline hydrochloride (fenetylline) was investigated in male Sprague-Dawley rats and three male volunteers.
> 
> 2. Six metabolites were identified in the rat urine as amphetamine(AP), p-hydroxy-AP, acetylaminoethyl-theophylline(TP), aminoethyl-TP, hydroxyethyl-TP and carboxymethyl-TP by comparison of their spectral properties and h.p.l.c. and g.l.c. characteristics with those of authentic samples. All these metabolites was also detected in the urine of humans receiving fenetylline.
> 
> 3. Quantification of these metabolites using h.p.l.c. and g.l.c. showed that carboxymethyl-TP, p-hydroxy-AP and acetylaminoethyl-TP were the major metabolites in 0-24h rat urine at 13.7%, 11.2% and 9.3% of dose, respectively. In men, carboxymethyl-TP(39–43% dose) and AP(23–33% dose) were the major metabolites in 0–48 h urine.
> 
> 4. These results suggest that fenetylline metabolism proceeds via oxidative cleavage at two different sites to produce aminoethyl-TP and AP, respectively. The pathway producing AP predominates, in both man and rat, but is more predominant in the former.


----------



## roi

Well, the US military uses (dextro)amphetamine as well, not methamphetamine.

Anyway, more structures, less talk.


----------



## sekio

> the US military uses (dextro)amphetamine



I don't think they approve amphetamine any more, I beleive it's all modafinil now.


----------



## roi

http://static.e-publishing.af.mil/production/1/afsoc/publication/afsoci48-101/afsoci48-101.pdf



> The recommended dosage of Modafinil for operational fatigue management is 200 mg every 8 hours as needed for sustained wakefulness. Modafinil usage should not exceed a dosage of 400 mg in any 24-hour period. Maximum approved dispensing quantity is twelve 200 mg tablets for each 30 days of deployment. The use of Modafinil for fatigue management should be limited to the fewest number of doses required to effectively complete a mission. The maximum approved period of continuous operational use of Modafinil is 72 hours.



72 hours modafinil binges sound wonderful.


----------



## Friman1987

*Some modified 2C-B/DOB (with primary amine):*

*NSFW*:


----------



## Nagelfar

^^^
(2S)-2-benzylpiperidine ('cause I don't believe the figures for just straight "2-benzylpiperidine" potency were non-planar as given on WP) + phenyltropane piperidine homologue benzene orientation and nitrogen added, and finally the 'restricted rotational' methylphenidate cyclohexane and nitrogen.


----------



## Friman1987

Can the last molecule serve as a prodrug for 4-MMC? Iris-ciliary body supposed to be the primary site of the reduction lol.
Which maybe makes the molecule not so safe.

*1.Oxime and Methoxime Analogs of B-blockers *https://www.researchgate.net/public..._eye_Soft_drugs_and_chemical_delivery_systems
*2. See the last step:* http://www.intechopen.com/source/html/41174/media/image10.jpeg


----------



## aced126

roi said:


> http://static.e-publishing.af.mil/production/1/afsoc/publication/afsoci48-101/afsoci48-101.pdf
> 
> 
> 
> 72 hours modafinil binges sound wonderful.



It genuinely is way more benign than you think!


----------



## DotChem

QUOTE=TheBlackPirate;13393595]This was discussed in an older PD thread. The verdict was DOX drugs last extremely long durations, cause vasoconstriction, and have resulted in fatalities. The captagon DOXs should create longer durations, worse vasoconstriction, and increased health risks. This is the thread here:

http://www.bluelight.org/vb/threads/764190-Caffinated-DOx?[/QUOTE]
Thanks for the link. I missed the thread. But the verdict on DOxethyllines? I don't see why would they have more vasoconstriction pbs than the parent DOx and/or caffeine. If anything they would probably have less cardiovascular (of course if properly doses) like Captagon. I mean REAL Captagon which apparently is nowhere to be found as @SKL pointed out here:




SKL said:


> This is important to note and often overlooked.
> 
> Detailed study from Saudi drug agency


 much of marketed "captagon" is just pressed AMPH+caffeine(at least according to this report from middle-east)

But the big killer IMHO is the extremely long duration of action. They would make nice Nootropics tho!


----------



## Incunabula

roi said:


> Most likely yes. The problem is: Captagon has not been spotted for years (even in the middle east), it's just amphetamine + caffeine pills (basically street amph pressed in pills).



....and doesn't this say it all? They could make fenethylline, but choose to make amphetamine instead, because it just _is_ "better". The only reason to make captagon/lysine-style prodrug stims of scheduled classics would be to skirt local laws. I think that many (or most even?) research chemical stimulants available are better than captagon (except if it's for studying or warfare).

But what do I know, I might be completely wrong. I stopped taking amphetamine and stuff like that a long time before the RC stim marked exploded. I'm a strictly psyguy.


----------



## Dresden

DARK and






DARKER

3-chlorophenyl analogues of ketamine and MXE.






HORNED DEVIL

Happy Winter Solstice 2015!


----------



## aced126

Funny you posted that 3rd compound, I was thinking of similar ones...

These compounds wouldn't be metabolised into the sketchy 3,4-dihydroxy compounds which many blame to be one of the causes of neurotoxicity as well as other problems. Maybe these compounds might lack DA selectivity however...














Indanyl derivative already made, less potent than parent compound for reasons discussed in this thread: http://www.bluelight.org/vb/threads...And-methamphetamine-only-releases-1-10-of-5HT
Benzocyclohexane derivative has also already been made, and I don't think it was very effective at all. That leaves just one more:


----------



## Dresden

DotChem said:


> that's what I thought.. a bit too polar but it could use active transport system of small molecules like pyridoxin to sneak in past BBB!
> 
> how about the methylenedioxyDMT??
> 
> like this:
> 
> 
> 
> 
> 
> 
> or the aAMT analog
> 
> like this








Is in TiHKAL and was active.  Yours probably are too.



aced126 said:


> Funny you posted that 3rd compound, I was thinking of similar ones...



I called it HORNED DEVIL based on the fact that the three methyl's look like horns and because PiHKAL mentions 






and says it is "very hard on cats."

Your first one is N-methyl-xylopropamine.  See wikipedia for the nor-methyl version, xylopropamine, which was a stimulant developed as a prescription drug in the 1950's which also had anti-inflammatory and analgesic properties but which caused hypertension often also, from what I gather.

The second one I know nothing about.

The third one is a synthetic impossibility I think, based on Sasha's comments about






which he clearly knew to be impossible to synthesize using establish chemical methods at the time of PiHKAL's writing anyway.

The last one looks like it has a lot of steric strain.  Don't know anything to say about it other than that, one way or another.


----------



## roi

Halogen free benzos. Why not?


----------



## neurotic

@ace

i think that 3,4-dimethyl amph or meth already exists and it's not very interesting. just googled it, yes it exists and it's called 'xylopropamine'

your molecules made me think of p-ethyl amph. it's pretty obvious so i take it has been thought of before. p-methyl amph was a very powerful 5HT releasing agent IIRC so there's some room for loss of potency. i searched it on isomer design but nada. it has a wiki page but zero references on it (?), so it might not even have been made. no CAS number even apparently.  didn't expect so from such an obvious one.






the cathinone derivative does exist though. anyone know how it was? i just ran a quick search a found one erowid report that looked like it was active enough.


*NSFW*: 




from here


> Conclusions:
> 4-EMC is dubby, psychedelic entactogenic/empathogenic and aphrodisiac cathinone derivative that possesses strong euphoriant properties directly comparable to MD(M)A for me.
> Though I had little success plugging/eating it and insufflation felt too caustic, I came to know it via IV administration. I'm not sure I'd trust this IM.
> Co-administration with 4-FA was optimal (for me) and produced no irritation or swelling at the injection site despite how much 4-FA burns when insufflated..
> 4-EMC's addiction potential is quite high with IV administration, and those not otherwise predisposed would do well to avoid it, if possible.
> 
> I would say that I enjoy 4-EMC moreso than Mephedrone. The effects profile being more favorable and expansive, the duration longer, the potency by weight a degree higher, and lacking characteristic feelings of Mephedrone-induced cardio- and neuro-toxicity.
> *That's not to say that it isn't toxic, but it lacks the palpable feeling of bodily abuse that I get from 4-MMC and 4-MEC.


----------



## Incunabula

neurotic said:


> @ace
> 
> i think that 3,4-dimethyl amph or meth already exists and it's not very interesting. just googled it, yes it exists and it's called 'xylopropamine'
> 
> your molecules made me think of p-ethyl amph. it's pretty obvious so i take it has been thought of before. p-methyl amph was a very powerful 5HT releasing agent IIRC so there's some room for loss of potency. i searched it on isomer design but nada. it has a wiki page but zero references on it (?), so it might not even have been made. no CAS number even apparently.  didn't expect so from such an obvious one.
> 
> 
> 
> 
> 
> 
> the cathinone derivative does exist though. anyone know how it was? i just ran a quick search a found one erowid report that looked like it was active enough.
> 
> 
> *NSFW*:
> 
> 
> 
> 
> from here


www.bluelight.org/vb/threads/502836-4-ethylmethcathinone


----------



## Solipsis

4-MA sounds pretty scary / dangerous though, so I would want to modify a drug far away from that...


----------



## DotChem

talking about prodrugs .. 2-cyanoethyl look neat






https://en.wikipedia.org/wiki/Fenproporex


----------



## aced126

What's the point of the cyanoethyl group?


----------



## DotChem

Incunabula said:


> ....and doesn't this say it all? They could make fenethylline, but choose to make amphetamine instead, because it just _is_ "better"....


could it be b/c it makes more money?..why bother going further in the synthesis.  you make more dough!


----------



## DotChem

the law for one! (was developed for athletes in the 60s if i am not mistaken).  But you're right. I don't the see the point as far meth is concerned. Longer duration maybe. 
But it was good for PEA though. Get it pass through BBB and get converted there to PEA giving sustained level PEA levels 
PEA half-life = 5 min 
CEPEA half-life = 3 h  







half-life = 5 min 








Half-life = 3 h


----------



## DotChem

aced126 said:


> What's the point of the cyanoethyl group?




Neuropharmacological and neurochemical properties of N-(2-cyanoethyl)-2-phenylethylamine, a prodrug of 2-phenylethylamine 
http://www.ncbi.nlm.nih.gov/pubmed/2890391


----------



## Solipsis

So let's make dicyanoethyltryptamine? CE-2C-D ? MDECA ? MXEC ? Cyanoethanol? Wait... strike that last one : P


----------



## DotChem

claims "priority" for the diCE-T.. the mono are "prior art"


----------



## Nagelfar

So I was trying to make a simple dopamine releaser from one end (using phenmetrazine as the basis after noticing the phenyltropane piperidine homologues as an example of similar but with one distance of the nitrogen difference) with a dopamine reuptake inhibitor from the other (using the aforementioned PT piperidine homologue as the basis, but used the styrene length that was quite efficacious among the cocaine analogues) -

what I wound up with was looking more like an opioid, so that is how I skewed it @ the end. Hoping some residual stimulant efficacy may remain:


----------



## aced126

DotChem said:


> the law for one! (was developed for athletes in the 60s if i am not mistaken).  But you're right. I don't the see the point as far meth is concerned. Longer duration maybe.
> But it was good for PEA though. Get it pass through BBB and get converted there to PEA giving sustained level PEA levels
> PEA half-life = 5 min
> CEPEA half-life = 3 h
> 
> 
> 
> 
> 
> 
> 
> half-life = 5 min
> 
> 
> 
> 
> 
> 
> 
> 
> Half-life = 3 h



I don't think the problem with PEA is low logP (it has an alright logP, it would be lipophilic enough to pass through) but rather instead that it is pretty much a perfect substrate for the MAO enzymes. I can see how adding the cyanoethyl group increases half life of the compound in the blood, but what I don't understand is how the N-cyanoethyl group is selectively cleaved in the brain (compared to being cleaved in the stomach or elsewhere)?


----------



## aced126

Nagelfar said:


> So I was trying to make a simple dopamine releaser from one end (using phenmetrazine as the basis after noticing the phenyltropane piperidine homologues as an example of similar but with one distance of the nitrogen difference) with a dopamine reuptake inhibitor from the other (using the aforementioned PT piperidine homologue as the basis, but used the styrene length that was quite efficacious among the cocaine analogues) -
> 
> what I wound up with was looking more like an opioid, so that is how I skewed it @ the end. Hoping some residual stimulant efficacy may remain:



How would you even make that heterocycle? I'm doubtful of its stability. Surely mixing 2 different pharmacophores into one molecule is very likely to destroy both types of activity...?


----------



## Incunabula

NSFW for size. Some molecules in there, unwrap it like a christmass present for the _I like to draw pictures of random molecules thread _


*NSFW*: 



2C-G3-indane (an obvious cross of jimscaline and 2C-G3. I dig the symmetry)






2C-G-1-aminoindane (looks like a spaceship  Most likely unsynthable, as I understand it)






psi-3,4,5-trimethyl-phenethylamine or psi-trimethyl-2C-G (2C-G is known to be active, psi orientation aswell, unlikely that the methyl at the 5-position wil abolish activity. So I think this one actually has a chance of being interesting - nevermind the fact, that 2C-G itself already sounds awesome. I can't really recall why I didn't add an alpha methyl, making it psi-trimethyl-Ganesha. Woulda been even more cool )











DotChem said:


> could it be b/c it makes more money?..why bother going further in the synthesis.  you make more dough!



Yes, absolutely. The only reason to go further in the synthesis would be, if you then made something more desireable, something better. Why spend time and money making your product subpar


----------



## DotChem

aced126 said:


> I don't think the problem with PEA is low logP (it has an alright logP, it would be lipophilic enough to pass through) but rather instead that it is pretty much a perfect substrate for the MAO enzymes. I can see how adding the cyanoethyl group increases half life of the compound in the blood, but what I don't understand is how the N-cyanoethyl group is selectively cleaved in the brain (compared to being cleaved in the stomach or elsewhere)?



You're right. LogP is not the issue with PEA but rather its metabolic stability towards MAO (both peripheral and central!). Which may help explain its short half-life in brain, blood and other tissues. If BBB transport was issue then in combination with MAO inhibitor you should be able to get decent levels in CNS. But I think it's not the case unless you dose massive amounts to overwhelm MAO which may not be a good idea!. So even you get it to the brain, it will get quickly chewed up by central MAO (at least in rats and since humans are not that different from rats!... I know a lot  

Now question is: how do you get sustained CNS levels of PEA? That's I think the rational for using the 2-cyanoethyl by the authors of study. CE-PEA distribution half-life is not that different from PEA but it is a weaker MAO substrate; getting chewed up by MAO much more slowly thus releasing sustained levels of PEA. It may also be active on its own!!

Now as to how the CE is selectively cleaved off by MAOs to give PEA and cyanoacetate, we'll have to ask rats. But my guess MAO prefer less "bulky" side to chew on. So it will oxidize the carbon beta to the cyano leading to breaking off the bond....Does it make sense? But one word of caution: the study in the paper was done on R.A.T.S

now @ mentioned the diCE-P: 





would be expected to have even longer half-life and sustained release of PEA.


----------



## DotChem

Dresden said:


> DARK and
> 
> 
> 
> 
> 
> 
> DARKER
> 
> 3-chlorophenyl analogues of ketamine and MXE.
> 
> HORNED DEVIL
> 
> Happy Winter Solstice 2015!



DARKEST 







Dissociative opioid stims 

ketamine(NMDA) + meperidine(Mu) + desmethylPiperidine(DAT)


----------



## Dresden

I dig this one






of yours, Incunabula.  Particularly the way the two phenyl methoxies are sure to raise the energy or 'activity' of the otherwise indolent and greasy hydrocarbon (with one amine, so maybe I should say, 'hydrocarbonamine').  Anyway, thank you for taking the time to notice and then offer structural improvements to my very own HORNED DEVIL.

The high degree of symmetry of another one of your creations, 2C-G3-INDANE, piques my fancy as well, kind of like this 2ce analogue of my imagination:






It looks like a 2C born with two penises or something.


----------



## Incunabula

Thanks  Yes, my psi-trimethyl-2C-G and your _HORNED DEVIL_ do resemble each other a lot, but I did actually drew these molceules quite some time a go. I think maybe I was reminded of it when I saw your _DEVIL_. I have more molecules in a folder, and I'll probably post some more next time I'm bored.


----------



## aced126

I decided to propose some structures based on Amfonelic acid.

https://en.wikipedia.org/wiki/Amfonelic_acid

It is an antibiotic (topoisomerase II inhibitor) with DRI properties and a poorly understood MOA. SAR work has probably been done but none of it seems to have been published.

Amnofelic acid:




*


----------



## Nagelfar

aced126 said:


> How would you even make that heterocycle?



Shhhh... No synthesis discussion ;-P ;-j



aced126 said:


> I'm doubtful of its stability. Surely mixing 2 different pharmacophores into one molecule is very likely to destroy both types of activity...?



I gave up on the dopaminergic original thought when I aimed for the opioid structuring, but it's close to both a DRI & DRA in some regard


----------



## DotChem




----------



## Nagelfar

This looked a lot better in my sketch @ home:






(Paroxetine + Nisoxetine + esCitalopram)

I also think I used reductionism instead of inclusionism when merging them, so the prototype of above compound was in all likelihood more viable, but once I get onto a computer and use Marvin Beans I go a little wacky. ;-p


----------



## Fruitofknowledge

I thought of some good chemical structures of RC opioids and other psychoactive compounds, some of them I though up years ago are now showing up on the RC market. Imagine taking tramadol and replacing one of the nitrogens methyl groups with a phenethyl group, this modification increases potency by a factor of 8-14. Which in return would increase the Mu opioid binding and would make the new compound 0.8X-1.4X as morphine by weight, if you remove the methyl ether group it would increase the potency again by 6-10 time making it 3-4 four times stronger then heroin. Add a methyl group at the beta carbon of the cyclohexane ring would make it even stronger maybe around half the potency of fentanyl. The synthesis wouldn't be too difficult all the analogs mentioned, the normethylphenethyltramadol being the easiest to synthesize, but the number one rule in fight club is that you don't talk about fight club!


----------



## Fruitofknowledge

I thought of several dissociative and opioid aryl cyclohexylamines and dissociative diphenylethylamines like diphenidine. What program do you use to draw your molecules?


----------



## roi

MarvinSketch is good and free.


----------



## aced126

Use opsin and just name your compound, then right click the compound and select copy image address, then type 
	

	
	
		
		

		
		
	


	




 to put the picture here.


----------



## roi

CUMYL-FUBINACA/BzODZ-EPyr hybrid.


----------



## aced126

Fruitofknowledge said:


> I thought of some good chemical structures of RC opioids and other psychoactive compounds, some of them I though up years ago are now showing up on the RC market. Imagine taking tramadol and replacing one of the nitrogens methyl groups with a phenethyl group, this modification increases potency by a factor of 8-14. Which in return would increase the Mu opioid binding and would make the new compound 0.8X-1.4X as morphine by weight, if you remove the methyl ether group it would increase the potency again by 6-10 time making it 3-4 four times stronger then heroin. Add a methyl group at the beta carbon of the cyclohexane ring would make it even stronger maybe around half the potency of fentanyl. The synthesis wouldn't be too difficult all the analogs mentioned, the normethylphenethyltramadol being the easiest to synthesize, but the number one rule in fight club is that you don't talk about fight club!



This is the molecule Fruit is referring to (I'm not sure what is the beta carbon on the cyclohexane): 






N-phenethyl substitution increases potency in morphine by ~10 times because there is a small lipophilic pocket in the mu binding site to which the phenethyl can fit into. With tramadol the molecule has a lot more flexibility and nor(N-phenethyl)tramadol would likely not be in a good conformation for binding interactions with this lipophilic pocket. I think this goes for all open chain opioids as far as I know. 

You are right, however, about removing the methyl ether group. Tramadol doesn't have much analgesic potency in itself (but more SNRI activity I believe), and the liver normally does the job anyway. Tramadol is probably intended to have the methyl group to make it a prodrug, which has advantages in its own right. It means IVing the drug and taking it by routes other than oral will be a lot less effective than oral itself. The O-methyl also aids with digestion obviously by increasing logP of the compound. 

If SNRI activity is heavily impaired by O-demethylation, I would have to agree with you that it's a good substitution; tramadol in high doses can result in serotonin syndrome and/or seizures as a result of this I believe. However SNRI activity could play an important part in the overall effectiveness of the drug on life quality of user/patient. Nevertheless, a free phenolic group anyway has a very good calculated logP anyway (O-desmethyltramadol logP calculated: 2.64; tramadol logP: 3.18 ).

O-desmethyltramadol was sold as a research chemical for a while.


----------



## Dresden

2-piperonyl-pyridine (2-PP)

A bare bones MDMA and amfonelic acid inspired structure.






MethyleneDioxyAmfonelic Acid (MDAA)

Amfonelic acid is notoriously difficult to synthesize.


----------



## roi

Slightly reminds me of Methylone. Called Oxolinic acid, also a DRI.


----------



## neurotic

Incunabula said:


> www.bluelight.org/vb/threads/502836-4-ethylmethcathinone



yeah, i saw it too but was too lazy to read it through, so had to ask  got tired of your old name man?



Solipsis said:


> 4-MA sounds pretty scary / dangerous though, so I would want to modify a drug far away from that...



i've read that old BL thread with Erny about 4-MA too, but that's pretty much all the info i can find on it, unfortunately, and it leaves me wondering. Erny looks like he was an intelligent poster and everything, but honestly what he's mentioning i can imagine happening with MDMA, for example.


----------



## DotChem

biCoke


----------



## Friman1987

I was bored when I made this one.


----------



## Dresden

aced126, 

I like your methyl carboxylate amfonelic acid idea.


----------



## Friman1987

Dresden said:


> aced126,
> 
> I like your methyl carboxylate amfonelic acid idea.



Nice idea. The antibiotic part looks like Fluro-Quinolones. They can inhibit DNA synthesis indirectly by inhibiting DNA gyrase which is an topoisomerase that is uniquely for bacteria.

The Fluro group that attached to the Quinolones enhances the antibiotic effect significantly. I guess that amfonelic acid has not strong antibiotic effect like the F-Quinolones. I wonder in what dose amfonelic acid gives antibiotic effect?


----------



## DotChem

FA notoriously difficult to synthesize and terribly insoluble even the  salt will barely dissolve in water. only in very unfriendly solvent like  DMSO or DMF. Can you make it somehow more soluble and synthetically  accessible eg by reacting...euhhhhhhh! wait nothing!

Any reasons  tho why Amfonelic acid didn't really become popular in RC market? some  years ago(circa 2010ish) the analog where the benxyl is replaced by a  phenoxy was available from some vendors. Easier to prepare and cheaper I  guess and It does pretty much the same thing as AFA. Any thoughts on  why it never took off??


----------



## aced126

The reports I've read on Amfonelic acid have all been pretty positive. Even fastandbulbous thought it was very nice. Amfonelic acid probably didn't take off because of the fact that it's a hard synth. The phenoxy derivative, I'm not sure why it isn't popular. Maybe it just isn't as good as Amfonelic acid. Can you link any anecdotal reports on the phenoxy derivatives?


----------



## roi

PheniGHB. Could that even work?


----------



## aced126

Interesting, it might well work. Your compound has a few possible ways it could exert its action. Any affinity at the GHB receptor will result in excited neurons. It might agonise GABAR (stronger or weaker) which will result in inhibitory responses. It might even (especially if the alcohol is replaced in the amine; this compound would have definitely been made and tested while making Lyrica) block a2-delta voltage gated calcium channels, resulting in normally inhibitory responses as well.


----------



## belligerent drunk

aced126 said:


> (especially if the alcohol is replaced in the amine...



Do you mean replaced with an amino group? In that case that'd make it phenibut, which does work on the VDCCs. Actually I'm intrigued as to what kind of pharmacology this (roi's) compound would display; GHB with a long half-life?


----------



## pharmakos

roi said:


> PheniGHB. Could that even work?



if that phenyl ring was a cyclohexyl ring, that would be gabapentin with a change analogous to the change from GABA -> GHB (amino -> hydroxy)

edit -- almost... i overlooked a carbon.  still probably an active compound, just who knows what that activity would be.


----------



## aced126

Yeah, I meant that Belligerent. I'm sure lots of SAR work has been done on VDCC blockers, seeing as there are many complex gabapentinoid derivatives on Wikipedia itself.


----------



## roi

Few more:





















Problem is that none of these are likely to be somewhat potent (dose < 100mg).


----------



## Dresden

Tolerance is a big problem with AFA.


----------



## Friman1987




----------



## roi




----------



## aced126

Rationale?


----------



## roi

WAY-161503 + 2C-B hybrid.

Few stims:


----------



## roi

Best benzo ever:

Pyntizolam


----------



## Friman1987

*Modification: *

*NSFW*: 
















*Modification: *

*NSFW*:


----------



## aced126

Nice molecules, you've got a good eye for seeing links between structures!


----------



## DotChem

Can't be more drug-like than that. But beware of being too good for CNS drugs. i.e. can bind at multiple receptors besides 2a eg D4 will probably like it (but then again you get a horny trip! as D4 agonists make males rats incredibly horny!). But pretty cool! reminds me vaguely of this dewormer structurally


----------



## SKL

all these pure dopamine agonists (afa,etc) also scream psychosis to me
especially if they are tweaked to add a dash of nmda actvity as random molecule thread likes to do


----------



## DotChem

the first one may well be dissociative stim! PCP+(retro)Methylphenidate


----------



## SKL

DotChem said:


> the first one may well be dissociative stim! PCP+(retro)Methylphenidate



cool molecule
but a troubling genre 
combine 2 major neurotransmitter models of schizophrenia
(as I was saying probably as you were posting this)
what could go wrong?????
(yes, PCP and diphenidine, _inter alia_, do this and surprise they make you crazy, 
i.e. the 'therapeutic' window between tripping and eating someone's lungs is small)


----------



## Nagelfar

SKL said:


> (....e. the 'therapeutic' window between tripping and eating someone's lungs is small)



In his defense, he thought she was a sock.


----------



## DotChem

Nagelfar said:


> In his defense, he thought she was a sock.



Oh fuck! serious? he thought she was a sock??..can't stop LMAO


----------



## DotChem

SKL said:


> cool molecule
> but a troubling genre
> combine 2 major neurotransmitter models of schizophrenia
> (as I was saying probably as you were posting this)
> what could go wrong?????
> (yes, PCP and diphenidine, _inter alia_, do this and surprise they make you crazy,
> i.e. the 'therapeutic' window between tripping and eating someone's lungs is small)



weird you posted this at exact same time I was drawing these molecules.  Actually I didn't intend nmda-like stims just tweaking MPH and realize after that you might end up with a NMDA-stim. 
But then again its is really hard to tell what could go wrong? "random" molecules such as these may or may not have either activity... 
eg Benocyclidine (designed as NMDA) is a *PURE DRI* with no NMDA Serotonin or NE ..etc completely unexpectedly!


----------



## SKL

yeah especially in this rough genre of heterocyclic/multicyclic compounds you can definitely get all sorts of weird affinities popping up
not like PEAs which are relatively predictable


----------



## Fruitofknowledge

Imagine taking all structure motifs that give synthetic certain synthetic opioids their potency and merging them all in to one. I took the structure of Anilidopiperidines like Carfentanil and Bentley compounds like Etorphine and did the hypothetical merger of structures to make a ultra-potent mu agonist! Stop you're mad, ha ha ha! If you replace the propanamide group of fentanyl with a acrylamide group it doubles the potency, if you add a fluorine atom at the ortho position of the benzene ring it doubles the potency of fentanyl. Research on Bentley compounds denotes that pentyl, butyl, and isopentyl on the 7 carbon on the cyclohexane ring are the most potent substitutes 4500, 5200, and 9200X the potency of morphine respectively. Adding a isopentyl instead of Etorphine's butyl group produces a compound almost twice the potency. Targeting substitutes that increase binding affinity and you get this!


----------



## Fruitofknowledge

R-4066 an open chain opioid drug which is an analogue of the opioid analgesic methadone, or more accurately Norpipanone, where the metabolically labile dimethylamino group has been replaced by a piperidinospiro group. Developed by Janssen Pharmaceutica,[1] it is around 212x more potent than methadone as an analgesic in animal tests, with an effective oral dosage of 0.07 mg/kg, but is slightly shorter acting, with a duration of action of around 3 hours.


----------



## SKL

Fruitofknowledge said:


> Imagine taking all structure motifs that give synthetic certain synthetic opioids their potency and merging them all in to one. I took the structure of Anilidopiperidines like Carfentanil and Bentley compounds like Etorphine and did the hypothetical merger of structures to make a ultra-potent mu agonist! Stop you're mad, ha ha ha! If you replace the propanamide group of fentanyl with a acrylamide group it doubles the potency, if you add a fluorine atom at the ortho position of the benzene ring it doubles the potency of fentanyl. Research on Bentley compounds denotes that pentyl, butyl, and isopentyl on the 7 carbon on the cyclohexane ring are the most potent substitutes 4500, 5200, and 9200X the potency of morphine respectively. Adding a isopentyl instead of Etorphine's butyl group produces a compound almost twice the potency. Targeting substitutes that increase binding affinity and you get this!



^yeah but would it be any fun? as a former opiate addict fentanyl sucks to begin with and a lot of the analogs are even worse ...

reminds me of this Shulgin quote:



> The extension of the two-carbon chain of mescaline by alpha-methylation to the three carbon chain of TMA approximately doubled the potency of the compound. And it was felt to be a completely logical possibility that, by extending it one more carbon atom, to the four carbon chain of alpha-ethyl-mescaline, it might double again. And following that logical progression, the doubling of potency with each additional carbon atom, the factor would be 2 to the 7th power by the alpha-octyl (or 256x that of mescaline, or a milligram as active dose) and with a side chain of a 70-carbon alkyl group (alpha-heptacontylmescaline) it would take just a single molecule to be intoxicating. This was rich fantasy stuff. As an active compound, just where would it go in the brain? With an 80-carbon side-chain, would one-thousandth of a single molecule be enough for a person? Or might a single molecule intoxicate a thousand people? And how long a chain on the alpha-position might be sufficient that, by merely writing down the structure on a piece of paper, you would get high? Maybe just conceiving the structure in your mind would do it. That is, after all, the way of homeopathy.


----------



## Fruitofknowledge

I talked about Normethylphenethyltramadol and its desmethyl ether counter part as potential potent legal analogs not covered by the US Analog Act with a estimated potency of 1-1.4X for the first compound and 6-10X for the second compound. I received a post that it would fit into the addition binding pocket because its an open chain. Diampromide around morphine strength open chain fentanyl analog. If you remove the N-phenyl group off of fentanyl it almost abolishes all activity, where in fact tramadol and O-desmethyltramadol are way more active by there selves.


----------



## Fruitofknowledge

I talked about Normethylphenethyltramadol and its desmethyl ether  counter part as potential potent legal analogs not covered by the US  Analog Act with a estimated potency of 1-1.4X for the first compound and  6-10X for the second compound. I received a post that it wouldn't fit into  the additional binding pocket, because its open chain structure. Diampromide  around morphine strength open chain fentanyl analog. If you remove the  N-phenyl group off of fentanyl it almost abolishes all activity, where  in fact tramadol and O-desmethyltramadol are way more active by there  selves. The open chain structure doesn't make a difference to binding etorphine, fentanyl and bromadol all have additional substitutes that reach the extra binding ''pocket''.


----------



## Fruitofknowledge

opioids I imagined


----------



## Fruitofknowledge

*Opioids analogs I imagined*


----------



## Fruitofknowledge

I can get my picture to paste!


----------



## SKL

your image links are an indecipherable mess, dunno where you are trying to post from
best thing to do is just upload to tinypic.com
also this site produces very attractive structures if you just IUPAC name your molecule


----------



## roi

Actually please use imgur.com.

Tinypic is so 1990.


----------



## Friman1987

*PRO-LAD: *https://en.wikipedia.org/wiki/PRO-LAD
*OSU-6162 (PNU-96391): * https://en.wikipedia.org/wiki/OSU-6162
*UH-232:* https://en.wikipedia.org/wiki/UH-232
*5-OH-DPAT:*https://en.wikipedia.org/wiki/5-OH-DPAT


----------



## Dresden

Opsin doesn't even require a strictly IUPAC name to do its magic.  For most molecules, it accepts a wide variety of butchered, though still basically logical, monikers.  

And Friman1987, please consider using http://opsin.ch.cam.ac.uk in the future, as the molecular sketches you're posting now are far too small and faint to be easily understood.  Just a friendly suggestion (aka subtle command, lol).

As for the PiHKAL quote, I actually did get high once about 10 years ago after drawing this molecular structure






on a piece of paper with a Sharpie, never to be repeated.  I'm sure other factors which I was not aware of were at play, though.  Still, it was an all around awesome time and is actually one of the best memories of my life thus far.


----------



## aced126

Dresden said:


> Opsin doesn't even require a strictly IUPAC name to do its magic.  For most molecules, it accepts a wide variety of butchered, though still basically logical, monikers.
> 
> And Friman1987, please consider using http://opsin.ch.cam.ac.uk in the future, as the molecular sketches you're posting now are far too small and faint to be easily understood.  Just a friendly suggestion (aka subtle command, lol).
> 
> As for the PiHKAL quote, I actually did get high once about 10 years ago after drawing this molecular structure
> 
> 
> 
> 
> 
> 
> on a piece of paper with a Sharpie, never to be repeated.  I'm sure other factors which I was not aware of were at play, though.  Still, it was an all around awesome time and is actually one of the best memories of my life thus far.



Expand on this event?

Also, the images Friman posts appear very large for me.


----------



## Solipsis

Must be your screen resolution then...

I don't know about that 'getting high' event but the structure would be what Shulgin called A for amylescaline. Not pentescaline since P is used for proscaline. It's in the B / buscaline entry. Not that promising?

Personally I'd be curious what is beyond MAL? Say isobuscaline or even neopentescaline..
Then again the thio's or haloalkyls could be just as promising - like say a 2C-T-7 (fluoropropylthio) analogue?


----------



## Dresden

"Expand on this event?"

Before I had finished the drawing, I noticed small figures of usually naked men all over my room.  I saw my grandfather who is dead watching me from a picture frame.  I looked out the window and saw armed soldiers from V for the Visitors charging me from the woods.  There was a man on the back porch shrinking my now (I thought) dead roommate's head.  He disappeared every time I walked out there.  The overall feeling was that of floating, and it felt very ethereal..  I saw my raver friends in the reflection of the windowpane.  They could see me too.  Some of them appeared to be mainlining some kind of very pleasurable drug through butterfly needles with ultra thin tubing.  The overall feeling was that of being in heaven.  There was a fairy in the windowpane playing a flute which I could not hear.  He appeared shocked when he saw that I could see him.


----------



## DotChem

Designer In the News..Early warning
US HR bill to put synthetic opioid *1-(4-Nitrophenylethyl)piperidylidene-2-(4-chlorophenyl)sulfonamide* aka W-18 on Synthetic Drug Control Act. So far it is completely legal technically as it doesn't look like analog of anything (save far far fectched fentanyl!!!!) I guess that will include all its analogs. H.R. 3537 21 December 2015 








Wiki entry : 


> *1-(4-Nitrophenylethyl)piperidylidene-2-(4-chlorophenyl)sulfonamide* (*W-18*) is a potent μ-opioid  agonist with a distinctive chemical structure which is not closely  related to other established families of opioid drugs. It was invented  by the chemists Edward Knaus, Brent Warran and Theodore Ondrus in 1981.[1]
> 
> *This compound was found to be around 10,000x more potent than morphine in animal studies*.[_citation needed_]
> 
> It has never been studied in humans, but would be expected to produce  effects similar to those of other potent opioid agonists, including  strong analgesia, sedation, euphoria, constipation, itching and respiratory depression which could be harmful or fatal.[_original research?_] .. and blabla and blabla


----------



## DotChem

amazing! remove the nitro of W18 and the activity decrease dramatically: W15 is only around 5 times more potent that morphine in animals


----------



## Dresden

I expect this






would knock your socks off but might smell really bad.


----------



## SKL

DotChem said:


> amazing! remove the nitro of W18 and the activity decrease dramatically: W15 is only around 5 times more potent that morphine in animals



appealing but short t1/2?


----------



## aced126

Nitro group increases potency by 20,000. Wow. Have they explored other substitutions?

Where did you get the short half life from?


----------



## Dresden

I know, right.  I can only imagine what






would do ( kill you?) and what its proper dosage would be? 

Or check this out






Wow, talk about death by adrenergia! 
Or this






TNT-AMP

An explosive amphetamine!


----------



## SKL

aced126 said:


> Nitro group increases potency by 20,000. Wow. Have they explored other substitutions?
> 
> Where did you get the short half life from?



baseless speculation on my part to be honest, was more asking the question


----------



## Dresden

More improved NTs.  The first two might be almost sedating!











Now, forget about toxic catechols!














































So many different ways to set up the nervous system!

These chloro improved neurotransmitters cannot be 3-methoxylated to the inactive vanillin derivates like catechols are.

Ok, back to reality.  Is the methcathinone research chemical fad over already?  I think it might be, but ever since safe or scam went offline, I don't buy research chems blindly.






And what about this one






from sesamol?  I think it might metabolize into the dreaded






after crossing the BBB and reek havoc on the CNS of whatever mammal is unlucky enough to have ingested it, but that could be based on some kind of urban myth that the latter compound is terribly neurotoxic if injected into the brain.  Otherwise, it's not about to cross the blood brain barrier.  It's even worse at that than






Don't know what the minor (1 percent) metabolite of amphetamine






does exactly, except I think they use it in eye drops to dilate one's pupils?  And I think its log P is good enough to predict it will diffuse across the hydrophobic blood brain barrier.  Does anybody have any information on 4-OH-AMP?

Disrespect my prolific pen as I send the minds of the weak to rise and take power over the land as we stand a solitary piece of sand let the mind use the physical as planned.


----------



## Friman1987

Dresden said:


> And what about this one
> 
> 
> 
> 
> 
> 
> from sesamol?  I think it might metabolize into the dreaded



Perhaps a less active version of MMDA-2?


----------



## DotChem

I hereby name it Shulginamine


----------



## Incunabula

Nice one, Dotchem


----------



## DotChem

thx @Incunabula ..actually I thought of adding a dash of LSD:






 you ended up like this:






I wouldn't trip on that tho! half-life would probably be WEEKS not days as FLY already can last anywhere from 2 to 4 days!!! but it look nice. how you synthesize that? don't even ask! Would make nice student thesis with chiral versions and all that!!?


----------



## aced126

Nice molecules


----------



## Solipsis

Good for cluster headaches perhaps 

https://en.wikipedia.org/wiki/2-Bromo-LSD

But maybe without the bromo the above becomes active? Still waiting for someone to try that simplified 3-ring lysergoid haha, whatsitcalled


----------



## Friman1987

https://bitnest.netfirms.com/external.php?id=%7DbxUgXXCIXP%27d%7D%04%05_%5BQ%03WJ


*NSFW*:


----------



## Nagelfar

Whoever started the trend of graphing out every derivative down the line of whatever specific random molecule you post instead of just posting the single compound, die. 

Ever since I discovered that TSA chelated benzenes double the binding potency of DRIs without diminishing much else (someone correct me if it throws the LogP way off or the PSA or etc.)






Then I wondered, the electrostatic improvement of chelating the benzene thus; could it be transferred to a functional facet of DRAs too? Since DRIs and DRAs overlap, but DRAs smaller fits the substrate spot, what on earth would a chelated amphetamine do? Best case scenario in my wild imagination; the transitional metal makes it so, although it acts as a subtrate at MAT, it's unable to cross the cell membrane into the vesicular area (VMAT) perhaps then it just act as a substrate, phosphorylating MAT at the surface of the axon and not within it. Maybe even it wouldn't trigger autoreceptors as much that way?






[_η_6-(D-_N_-methyl-amphetamine]tricarbonylchromium (??)


----------



## sekio

you may want to consider that Cr is not very nice for biological systems....


----------



## Nagelfar

sekio said:


> you may want to consider that Cr is not very nice for biological systems....



What, me? Mr. Unintentional Energetic Molecule-Should-Make-Tool-Compounds-Over-The-Top-Chirality-Makes-Chemists-Wake-In-Cold-Sweat-From-Nightmares-'bout-'em Nagelfar? NaV blocking isn't either, nor is m-amp neurotoxicity (um. Just how *not nice* / 'toxic' are we speaking here sek?)


----------



## Friman1987

The chromium tricarbonyl compounds should act as a carbon monoxide-releasing agent. They release CO to myoglobin and hemoglobin. CO Bind to the same binding site as O2. CO have also better binding affinity then oxygen. CO will displace O2 and impairs the transport of oxygen.


*Edit:* Something like [{(MeO)2C6H4}Cr(CO)3]. See page 267. 
_Besides that, i don't think you want chromium in your body lol._


----------



## DotChem

Solipsis said:


> Good for cluster headaches perhaps
> 
> https://en.wikipedia.org/wiki/2-Bromo-LSD
> 
> But maybe without the bromo the above becomes active? Still waiting for someone to try that simplified 3-ring lysergoid haha, whatsitcalled



Yes probabbly but the 2-BrLSD is pretty fascinating..apparently 2a receptors are picky! don't like Br at 2 position but can accomodate them in dob-like Br substitution pattern.

the simplified tricyclic lysergoid (or shall we call them lysergonan like morphinans? look very appealing.worth the effort. 







 They look like morphinans with the opposite stereochemistry!!
So beware! racemic mixture might well give a opioid psychedelic!, similar to this:





may be a bit less active without the phenolic OH!
so potentially you could end up with opioid psychedelic: LSD+Morphine (at quite close dosage range!!!)

re: simplified LSD
Further simplification I thought. Replacing pyrrole ring of LSD with phenyl (easier to synthesize!) and give LSD hair-cut ended up like this:






Would be surprised if it wasn't described somewhere in literature!!). But then again naphthalenes tend to be carciogenic, isnt it?


----------



## DotChem

how about this one on HT2a/2c? wouldnt it be closer to LSD than the dihydro congener??


----------



## DotChem

I meant compared to this 





> @Friman1987



The first one!


----------



## sekio

> (um. Just how *not nice* / 'toxic' are we speaking here sek?)



i'm gonna say that an organic-soluble Cr(0) source is probably a great way to fuck up enzymes non-specifically by delivering heavy metal ions to all sorts of places they normally would never make it.... so toxic like lead, uranium, thallium, polonium type stuff. heavily bioaccumulative i'd bet. methamphetamine's monoamine release/pro-oxidative effects are tame in comparison. 

look at the toxicity of nickel carbonyl for a scare... and also for why nobody uses metal carbonyls as drugs.


----------



## Dresden

Just to keep things straight, this is






(S)-METHAMPHETAMINE, and this is






(S)-METHAMPHETAMINE, but this is






**not** (S)-METHAMPHETAMINE.


----------



## pharmakos

i haven't taken orgo yet.  how do you know which one is the S and which one is the R in any given chiral molecule?


----------



## Solipsis

You first locate the chiral center, that would be the one (virtually always carbon) atom that is bonded to 4 groups or atoms that are ALL different / distinguishable from each other, so anything 'symmetrical' doesn't count since that means that the mirror images of a molecule are actually identical, just like that is true for simple geometry.

Then you list those 4 groups in terms of 'priorities' which are defined by these rules https://en.wikipedia.org/wiki/Cahn–Ingold–Prelog_priority_rules  by atomic number.

Then take the molecule and note the direction of the circle you draw when following the prioritized groups. If you go left, then its S (for sinister, left), if you go right then its R (rectus).

I think you do that by rotating the molecule in 3D and pointing the lowest priority group away from you, then numbering the rest.


----------



## roi




----------



## Friman1987

DotChem said:


> I meant compared to this
> 
> The first one!



Maybe, Benzofuran is aromatic. You have sp2-hybridization everywhere, that might work differently in comparison to 2,3-dihydrobenzofuran? The R isomer is the active isomer when you have DOB or Bromo dragonfly and other DOB derivatives. They have some form of shape similarities. S and R DOB gave differences shape to the nitrogen. R DOB is the must active one and S have not so good activity.  But how about the molecule that you mentioned? If you look at the 3D structure, the R isomer seems to changes the shape of the molecule, and make the structure a bit different in comparison to the other active substances.


----------



## Friman1987




----------



## SKL

^ a thing of beauty


----------



## sekio

introducing the biphenyl probably destroys the bulkiness needed to have a good nmda antagonist though


----------



## Friman1987

Yes you have right.
diphenylmethane Should work. But however, the structure then well becomes something like dizocilpine.


----------



## DotChem

somebody suggested phenethyl tramadol or its metabolite sometimes ago?? I guess on this forum, can't remember!






it is less active than simple desmethyl-tramadol. the whole series







here is a link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648120/


----------



## DotChem

Friman1987 said:


> Maybe, Benzofuran is aromatic. You have sp2-hybridization everywhere, that might work differently in comparison to 2,3-dihydrobenzofuran? The R isomer is the active isomer when you have DOB or Bromo dragonfly and other DOB derivatives. They have some form of shape similarities. S and R DOB gave differences shape to the nitrogen. R DOB is the must active one and S have not so good activity.  But how about the molecule that you mentioned? If you look at the 3D structure, the R isomer seems to changes the shape of the molecule, and make the structure a bit different in comparison to the other active substances.




Oh absolutely. The benzofuran will give a different shape closer to that  of LSD pyrrole.  While the benzodihydrofuran a shape closer to that of  morphinans(not withstanding stereochemistry at C-N).  Since we don't  discuss synthesis here, just for the sake, the reason I thought maybe  data on 5HT2a/2c of the dihydro derivatives available is that you  synthesize it en route to the benzofuran (ie by catalytic reduction)  among others. So I thought since whoever prepare it might have in hand  the benzofuran, why not test it too?

For BromoDragon-Fly the bis-dihydrofuran is 20 times less active than the parent molecule if I remember.

As for stereochemistry, true the S isomer is the active DOB FLY while the R is inactive. Same with amphetamines.

Now  the oipiods (ie morphinans) on the other hand the R will be expected to  the active isomer. Check it out with the morphine molecule below.   Which lead me to suggest that the S-isomer of both (furnao and  dihydrofurano) might be LSD-like and the R-isomer opioids like.  with  lefetamine, one might expect the R to be opioid agonist (albeit partiel)  and the S stimulant ie S-amphetamine like. is there any data on R and S  lefetamine??

Now as for the molecule I drew notice it is actually not chiral (it is symmetrical!) so can well equally bind LSD receptors (2a/2c) opioids (compare to morphinans) and NMDA (compare to lefetamine) in addition to potentially beeing DRI DRA .. PRETTY NASTY I GUESS


----------



## DotChem

read : data on 5HT2a/2c of the FURAN derivatives


----------



## DotChem

let me try again! discussing synthesis make me nervous I guess; read :



> the reason I thought maybe  data on 5HT2a/2c of the furan derivatives  available is that you  synthesize it en route to the benzoDIHYDROfuran (ie by  catalytic reduction)  among others


 ie reduction of benzofuran to dihydrobenzofuran (not suggesting synthesis tho just for the sake of discussing


----------



## roi

UWA-001 (methylenedioxymephenidine, substance 11g in doi 10.1039/C0MD00108B):



> As indicated in Fig. 6, the human-psychoactive drugs MDMA and PMA reduce prepulse inhibition in a dose-dependent manner. Conversely, compound 11g clearly shows the opposite trend, marginally increasing prepulse inhibition, much like some antipsychotic drugs (see above). These data strongly suggest that 11g does not exhibit psychoactivity



Mhm wouldn't be surprised if it's a NMDA receptor antagonist. Ketamine increases PPI as well.


----------



## aced126

Tramadol losing potency as the alkyl chain between N and phenyl group increases is not surprising. Tramadol and other open chain opioids are more likely to conform in a slightly different and more accessible way than classical opiates to the receptor. Adding the N-phenalkyl group will not mean that it is likely to interact with the hydrophobic pocket as it would be with classical opioids. Steric hindrance is more likely the case here, and this should be the case especially if activity drops as n increases (I haven't read the paper yet).


----------



## aced126

Also I think for synthesis discussion, saying "reduction from x to y" etc should be allowed given that absolutely no reagents or practical details are given. Especially if doing so can open up on new insights relating to pharmacodynamic and pharmacokinetic properties of said compound.


----------



## Solipsis

I like that... no synthesis but magical transformations  rules on alchemy?? : p


----------



## Nagelfar

Friman1987 said:


> The chromium tricarbonyl compounds should act as a carbon monoxide-releasing agent. They release CO to myoglobin.
> 
> *Edit:* Something like [{(MeO)2C6H4}Cr(CO)3]. See page 267.



"...on photolysis..." I don't think there's much room for light to get into an intravenous preparation. ;-P or am I showing my ignorance dramatically? ;p



sekio said:


> i'm gonna say that an organic-soluble Cr(0) source is probably a great way to fuck up enzymes non-specifically by delivering heavy metal ions to all sorts of places they normally would never make it.... so toxic like lead, uranium, thallium, polonium type stuff. heavily bioaccumulative i'd bet. methamphetamine's monoamine release/pro-oxidative effects are tame in comparison.
> 
> look at the toxicity of nickel carbonyl for a scare... and also for why nobody uses metal carbonyls as drugs.



Well, I think of the man who ate colloidal silver as a daily supplement for years straight, but all it did to him was turn him into a smurf (or hindu God?)


----------



## Friman1987

> Now as for the molecule I drew notice it is actually not chiral (it is symmetrical!) so can well equally bind LSD receptors (2a/2c) opioids (compare to morphinans) and NMDA (compare to lefetamine) in addition to potentially beeing DRI DRA .. PRETTY NASTY I GUESS


This one should works as you say, DRI,NRI and mybe like amphetamine have some kind of monoamine releasing property. 







> Would be surprised if it wasn't described somewhere in literature!!). But then again naphthalenes tend to be carciogenic, isnt it?


Why not making it more polar? 




some of these should be active. I dont no which one. You can do 1000 other structures with this one, you might come up with something better.


----------



## roi




----------



## DotChem

aced126 said:


> Tramadol losing potency as the alkyl chain between N and phenyl group increases is not surprising. Tramadol and other open chain opioids are more likely to conform in a slightly different and more accessible way than classical opiates to the receptor. Adding the N-phenalkyl group will not mean that it is likely to interact with the hydrophobic pocket as it would be with classical opioids. Steric hindrance is more likely the case here, and this should be the case especially if activity drops as n increases (I haven't read the paper yet).


You're right. Like I said someone on this thread sometime ago (cant remember) suggested phenethyl tramadol. The rational beeing that replacing the N-methyl of morphine or meperidine with a phenethyl increase potency by at least 10times. So theoretically it should be at lest 10x tramadol at mu. The authors of that paper use similar reasoning. But apparently it doesnt work (no more active than the N-methyl).


----------



## DotChem

Friman1987 said:


> This one should works as you say, DRI,NRI and mybe like amphetamine have some kind of monoamine releasing property.
> 
> 
> 
> 
> 
> 
> Why not making it more polar?
> 
> 
> 
> 
> some of these should be active. I dont no which one. You can do 1000 other structures with this one, you might come up with something better.


Why would you want make'em more polar? cLogP of 2.37 seems pretty excellent to me as far as BBB transport is concerned + shorter distribution T1/2 giving fast acting drug molecule because of less non-specific protein binding!


----------



## DotChem

> @Friman1987


Oh  I see: so the indole NH is required for LSD binding (as agonist!!!?) to  2a. Hydrogen bond to Ser 546? But usually H-bond gain of affinity is  not that huge (10x times at best!) and since LSD is EXTREMELY POTENT  5HT2a agonist, one can live with that I guess. Problem is if that (not having H-bond donor there) will  still result in agonist rather than antagonist!

So may be this?









ie 








extremely  easy synthesis but CAUTION the opposite stereochemistry at the C-N  might well results in a potent opioid so a racemic mixture might well  give psychedelic opiates. But that's all theoretical until someone make  and test it!!!


----------



## aced126

Solipsis said:


> I like that... no synthesis but magical transformations  rules on alchemy?? : p



Not necessarily a "magical transformation" lol, but a transformation which is known to be possible, but nothing is revealed practically in achieving that.


----------



## aced126

roi said:


>



It would be interesting to see how the thiophene moiety substitutes for the methyl in compounds 2 and 5.

I thought of and posted guanidine amphetamine a while ago here. It could work. Provided it's a fair substrate at DAT and can agonise TAAR1 effectively, it is likely to increase cytosolic [DA] loads due to increased basicity over amphetamine, and thus increase synaptic [DA]. There might be pharmacokinetic problems however.


----------



## aced126

Friman1987 said:


> .





DotChem said:


> .





Really enjoying the rational drug design from both of you, keep it up

Open chain lysergic acid analogues seem like a great idea


----------



## aced126

Have benzodiazepine derivates with isosteres for the heteroatoms been synthesized?

https://en.wikipedia.org/wiki/Medazepam
http://www.benzo.org.uk/bzequiv.htm

Medazepam is diazepam without the carbonyl oxygen; it is of equivalent potency according to the table above. It'd be more lipophilic so one could assume increased lipophilicity compensates for reduced binding interactions, but the 2 molecules as a whole are so lipophilic anyway I don't think it matters. Anyway if the carbonyl oxygen is not crucial to activity, what says other heteroatoms are?

If anyone knows of a SAR study considering these ideas, a link would be much appreciated.

Diazepam: 
	

	
	
		
		

		
		
	


	




Proposed derivatives:






One like the above but nitrogen in 4 position instead of 1, 1 position replaced by a carbon (Opsin not rendering it correctly).


----------



## Solipsis

The oxygen and nitrogen are involved in hydrogen bond accepting sites of the benzo binding site..
But no they are not the most important for receptor affinity... that would be the 7 and 2' position. 

As long as you keep the 4-5 double bond it should be fit for hydrogen bond accepting... but your omittance of the oxygen might not be so affordable because it doesn't allow a hydrogen bond. So get some electronegative shizzle going over there, not a methyl..

http://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.1999.tb00094.x/pdf


----------



## aced126

Solipsis said:


> The oxygen and nitrogen are involved in hydrogen bond accepting sites of the benzo binding site..
> But no they are not the most important for receptor affinity... that would be the 7 and 2' position.
> 
> As long as you keep the 4-5 double bond it should be fit for hydrogen bond accepting... but your omittance of the oxygen might not be so affordable because it doesn't allow a hydrogen bond. So get some electronegative shizzle going over there, not a methyl..
> 
> http://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.1999.tb00094.x/pdf



Cheers, I'll look into that.


----------



## Friman1987

> Why would you want make'em more polar? cLogP of 2.37 seems pretty excellent to me as far as BBB transport is concerned + shorter distribution T1/2 giving fast acting drug molecule because of less non-specific protein binding!


- Naphthalene is carcinogenic because of the formation of epoxide metabolism.
- Naphthylamine is also carcinogenic, gives bladder carcinogenesis.




http://pharmrev.aspetjournals.org/content/49/4/403.full

The amino-group is directly attached to an aromatic ring and that makes it impossible to metabolize away the amino group from the naphthylamine. That complicates the metabolism.
But that structure that you gave have not the same kind of issue as naphthalene amine. I wonder if it will act as an MAO inhibitor like many other alpha-substituted amphetamine? I guess that this molecule should be difficult to metabolize.
We do not know how toxic it is, making it more polar makes you care less about toxicity.
If you have para Chloroamphetamine which have neurotoxic property and then you add beta-keton to it, then you will get 4Cl-cathinone which do not have same toxicity or mechanism of action as p-Chloroamphetamine.


----------



## roi

UWA-001 and Ephenidine hybrid. Possible psychedelic, stimulant and dissociative in one molecule?


----------



## Friman1987




----------



## DotChem

aced126 said:


> Have benzodiazepine derivates with isosteres for the heteroatoms been synthesized?
> 
> https://en.wikipedia.org/wiki/Medazepam
> http://www.benzo.org.uk/bzequiv.htm
> 
> Medazepam is diazepam without the carbonyl oxygen; it is of equivalent potency according to the table above. It'd be more lipophilic so one could assume increased lipophilicity compensates for reduced binding interactions, but the 2 molecules as a whole are so lipophilic anyway I don't think it matters. Anyway if the carbonyl oxygen is not crucial to activity, what says other heteroatoms are?
> 
> If anyone knows of a SAR study considering these ideas, a link would be much appreciated.
> 
> Diazepam:
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> Proposed derivatives:
> 
> 
> 
> 
> 
> 
> One like the above but nitrogen in 4 position instead of 1, 1 position replaced by a carbon (Opsin not rendering it correctly).





I guess it should work in principles as long as the crucial 7-Cl is  there! conformation is similar to diazepam. For the first one but with  the carbonyl (similar molecule described here






just  add chlorine at 7 (and 2') but then it gets way too lipoliphilic which  may be a good thing for benzos since it might give them longer  duration(depot in fat tissues and released slowly). but how crucial the  C=N is besides making diazepam more polar than the C=C analog???






and diazepam








I like the last molecule


----------



## DotChem

I mean this one:







It is actually known molecule described here and in some old patents in the 80s


----------



## DotChem

> @Friman184
> Naphthalene is carcinogenic because of the formation of epoxide metabolism.
> Naphthylamine is also carcinogenic, gives bladder carcinogenesis.


That's  right. they tend to give electrophilic epoxides metabolites leading to  DNA damage among other is big issue which I was mentioned earlier. But  notice that not all naphthalenes are carcinogenic: the common  antiinflammatory Naproxen (AleveTM) is pretty safe drug!









> @Friman187  But that structure that you gave have not the same kind of issue as  naphthalene amine. I wonder if it will act as an MAO inhibitor like many  other alpha-substituted amphetamine? I guess that this molecule should  be difficult to metabolize.
> We do not know how toxic it is, making it more polar makes you care less about toxicity









True it is not really an aromatic amines which might give rise to toxic nitroso metabolites.. 
and  yes it might be pretty resistant to MAO metabolism (may or not be MAO  inhibitor!) hard to tell but my guess it would probably be close to  Bromo-dragonFLY in terms of ADMET but definetely different from simple  amphetamines. 
	

	
	
		
		

		
		
	


	





> wiki BromoDragonFLY It has a much longer duration of action than LSD and can last for up to 2–3 days[3] following a single large dose, with a slow onset of action that can take up to 6 hours before the effects are felt.


----------



## Friman1987

> That's right. they tend to give electrophilic epoxides metabolites leading to DNA damage among other is big issue which I was mentioned earlier. But notice that not all naphthalenes are carcinogenic: the common antiinflammatory Naproxen (AleveTM) is pretty safe drug!


I did not mean that all molecules containing Naphthalene is toxic. 


> True it is not really an aromatic amines which might give rise to toxic nitroso metabolites..
> and yes it might be pretty resistant to MAO metabolism (may or not be MAO inhibitor!) hard to tell but my guess it would probably be close to Bromo-dragonFLY in terms of ADMET but definetely different from simple amphetamines


I found the following patents: http://www.google.com/patents/WO1987004153A1?cl=en _(from the 80's)_
You can find some information about the N-methyl version of dihydro-2phenalene-amine there, They call it U-64,273A.







> *U-64,273A:*
> By the intravenous (i.v.) route of administration to anesthetized rats, U-64,273A is potent in reversing the effect of d-amphetamine on nigral DA neuronal firing. Standard antipsychotic agents such as haloperidol and clozapine also reversed amphetamine's depressions of DA neuronal firing, as has been reported by other laboratories (1). The ability of neuroleptics to actually increase firing rates above control values has been associates (1,2) with the tendency of that agent to induce extrapyramidal side effects (EPS). Thus, haloperidol, which induces severe EPS in patients, increased firing rates to a level 64% greater than controls whereas clozapine, which induces far less EPS, (3), completely reversed the amphetamine effect but did not increase rates above controls (*Table 2*) . Unlike haloperidol the amphetamine effect reversal by U-64,273A was not quite complete. This suggests that U-64,273A in addition to being a dopamine antagonist has a small amount (partial) of dopamine agonist activity. A partial agonist property is further suggested by the fact that U-64,273 is able to weakly inhibit the DA neuronal firing when given alone. This pattern of effect is similar to that other partial agonists, trans-dihydrolisuride (TDHL) , and (-)PPP(4,-5). However, the dopamine antagonist properties of TDHL and (-)PPP are much less prominant than with U-64,273A. Thus, U-64,273A is 70% antagonist and 30% agonist while the antagonist/agonist ratios for TDHL and (-)PPP are approximately 50:50 and 30:70 respectively (*Table 2*). In addition the antagonist potency of U-64,273A is considerably greater than that of clozapine. The dopamine antagonist properties of U-64,273A should be sufficient to antagonize overactive DA systems such as those though to underly schizophrenia. By avoiding a complete blockage, there may be a reduced severity of side-effects such as pseudo-parkinsonism and tardive dyskinesia in using this compound as an antipsychotic drug.
> 
> Consistant with its having a minor amount of agonist activity, the overall behavioral effects of U-64,273A conform to that of a weak DA antagonist (*Table 3*). It antagonized apomorphine in the following tests: mouse climbing screen, locomotor stimulation in reserpinized mice, emesis in dogs and discriminative effects in monkeys. U-64,273A also antagonized d-amphetamine in the turning behavior of striatal-lesioned rats. However, it did not protect mice from a lethal dose of d-amphetamine nor did it block the stereotypic behaviors produced by apomorphine. When given by itself, U-64,273A affected locomotor activities in rodents in a way resembling both DA auto-receptor and postsynaptic receptor agonists. It suppressed conditioned avoidance behavior of rats with a limited efficacy. It produced no locomotor stimulation in reserpinized mice.
> 
> The effects of U-64,273A on the metabolites of DA and 5-HT in rat brains suggest an antagonist action of DA and an agonist action of 5-HT (*Table 4*) . The elevation of HVA was only moderate in comparison to that produced by haloperidol. It did not increase the plasma level of prolactin as did haloperidol. Both the HVA and prolactin effects are consistent with the expected low EPS. U-64,273A is relatively weak in the in vitro receptor binding screen but did displace spiperone in vivo. (The numbers in parenthesis are to References listed below *Table 5* hereinbelow). The dimethylated derivative, U-65,556, is also of interest because it has antipsychotic activity with little or no propensity to produce EPS since it, 2,3-dihydro-N,N-dimethyl-1H-phenalen-2-amine, like U-64,273A, also reversed amphetamine's depressions of DA neurons without causing firing rates to increase over control.











http://www.freepatentsonline.com/EP0234113.pdf

This patent does not say match about the receptor binding assay properties.
According to this patent U-64,273A bind to the *5HT1A *receptor: (http://www.google.com.ar/patents/WO1989010741A1?cl=en) 


> 2,3-Dihydro-N-methyl-1H-phenalen-2-amine (U-64,273A), and 2,3-Dihydro- ,N-dimethyl-lH-phenalen-2-amine, tested as their hydrochloride salts, are both DA antagonists in addition to being 5HT1A agonists...



I know that 5HT1A acting as an auto receptor for dopamine, it releasing dopamine in the striatum. That should reduce the EPS. 

U-64,273A has some similarities with Xaliproden ( 5HT1A agonist), both are naphthalenyl-ethanamine.



> 2-Amino-2,3-dihydro-1H-phenalene(16) also appeared to bea weak binder to the 5-HT7 receptor.







http://www.rug.nl/research/portal/files/2904567/c5.pdf


----------



## aced126

Some more simplified/unrigidified bzp-receptor agonist structures based on this benzoazepine:


----------



## DotChem

> I found the following patents: http://www.google.com/patents/WO1987004153A1?cl=en _(from the 80's)_
> You can find some information about the N-methyl version of dihydro-phenalene-amine there, They call it U-64,273A.



Nice!  you dug up some data on that compound. Yes I thought so: somebody might  have tried it.  So the N-methyl derivative is a DA antagonist (it won't  be surprising since lots ot aminotetralines are!).  It has pretty  decent HT2A activity tho. Actually it is quite potent 5HT2a ligand (1uM displaces 67% LSD from rat brains  - table 5). Not bad not bad at all  as LSD Ki at 5HT2a = 2.9nM. My guess it will be as potent as DMT  as 5HT2a ligand (DMT Ki range 0.118-0.989uM at 2a). Now big question  is: will it be an agonist or an antagonist?  LSD displacement won't  show that. Only that it compete with LSD for binding at 2a. 
 wish the  authors watched their mouse headtwitch for HT2a agonism.  But they were  looking for antipsychotics after all, so they might have missed it 8)
@Friman1978 But really nice data.. 

now that LSD indole NH H-bond donor?





cLogP1.58
PSA46.25
water solubility: very high

But  again CAUTION the opposite stereoisomer might well be a potent mu opiod  so racemic mixture might well give a psychedelic opiate!
compare to morphine!


----------



## DotChem

dissociative opioid stims:







metabolize to (aza)ketamine?  like this:








may or not be NMDA antagonist but very likely SNDRI and/or releaser!


----------



## Friman1987

*Modification: *


----------



## roi

TCE - would love to try that one


----------



## Friman1987

> cLogP1.58
> PSA46.25
> water solubility: very high
> 
> But again CAUTION the opposite stereoisomer might well be a potent mu opiod so racemic mixture might well give a psychedelic opiate!
> compare to morphine!



That might work, hard to say. Interesting theory

Some of these might also work, I don't know which one.


----------



## DotChem

Friman1987 said:


> That might work, hard to say. Interesting theory


see how it superimposes nicely on morphinans (*the S stereochemistry*!!) but not the R which may bind HT2a in LSD fashion. I would expect opioid activity at least as potent as codeine (80%morphine) may be more! who knows?





certainly more if you play around like this:


----------



## DotChem

Friman1987 said:


> Some of these might also work, I don't know which one.



they all have pretty nice logP. but for some reason I like the first one: the benzoquinoline. Look very drug-like but maybe incredibly long-acting like this 







with half-life of up to 2 weeks! ugh! that would be one heck of a trip!!  
(CF3 instead of CH3)


----------



## Friman1987

> with half-life of up to 2 weeks! ugh! that would be one heck of a trip!!
> (CF3 instead of CH3)


haha, Does not sound good at all.


----------



## roi

2C-B-AI - don't see any reason why it wouldn't work.


----------



## aced126

roi said:


> 2C-B-AI - don't see any reason why it wouldn't work.



It would indeed very likely work, with very high potency.

You'd be better off calling it DOB-AI to reflect its high potency.


----------



## Friman1987

The inspiration comes from DotChems molecule (N-phenethylamine sub of U-64,273A)

*N-Phenethylnormorphine:* https://en.wikipedia.org/wiki/N-Phenethylnormorphine
*Tapentadol:* https://en.wikipedia.org/wiki/Tapentadol




I calling the last one N-Phenethylnortramadol. 

*Tramadol:* https://en.wikipedia.org/wiki/Tramadol


----------



## DotChem

Friman1987 said:


> *N-Phenethylnormorphine:* https://en.wikipedia.org/wiki/N-Phenethylnormorphine
> *Tapentadol:* https://en.wikipedia.org/wiki/Tapentadol
> 
> 
> 
> 
> I calling the last one N-Phenethylnortramadol.
> 
> *Tramadol:* https://en.wikipedia.org/wiki/Tramadol



@Friman1987 : the N-phenethyl substitution doesn't work for Tramadol as it does with morphine(20x) and piperidines like meperidine(20-100x). No difference in activity even with 3-desmethylTramadol! SAR doesn't make lots of sense! 



DotChem said:


> somebody suggested phenethyl tramadol or its  metabolite sometimes ago?? I guess on this forum, can't remember!
> 
> 
> 
> 
> 
> 
> it is less active than simple desmethyl-tramadol. the whole series
> 
> 
> 
> 
> 
> 
> 
> here is a link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648120/


----------



## DotChem

Foxy methoxy 





ie 







Now make bond a and b






HORNY METHOXY


----------



## Friman1987

> the N-phenethyl substitution doesn't work for Tramadol as it does with morphine(20x) and piperidines like meperidine(20-100x). No difference in activity even with 3-desmethylTramadol! SAR doesn't make lots of sense!



Yes you are right. thanks for the information. 




Maybe it has something with the hydroxyl group on the cyclohexane to do? that is one thing that makes Tramadol different relative to morphine. 

What do you think about these molecules?


----------



## aced126

DotChem said:


> Foxy methoxy
> 
> 
> 
> 
> 
> ie
> 
> 
> 
> 
> 
> 
> 
> Now make bond a and b
> 
> 
> 
> 
> 
> 
> HORNY METHOXY



Nice one, rigidified structures like these are gonna help us understand the binding pocket of 5HT2a more


----------



## aced126

https://en.wikipedia.org/wiki/Oxolinic_acid
https://en.wikipedia.org/wiki/Amfonelic_acid

Have 2Cx analogues been synthesised with bioisosteres for the methoxy group?


----------



## sekio

I think phenoxy amphetamine is known and not very active - too bulky at the 4' pos...


----------



## Friman1987

*Ciprefadol:* https://en.wikipedia.org/wiki/Ciprefadol




The stereochemistry is not corect. I have drawn them like that just to indicate that the substance originates from morphine. 
*Fluorophen:* https://en.wikipedia.org/wiki/Fluorophen
*8-Carboxamidocyclazocine:* https://en.wikipedia.org/wiki/8-Carboxamidocyclazocine
*Tapentadol:* https://en.wikipedia.org/wiki/Tapentadol
*Etazocine (NIH-7856):* https://en.wikipedia.org/wiki/Etazocine
*Axomadol:* https://en.wikipedia.org/wiki/Axomadol
*Tramadol:* https://en.wikipedia.org/wiki/Tramadol




*Picenadol:* https://en.wikipedia.org/wiki/Picenadol
*Ketobemidone*https://en.wikipedia.org/wiki/Ketobemidone
*PEPAP*https://en.wikipedia.org/wiki/PEPAP




*Methadone: *https://en.wikipedia.org/wiki/Methadone

*NSFW*: 










You can do 1000 other structures with those, someone else might come up with something better. 
Opioids are not my thing, I've tried tramadol 2-3 times (3-4 years ago) and it was good. But I prefer psychedelic, my favorite is 4 ho MET.


----------



## sekio

but what about analogs of morpheus, 5-meo-morpheus, 4-ho-morpheus, etc


----------



## DotChem

Friman1987 said:


> What do you think about these molecules?



Should work in principles as agonist or at least partial agonists. Similar molecule 






 Ki at mu = 0.021 uM(agonist) (compare to morphine Ki = 0.0026uM). So I guess adding phenethyl should get at least 10X (note this molecule is kind of not good example!) yours should be more close relative of morphine. Anyway yeah we got carried away threading opioids from the psychedelic LSD naphthalenes (benzo indole) congeners discussed earlier

Now, the pyrrolidino tetrahydro naphthalene you suggested, look like a cyclized version of prolintane (might well be stim+opioid ie speed ball !)


----------



## Dresden

I don't know about all those designer tetralin opioids, but I know that






2-AMINOTETRALIN

is bad news (like hospital news) at or above 100mg, which admittedly doesn't say anything much about yours necessarily.


----------



## Midnight Sun

using this image of DOI docked in 5HT2a (from http://www.bluelight.org/vb/threads/591265-modeling-the-5-HT-2a-receptor






there's a perfectly good spot to improve binding @ serine 159 but as you can see the nitrogen is already in its optimal position courtesy the alpha carbon - precluding any vanilla phenmetrazine derivatives for a multitude of reasons

with that in mind, anyone think this would work?


----------



## roi

Switch oxygen and amine, remove the N-methyl group and it'll work 

There's a paper on 2C-B-Norphenmetrazine somewhere out there. Kinda annoying synthesis, like 5 steps from bk-2C-B iirc...


----------



## Midnight Sun

roi said:


> There's a paper on *2C-B-Norphenmetrazine* somewhere out there. Kinda annoying synthesis, like 5 steps from bk-2C-B iirc...



I was trying to avoid this; one of the aforementioned reasons I cited phenmetrazine psychedelics as being a no-go is because constraining the nitrogen neuters its binding ability.  I would believe it still can, but it won't do it very well.  Then there's the matter of how it sits in 3D space...

I oriented the oxygen intentionally to get it as physically close to the residue as possible while still (hopefully) permitting the nitrogen to bind unhindered and still in the same "optimized" position that alpha-methylation provides.  Unconventional indeed

Another pose:




(I think I drew that right but I'm also quite hungover)


----------



## roi

GBL-style 1,4-BD prodrug. Sadly causes cancer.


----------



## Nagelfar

I'd like to see someone try going though a few permutations to find a potential cannibinoid-antagonist opioid-*_agonist_* (unlike the several cannibinoid + opioid-antagonist/inverse-agonist that seem to come hand in hand)


----------



## DotChem




----------



## DotChem

Man who has his brain fried(barin dead) and 5 other sent to hospital with irreversibe brain injury after clinical trial of endocannabinoid reuptake inhibitor (anandamide degrading enzyme inhibitor). 
http://www.nytimes.com/aponline/2016/01/17/world/europe/ap-eu-france-drug-trial.html?_r=0






https://en.wikipedia.org/wiki/BIA_10-2474


Pretty nice molecule. But wouldn't it be irreversible? ie covalently binding to whatever receptors happen to be nearby. The imidazole is pretty good leaving group.


----------



## aced126

It's not really a good leaving group, is it? pKa is 14.5, so it's only really a slightly better leaving group than alcohols (which aren't great leaving groups). You've also got the amide nitrogen lone pair (as well as being delocalised into the imidazole ring) contributing to N-C pi bond character, which makes that carbon less electrophilic to nucleophiles. So I wouldn't really say it's irreversible, but correct me if I'm wrong.


----------



## DotChem

Actually simple imidazole pKa = 6.99 at 25 °C (CRC Handbook of Chemistry & Physics) so it is way better leaving group than RO-. Not as good as Halo or even acetate (pka 3-5) but under the right conditions (eg with relatively strong nucleophiles) carbonyl imidazoles will react. Thats' why for example carbonyl-diimidazole (Im2C=O) is used as safer replacement of phosphege (Cl2C=O) to acylate amines or activated carboxylic acids. But yeah you're right the presence of the other nitrogen will certainly make this molecule even less reactive. But my take is that primary amines in protein (eg lysines - relatively strong nucleophile) may react and give irreversibly acylated protein. Under the right conditions! But who knows? hard to explain why this guy has his brain fried by this molecule!


----------



## neurotic

Dresden said:


> is bad news (like hospital news) at or above 100mg, which admittedly doesn't say anything much about yours necessarily.



you sure? why so? i was kinda interested in aminotetralin and its possible derivatives a while ago but wasn't able to find almost any info on it and the N-methyl homologue at all.


----------



## aced126

DotChem said:


> Actually simple imidazole pKa = 6.99 at 25 °C (CRC Handbook of Chemistry & Physics) so it is way better leaving group than RO-. Not as good as Halo or even acetate (pka 3-5) but under the right conditions (eg with relatively strong nucleophiles) carbonyl imidazoles will react. Thats' why for example carbonyl-diimidazole (Im2C=O) is used as safer replacement of phosphege (Cl2C=O) to acylate amines or activated carboxylic acids. But yeah you're right the presence of the other nitrogen will certainly make this molecule even less reactive. But my take is that primary amines in protein (eg lysines - relatively strong nucleophile) may react and give irreversibly acylated protein. Under the right conditions! But who knows? hard to explain why this guy has his brain fried by this molecule!



The pKa you describe is the one for imidazole which is already protonated, that is to say: imidazole(H+) <---> imidazole + H+; pKa=6.99
However, imidazole <-----> imidazole- + H+; pKa = 14.5. The only reason why the pKa of this acid-base reaction is way less than it should be (see ammonia pKa = 32.5) is because when deprotonated, the lone pair can delocalise into the imidazole ring and Huckel's rule is satisfied (the system gains extra stability from aromaticity).

Also lysines aren't really good nuclephiles because they're pretty much always charged, so the nitrogen lone pair is mostly unavailable. In hydrolytic enzymes, lysine is almost always never used as the nucleophile in the active site. It is normally serine or cysteine (which is first deprotonated by a base like histidine so nucleophilicity of the serine or cysteine residue is increased).


----------



## roi

5F-THC






And something more random


----------



## SKL




----------



## DotChem

aced126 said:


> The pKa you describe is the one for imidazole  which is already protonated, that is to say: imidazole(H+) <--->  imidazole + H+; pKa=6.99
> However, imidazole <-----> imidazole- + H+; pKa = 14.5. The only  reason why the pKa of this acid-base reaction is way less than it should  be (see ammonia pKa = 32.5) is because when deprotonated, the lone pair  can delocalise into the imidazole ring and Huckel's rule is satisfied  (the system gains extra stability from aromaticity).


You are absolutely right on the pKa values because imidazoles are  amphoteric (base and acid) so naturally you'll have 2 pKas.  But the pKa  that matter for the reaction I was mentionning is that of the the acid:  ImH+ <------> ImH . The reason being at physiological pH (7.4)  major form is ImH+ (not that much but at least 20%more than the neutral  form). Like this in the case of acyl-imidazoles like in the cannabinoid  molecule :








So  the pKa to use to measure the leaving group abilitity of imidazole in  that case should be the acid one (6.99).  as the leaving group is ImH  (not Im(-).. Does that make sense? 
You can see from example above(oversimplified of course! not taking account substitution or other factors). 



aced126 said:


> Also lysines aren't really good nuclephiles because they're pretty much  always charged, so the nitrogen lone pair is mostly unavailable. In  hydrolytic enzymes, lysine is almost always never used as the  nucleophile in the active site. It is normally serine or cysteine (which  is first deprotonated by a base like histidine so nucleophilicity of  the serine or cysteine residue is increased).


True Lysines are poor nucleophiles at physiological pH(7.4)  but not always.  Some lysines in proteins are actually quite good  nucleophile by happening to be either in a basic microenvironment where  pH is relatively basic (eg in some cell organelles eg lysosomes pH can  be as high as 10!!!). Or made "basic" for example by nearby groups eg  the Imidiazole =N of histidines. it all depends on the protein structure  microenvironment in which the lysine located. BUT you are absolutely  right at physiological pH (7.4) most lysines will be protonated  therefore not nucleophilic.
As for the cannabinoid molecule, that got  this guy brain dead, who knows? would be interesting to know how the  molecule act endocannabinoid reputake inhibitors en general


(may the man who's got his brain fried RIP.. he passed away.. 5 remained in hospital brain dead.


----------



## roi

It looks so sexy.


----------



## aced126

Oh yes my bad, the imidazole wouldn't be a bad leaving group I guess, at physiological pH. Still not as good as acetate or chlorine or anything.


----------



## aced126

The aminoindanes have been shown to cause less neurotoxicity. One explanation is the prevention of the alpha-methyl carbon easily forming radicals.


----------



## aced126

Aminoindanes were alright, apparently tetralins decreased seizure threshold, what about aminobenzocycloheptanes?


----------



## aced126

Some more... should have solid dopamine reuptake activity.


----------



## DotChem

[h=1]








> Aminotetralone analogues of ketamine: synthesis and evaluation of hypnotic and locomotor properties in mice. http://www.ncbi.nlm.nih.gov/pubmed?linkname=pccompound_pubmed&from_uid=126081


[/h]thefirst one should be pretty close to "cyclized" mephedrone. or pyrovalerone w/alfa methyl susbtitution?


----------



## aced126

DotChem said:


> *
> 
> 
> 
> 
> 
> 
> *
> 
> thefirst one should be pretty close to "cyclized" mephedrone. or pyrovalerone w/alfa methyl susbtitution?



First one looks quite like a cyclised hybrid of phentermine (an appetite suppressant, much less potent by mass than amphetamine itself) and mephedrone, yeah. It does indeed increase locomotor activity, as mentioned in the abstract. In the second one the amine is too far away to interact with its residue, so stimulant properties would not be observed.


----------



## DotChem




----------



## DotChem

aced126 said:


> First one looks quite like a cyclised hybrid of phentermine (an appetite suppressant, much less potent by mass than amphetamine itself) and mephedrone, yeah. It does indeed increase locomotor activity, as mentioned in the abstract. In the second one the amine is too far away to interact with its residue, so stimulant properties would not be observed.


Close to the aminoindanones you mentioned but with a pyrolidine. how do they compare prolintane?


----------



## sekio

roi said:


> GBL-style 1,4-BD prodrug. Sadly causes cancer.



this is an awful prodrug for GBL/BDO - in fact the commercial synthesis starts from BDO (catalytic dehydration over metal cat.) also the price is close to 100x more

THF is in fact used as a solvent, I work with it sometimes, it's a bastard ether (miscible with water)


----------



## aced126

DotChem said:


> Close to the aminoindanones you mentioned but with a pyrolidine. how do they compare prolintane?



What do you mean?


----------



## DotChem

aced126 said:


> What do you mean?



Sorry ! I meant these aminoindanes:







compared to prolintane (in terms of stim activity). since they're closer to prolintane than simpler amphetamine . 







or the corresponding indanone:







 compared to MDPV


----------



## roi




----------



## Nagelfar

Everything about the pharmacokinetics of this one except for the logP seem hunky-dorie


----------



## roi

*danger intensifies*


----------



## sekio

2cb-hydrazide might be a cool MAOI?


----------



## Nagelfar

tri-cyclic spirocentric cocaine analog


----------



## aced126

Nagelfar said:


> tri-cyclic spirocentric cocaine analog



Aromaticity lost; beware of lost binding interactions. Look at the drop in potency of methamphetamine to propylhexedrine.
Also that connection from the N back to the ring is likely to be highly strained and would pull the nitrogen back out of its optimal place possibly.


----------



## DotChem

Dissociatives Stims:  diphenidine 





P2P:
 logP = 3.5
 LogD (pH7.4) = 0.25 
PSA = 16.03
Water solubility: high
Synthesis: ++


----------



## roi

2C-E-AN






Although I'd much rather want to see


----------



## SKL

*2CD-FX*, a 2CD prodrug






Furfenorex, an MA prodrug.





> The major metabolic routes of furofenex in vitro were *N-demethylation and N-defurfurylation* which produced 1-phenyl-2-(N-furfuryl-amino)propane (*furfurylamphetamine*) and *methamphetamine*, respectively.


Inoue et al.

This should lead to 2CD and N-furfutyl-amino-2CD (which should yield again 2CD??? if not active itself and also apparently _p_-HO-2CDFX which I dunno about)


----------



## Nagelfar

aced126 said:


> Aromaticity lost; beware of lost binding interactions. Look at the drop in potency of methamphetamine to propylhexedrine.
> Also that connection from the N back to the ring is likely to be highly strained and would pull the nitrogen back out of its optimal place possibly.



I dunno, the tricyclics with the bridge from the N8-pos. to the phenyl3-pos. have *higher* affinity (@ least for SERT, some across the board)


----------



## aced126

Source?


----------



## roi




----------



## Nagelfar

aced126 said:


> Source?



Fused tropane-derivatives as neurotransmitter reuptake inhibitors US PATENT 5998405 A






^the last one has picomolar affinity for SERT, the others have 1.6 & 2.3, respectively (cf. cocaine's 155)






^many of these have picomolar affinity at DAT, NET *and* SERT


----------



## DotChem

> [h=2]Abstract[/h]_N_,_N_-Diallyltryptamine (DALT) and 5-methoxy-_N_,_N_-diallyltryptamine  (5-MeO-DALT) are two tryptamines synthesized and tested by Alexander  Shulgin. In self-experiments, 5-MeO-DALT was reported to be psychoactive  in the 12–20 mg range, while the unsubstituted compound DALT had few  discernible effects in the 42–80 mg range. Recently, 5-MeO-DALT has been  used in nonmedical settings for its psychoactive effects, but these  effects have been poorly characterized and little is known of its  pharmacological properties. We extended the work of Shulgin by  synthesizing additional 5-substituted-DALTs. We then compared them to  DALT and 5-MeO-DALT for their binding affinities at 45 cloned receptors  and transporter proteins. Based on in vitro binding affinity, we  identified 27 potential receptor targets for the 5-substituted-DALT  compounds. Five of the DALT compounds had affinity in the 10–80 nM range  for serotonin 5-HT1A and 5-HT2B receptors, while the affinity of DALT itself at 5-HT1A receptors was slightly lower at 100 nM. Among the 5-HT2 subtypes, the weakest affinity was at 5-HT2A receptors, spanning 250–730 nM. Five of the DALT compounds had affinity in the 50–400 nM range for serotonin 5-HT1D, 5-HT6, and 5-HT7  receptors; again, it was the unsubstituted DALT that had the weakest  affinity at all three subtypes. The test drugs had even weaker affinity  for 5-HT1B, 5-HT1E, and 5-HT5A subtypes and little or no affinity for the 5-HT3 subtype. These compounds also had generally nanomolar affinities for adrenergic α2A, α2B, and α2C receptors, sigma receptors σ1 and σ2, histamine H1  receptors, and norepinephrine and serotonin uptake transporters. They  also bound to other targets in the nanomolar-to-low micromolar range.  Based on these binding results, it is likely that multiple serotonin  receptors, as well as several nonserotonergic sites are important for  the psychoactive effects of DALT drugs. To learn whether any  quantitative structure–affinity relationships existed, we evaluated  correlations among physicochemical properties of the congeneric  5-substituted-DALT compounds. The descriptors included electronic (_σp_), hydrophobic (_π_), and steric (CMR) parameters. The binding affinity at 5-HT1A, 5-HT1D, 5-HT7, and κ opioid receptors was positively correlated with the steric volume parameter CMR. At α2A, α2B, and α2C receptors, and at the histamine H1 receptor, binding affinity was correlated with the Hammett substituent parameter _σp_; higher affinity was associated with larger _σp_ values. At the σ2 receptor, higher affinity was correlated with increasing _π_. These correlations should aid in the development of more potent and selective drugs within this family of compounds.



"Receptor binding profiles and quantitative structure–affinity relationships of some 5-substituted-N,N-diallyltryptamines"

Nicholas V. Cozzia, b, Paul F. Dale 
Bioorganic & Medicinal Chemistry Letters 
Volume 26, Issue 3, 1 February 2016, Pages 959–964

http://www.sciencedirect.com/science/article/pii/S0960894X1530367X ($paying$ article) enjoy the read!


----------



## Nagelfar

≡






I love my cubism:

protonate it, and be able to front and back bridge the tropane from the same nitrogen starting point (don't have to split off from one methylene unit away and possibly skew the optimum factors constraining the nitrogen)

i.e. (Scheel-Krüger et al. U.S. Patent 5,998,405 compound #1 + S. Singh's cocaine antagonist paper's compound # 131a)






≡


----------



## roi

pyroritalin


----------



## aced126




----------



## aced126




----------



## aced126




----------



## Nagelfar

Diphenyl-2-pyridylmethane as inspiration but along the lines of the phenylmorpholines


----------



## aced126

Neat find


----------



## Raihiar

*thanx a million*



DotChem said:


> "Receptor binding profiles and quantitative structure–affinity relationships of some 5-substituted-N,N-diallyltryptamines"
> 
> Nicholas V. Cozzia, b, Paul F. Dale
> Bioorganic & Medicinal Chemistry Letters
> Volume 26, Issue 3, 1 February 2016, Pages 959–964
> 
> http://www.sciencedirect.com/science/article/pii/S0960894X1530367X ($paying$ article) enjoy the read!



oh yaaaaay!

I LOVE you for this since i've been a huge fan of 5-meo-dalt (when it was still quasi-legal and relatively easly acquired here  )
binged on it - the only chemical i've ever vaped and generally had an amazing time with it, and all that in spite of the fact that many 'normal' psychedelics seem to overwhelm me and turn bad eventually.
maybe some promising ones hit the market, and i might try my luck once again 

And since i dont have anything picture-wise to show: behold the 1-minute-paint cyclomethane


----------



## DotChem




----------



## Nagelfar

DotChem said:


>








phenmetrazine inspired.

(You know its unnatural, when the structure is small, and it's name gets rendered like: _*6-phenyl-1λ⁶,2λ⁶-dithia-4-azacyclohexa-1(6),2,4-trien-1-yne*_ ;-j )






(_*3-phenylpyridine*_, there we go... Normalcy.)

And because what's a contribution of mine if there isn't a cocaine derivative in it?:


----------



## Dresden

All the low hanging fruit has now been harvested.  With the hundreds and hundreds of new drugs which flooded the RC market at some point in the last couple of years, the only two RCs notable enough to become street drugs were






MEPHEDRONE

and






MXE.






aPVP would have made the cut, except other stimulants work just as well as it and therefore it represented no real improvement over what was already available.

*WILL ALL THE CHEMISTS GO BACK TO FLOODING THE MARKET WITH MDMA LIKE IT IS FLOODED WITH METH RIGHT NOW; LET'S KEEP THE METH TOO! NOBODY WANTS RCS ANYMORE*






MDMA

On the subject of meth (my favorite), I just want to thank God that that the subversive Mexican cartels are giving America a middle finger by flooding our street markets with good meth.  WAKE UP PEOPLE. (literally)






METHAMPHETAMINE

And Nagelfar, I'm not trying to be rude, but that thing you drew right there is absurd to the point of fatuity from a chemical or pharmacological viewpoint and looks like an impossible train wreck.


----------



## aced126

Consider methylphenidate: 
	

	
	
		
		

		
		
	


	




Here are a few rigidified molecules which would help to uncover the binding roles of the alkyl esters in the methylphenidate series:


First, we consider this rigidified molecule:






Then:





Acetal hydrolysis is obviously a concern with the second molecule (the first one also has N-C-O which could act like an acetal), however this shouldn't be a problem if evaluated in vitro. The more potent molecule should suggest to which angle the alkyl group in methylphenidate is oriented.

The following molecule is simply rigidified methylphenidate but the pyridine ring is flipped (I doubt this compound would act effectively because I don't think the nitrogen is in the right place, but just to confirm anyway):







Now, look at some compounds with the ester switched for an amide. The non-basic nitrogen can't really function as a H-bond acceptor like the oxygen (amide double bond character). The carbonyl oxygen is now a better H-bond acceptor though, so we can see where the H-bond acceptor regions are:






Flipped amide:








Once the optimal position for the carbonyl oxygen and alkyl ester has been determined, the ester can be changed to a ketone derivative, and the alkyl chain can be expanded:






These molecules corresponds to ethylphenidate, depending on where the alkyl chain seems to fit best (which would be determined from the above molecules)










I understand the first of these molecules would result in the basic nitrogen possibly being quite hindered from binding to its residue.

The next one corresponds to isopropylphenidate, and they also block the labile carbon from metabolism:





Finally one to push the possible limits of this pocket:


----------



## aced126

This might've already popped up in this thread, but have 3-alkylaminobenzothiophene derivatives (indole bioisostere) been suggested? The sulphur could be a good metabolic handle to decrease half life.


----------



## Nagelfar

Dresden said:


> All the low hanging fruit has now been harvested.  With the hundreds and hundreds of new drugs which flooded the RC market at some point in the last couple of years, the only two RCs notable enough to become street drugs were



The MPH analogs too, don't forget. I did ethylphenidate, it was viable.



Dresden said:


> And Nagelfar, I'm not trying to be rude, but that thing you drew right there is absurd to the point of fatuity from a chemical or pharmacological viewpoint and looks like an impossible train wreck.



Compliment accepted.


----------



## DotChem

Nagelfar said:


> phenmetrazine inspired.
> 
> (You know its unnatural, when the structure is small, and it's name gets rendered like: _*6-phenyl-1λ⁶,2λ⁶-dithia-4-azacyclohexa-1(6),2,4-trien-1-yne*_ ;-j )
> 
> 
> 
> 
> 
> 
> (_*3-phenylpyridine*_, there we go... Normalcy.)
> 
> And because what's a contribution of mine if there isn't a cocaine derivative in it?:



what do you call that last tropane?.. does it smell??? not sure about those
But I like pyridines


----------



## DotChem

I like pyridines..now:






about twice as potent as cocaine as DAT reuptake inhibitor.. pure and clean DRI no SERT or NET.. now add a Nitrogen like this






20x Cocaine (my bet!) nice and clean DRI nice logP .. one more N like this:






200x cocaine? (my bet) but logP start becoming shitty (1.8 still decent..)  

Or change 1 phenyl with an indole like this: 






nice clogP= 3.3 too bulky for DAT but SERT might like it.. now append a dimethylaminoethyl like this ..et voila








1DP-DMT ("Fat Mao"


----------



## DotChem

aced126 said:


> This might've already popped up in this thread,  but have 3-alkylaminobenzothiophene derivatives (indole bioisostere)  been suggested? The sulphur could be a good metabolic handle to decrease  half life.



isn't thiophene isostere closer to naphthalene than indole?  2-naphthyl isopropyl amine is empathogen with binding profile very much similar to MDMAs (but 10x more potent).


----------



## Nagelfar

DotChem said:


> what do you call that last tropane?..



methyl (5S,6S,9S)-9-methyl-2-[(1R,2R,5S)-8-methyl-1'-(1λ⁶-thiopyran-1-ylidyne)-8-azaspiro[bicyclo[3.2.1]octane-3,3'-[1λ⁶,4]thiazole]-2-yl]-1,4-dioxaspiro[4.5]dec-2-ene-6-carboxylate



DotChem said:


> does it smell???



It isn't complex enough of a structure to constitute an olfactory organ. So it doesn't have the ability to smell you, worry not, your remaining stash won't shy away from you when you've been in your attic sweating for three days in a row awake on it.


----------



## aced126

Dotchem, if 2-napthylisopropylamine binds similarly to MDMA, that suggests the napthyl moiety is bioisosteric with the 1,3-benzodioxol-5-yl moiety. We know that the latter moiety is bioisosteric to benzofuran, which is bioisosteric to indole.


----------



## roi

The N-methyl analogue of that (Methamnetamine) is being sold on the grey market and rather similar to MDAI - too sedating on its own, needs to be combined with a stimulant.

EC50 values:

Naphthylaminopropane: 3.4 nM SERT,  11.1 nM NET, 12.6 nM DAT

Methamnetamine: 13 nM SERT, 34 nM NET, 10 nM DAT

Surprisingly the SERT:NET ratio stays about the same and only DAT is weaker.

Also at least the N-methyl is about as potent as MDMA.


----------



## atara

aced126 said:


> Dotchem, if 2-napthylisopropylamine binds similarly to MDMA, that suggests the napthyl moiety is bioisosteric with the 1,3-benzodioxol-5-yl moiety. We know that the latter moiety is bioisosteric to benzofuran, which is bioisosteric to indole.



Bioisosteres aren't transitive. If you have an 80% match with an 80% match with an 80% match, you end up at just 51%.

But IIRC benzofuranyl is closer to naphthyl than either is to benzodioxolyl. There's not a whole lot in the way of bioisosteres for simple aromatic ethers except the toxic-looking 2,1,3-benzothiadiazole.


----------



## DotChem

aced126 said:


> Dotchem, if 2-napthylisopropylamine binds  similarly to MDMA, that suggests the napthyl moiety is bioisosteric with  the 1,3-benzodioxol-5-yl moiety. We know that the latter moiety is  bioisosteric to benzofuran, which is bioisosteric to indole.


aced126: that's right: the naphthyl in that case is a good bioisosteric  replacement of the benzodioxolyl at least as far as binding to DAT SERT  NET in ratios similar to MDMA is concerned. 

but it is a bit more complicated since we're dealing with multiple targets here. 

Ex: naphyrone 






IC50 SERT 46.0nM 
       DAT  40.0nM and 
       NET 11.7nM 


But MDPV"







 IC50 SERT 3370nM
       DAT  105.4nM
       NET  95.0nM

In  this case, benzodioxolyl -> naphthyl replacement doesn't work as  intended. One is stim (MDPV) the other empathogen. So I think the concept doesnt work everytime especially with drugs targeting multiple receptors/transporters at the same time..etc .


----------



## DotChem

atara said:


> Bioisosteres aren't transitive. If you have an 80% match with an 80% match with an 80% match, you end up at just 51%.
> 
> But IIRC benzofuranyl is closer to naphthyl than either is to benzodioxolyl. There's not a whole lot in the way of bioisosteres for simple aromatic ethers except the toxic-looking 2,1,3-benzothiadiazole.



how about? 















the benzoxazole has pretty much similar steric, hydrophobic and electronic properties to the benzodioxole. The thiazole is a little more hydrophobic but i don't see why it shouldn't work.  Have those being tried? 

MDMA logP = 1.86 PSA = 30.49
BzXMA logP = 1.59 PSA = 38.06
ThZMA LogP = 2.38 PSA = 24.92


----------



## aced126

Thiazole derivative should in theory be the most effective


----------



## roi

Stimulating dissociative psychedelic

#believe


----------



## pharmakos

lol :D

did the guys that did the research on NBOMes ever play around with substituting piperidine derivatives on the nitrogen?  if so, i think we can make that molecule even more ridiculous.


----------



## Midnight Sun

pharmakos said:


> lol :D
> 
> did the guys that did the research on NBOMes ever play around with substituting piperidine derivatives on the nitrogen?  if so, i think we can make that molecule even more ridiculous.



I think something like this would be better https://en.wikipedia.org/wiki/25I-NBMD

cuz it adds another methylenedioxy


----------



## pharmakos




----------



## Incunabula

norketobemidone is responsible for the  NMDA-antagonist properties of ketobemidone. I wonder how strong, and recreational, it is as a NMDA-antagonist? And I wonder if it is an interesting avenue to explore for new RC dissociatives?


----------



## Dresden

LEVORPHANOL, a potent morphinan opiate.






LEVORPHANDIOXOLE






ISOLEVORPHANDIOXOLE






TRIMETHOXYLEVORPHANOL






LEVORPHANUTMEG






ISOLEVORPHANUTMEG






APIOLEVORPHANOL






CHLOROLEVORPHANOL

This is a pretty clever series, one that combines some of the essential spices with a simple, easy to synthesize morphinan based opiate to hopefully yield some new psychedelic or entactogenic opioids.

In unrelated news:






and






These last two simply scream, "MAKE ME!"


----------



## DotChem

3C-PEP






1-(3-Chlorophenyl)-4-(2-phenylethyl)piperazine
Pure  DRI with no significant SERT NET or Opioid activity..about 10,000 times  more potent than cocaine as Dopamine Reuptake Inhibitor (IC50 = 0.04nM v  IC50 = 461nM at DAT)
But logP = 4.55 PSA = 6.49 too lipoliphilic (fat depot).. slow onset of action ..now + a methylenedioxy and pyridine bioisostere replace phenyl ( I love pyridines!





IED
at least as potent as 3C-PEP (ie 5-10,000x cocaine) I bet!...but with
LogP = 2.35 
PSA = 37.83 

compare to cocaine 
LogP = 2.28 PSA = 55.84


now fast and furoius acting ..  IED (Improvised ExplOsive Drug)


----------



## Nagelfar

STOP THE PRESSES!!!

I had an epiphany leaving the library.

The hydrogen bond acceptor @ MAT is what gives the C2 substituent greater affinity, but the steric bulk of a big substituent at that two position can cause the tropane ring to flatten and distort, ruining the binding efficacy of the rest of the molecule. The acceptor only increases if its in the beta/rectus configuration. But since benzoyltropane has more affinity than benzoylecgonine (just not benzoyl_methyl_ecgonine; and remember it is de-methylated _in vivo_)

Why not this?:






So simple, yet never done. Is it unstable or something? Just make the basic hydrogen non-planar (in a beta-configuration). I may be on to something here...


----------



## roi

Can you draw anything else than phenyltropanes btw? I mean...what's the point?


----------



## sekio

Nag, you just drew tropacocaine? I think it's known but a shitty stimulant...


----------



## pharmakos

looks like the sort of thing that would need a stereoselective synthesis to be effective.  there are quite a few possible isomers there.


----------



## aced126

Which hydrogen is the basic hydrogen?


----------



## Dresden

I like to trip hard.


----------



## Nagelfar

sekio said:


> Nag, you just drew tropacocaine? I think it's known but a shitty stimulant...



Tropacocaine is planar (or am I mistaken?), can't the hydrogen be oriented one direction or another? I've seen quite a few compounds that get specific. (P.S. I know a hydrogen ≠ a "hydrogen acceptor", I was thinking simplicity, as the vinyl-Cl analog proved it wasn't necessary)



roi said:


> Can you draw anything else than phenyltropanes btw? I mean...what's the point?



I don't draw many PTs. Mostly cocaine analogs.

And it's because there's enough phenyltropanes, but not enough cocaine analogs _proper_.


----------



## aced126

The only planar parts of tropacocaine are the phenyl and the C=O double bond. The rest of the molecule is not planar.


----------



## Nagelfar

aced126 said:


> The only planar parts of tropacocaine are the phenyl and the C=O double bond. The rest of the molecule is not planar.



Even the implicit hydrogens along the entire circumference?

EDIT: since it has two open spots, probably one goes in each direction and is incapable of having them both facing that way? Another noob misunderstanding on my part. At least I'm doing something at the public library to learn things (unlike everybody on either side of me at the library, always just online to play solitaire; lets not get into an _ad hominem_ there too though; I'll concede that they're learning how to be better solitaire players, but I digress). Just last year I learned that para was the benzene 4 and ortho 2, etc. At least I know Me = CH3. ;-p


----------



## aced126

Nope; any carbon which has 4 single bonds is not planar.


----------



## Nagelfar

aced126 said:


> Nope; any carbon which has 4 single bonds is not planar.



this:






is the same as:






and can't be this:






then?


----------



## Solipsis

"entire circumference"?

The phenyl hydrogens are included in the phenyl so yes of course. 

If you mean entire as in also the tropane then no, like in cyclohexane there are all single bonds so sp hybridization. For carbon this means tetrahedral geometry which is not planar.

For C=O and phenyl the double bonds / sigma bonds are sp2 hybridized leading to planar geometry.

P.S. don't forget that e.g. O, N and S have lone electron pairs which are usually not drawn unless they participate in reactions / reaction mechanism drawing - each lone pair more or less takes up a place in the geometry like a single bond would. So even though in tropane the N counts 3 covalent bonds it is not planar like in a phenyl carbon.

I assume for you I'm saying too much, but look up 'ammonia geometry' to clarify.

--

Re: your post / question:

no the bottom one is incorrect because if you draw the tetrahedral geometry of such a single-bonded carbon, two bonds are drawn in plane with the 'screen' or paper you draw on. One hydrogen will here point towards us, this will be the solid wedge, the other hydrogen points away from us, that is the dotted wedge.
Again, check this: https://www.google.nl/search?q=sing...rome&es_sm=93&ie=UTF-8#q=tetrahedral+geometry

and in your mind rotate that structure - match it with drawing conventions.


----------



## aced126

Nagelfar said:


> this:
> 
> 
> 
> 
> 
> 
> is the same as:
> 
> 
> 
> 
> 
> 
> and can't be this:
> 
> 
> 
> 
> 
> 
> then?



All of those molecules are the same.

A carbon is only chiral if it has 4 different groups attached to it. In the 3rd structure you drew, the 2 hydrogens wouldn't be in the same plane because they would have repulsive forces pushing one of the hydrogens to the opposite plane (going into the page; dashed bond). The angle between 2 different groups in a carbon is always roughly 109 degrees, due to the repulsive forces. You can prove this for yourself by considering a tetrahedron and working out the internal angle.

I strongly suggest you pick up a copy of this and spend some time with it. http://www.amazon.co.uk/Organic-Chemistry-Jonathan-Clayden/dp/0198503466

I think it's worth it considering that you spend so much time thinking about these structures. I had a much lesser knowledge than anyone here about chemistry (less than even pre-university) until I got that book about 6 months ago. You don't even need to spend that long reading it, and it's all relevant to this.


----------



## Solipsis

If you draw methane, you *can* draw two of the hydrogens with such a solid wedge - then those two stick out in our direction. The other two must then point away from us and none of them will be in plane with the screen/paper.

Here it's not possible because the ring is too constrained to make the angle unless you would rotate the entire molecule - and that would require clarification drawing the correct dotted-wedged bonds.

It's a bit silly - there is no reason to try and picture the structure that way so it only adds confusion - you could say that is why it would likely be considered incorrect. You only draw unusual bonds (such wedges) to make clear what kind of isomer you have.
Here there is no chirality at that position, none of it matters.


----------



## Nagelfar

aced126 said:


> I strongly suggest you pick up a copy of this and spend some time with it. http://www.amazon.co.uk/Organic-Chemistry-Jonathan-Clayden/dp/0198503466
> 
> I think it's worth it considering that you spend so much time thinking about these structures. I had a much lesser knowledge than anyone here about chemistry (less than even pre-university) until I got that book about 6 months ago. You don't even need to spend that long reading it, and it's all relevant to this.



It's much appreciate aced. If I ever get any money whatsoever, I will seriously consider it.

Solipsis, I'll take you thinking you're saying too much as a compliment that I have enough sporadic knowledge to know, but since you don't know what knowledge I hold or do not, because it's so spotty, I appreciate the thorough way of going about your response. So thank you.


----------



## Dresden

That's funny, aced126, I would've sworn you were at least in your 3rd year of university.


----------



## DotChem

tropacocoiane in 3D.. would that help?


----------



## DotChem

and cocaine..


----------



## DotChem

or simplified..ie omitting Hydrogen atoms...


----------



## aced126

Dresden said:


> That's funny, aced126, I would've sworn you were at least in your 3rd year of university.



Turned 18 a couple a months ago lol, going to uni next year. It's just funny how much one can learn if they can find a way to rationalise it and make it relevant.


----------



## Nagelfar

I have another idea/question: Might hydrogen donors/acceptors present a possible mechanism or pathway that acts the way autoreceptors do in downstream downregulation of activity elicited from bonding by way of ionic H-acceptor/donor bonding?

I recently re-read that N-Ethylmaleimide (NEM), used to interfere with the residues (serine etc.) at the hydrogen acceptor site at MAT, almost totally blocks (95% ) mazindol specific binding; but the effect of 10 mM NEM was prevented by just 10 μM of cocaine (neither 300 μM of DA or D-amphetamine "afforded significant protection" against this affectation from cocaine). Also considering that replacing the carbmethoxy (H-acceptor) with differing heterocyclic substituents found electrostatic traits to affect binding more than even having an H-acceptor.... So potentially, "atypical" DAT ligands like mazindol rely on their binding via hydrogen acceptor/donor interactions, and steric, conformational, and electrostatic factors are what cocaine mainly relies upon to bind. If so, the entire "increase in firing rate" instead of slowing of it, may potentially be mediated by this facet, perhaps neurons are able to "notice" hydrogen exchange between targeted sites but not binding that weighs more on the latter kinds of binding and therefore downstream mediating reactions are less likely to be provoked?



aced126 said:


> Turned 18 a couple a months ago lol, going to uni next year. It's just funny how much one can learn if they can find a way to rationalise it and make it relevant.



Congrats, that's an admirable start. I got my interest in chemistry/joined this forum at 25y/o and @ that time knew next to nothing(!)


----------



## aced126

Nagelfar said:


> I have another idea/question: Might hydrogen donors/acceptors present a possible mechanism or pathway that acts the way autoreceptors do in downstream downregulation of activity elicited from bonding by way of ionic H-acceptor/donor bonding?
> 
> I recently re-read that N-Ethylmaleimide (NEM), used to interfere with the residues (serine etc.) at the hydrogen acceptor site at MAT, almost totally blocks (95% ) mazindol specific binding; but the effect of 10 mM NEM was prevented by just 10 μM of cocaine (neither 300 μM of DA or D-amphetamine "afforded significant protection" against this affectation from cocaine). Also considering that replacing the carbmethoxy (H-acceptor) with differing heterocyclic substituents found electrostatic traits to affect binding more than even having an H-acceptor.... So potentially, "atypical" DAT ligands like mazindol rely on their binding via hydrogen acceptor/donor interactions, and steric, conformational, and electrostatic factors are what cocaine mainly relies upon to bind. If so, the entire "increase in firing rate" instead of slowing of it, may potentially be mediated by this facet, perhaps neurons are able to "notice" hydrogen exchange between targeted sites but not binding that weighs more on the latter kinds of binding and therefore downstream mediating reactions are less likely to be provoked?
> 
> 
> 
> Congrats, that's an admirable start. I got my interest in chemistry/joined this forum at 25y/o and @ that time knew next to nothing(!)



Cocaine relies heavily on H-bond interaction in the carbomethoxy group at carbon-2. Observe the difference between tropacocaine and cocaine. I'm not fully sure if any electrostatic interactions are involved in cocaine binding to MAT. The only possible electrostatic interaction that could occur is if the basic nitrogen got protonated, and then this forming an ionic bridge with an aspartate residue or something. But, as shown in this study (http://www.ncbi.nlm.nih.gov/pubmed/12672255), a basic nitrogen is not required for DAT inhibition. This was one of the compounds synthesised in the study, only 6 fold less potent than methylphenidate itself (this suggests how important the basic nitrogen is; not very, in comparison to the carbomethoxy group):


----------



## Nagelfar

aced126 said:


> Cocaine relies heavily on H-bond interaction in the carbomethoxy group at carbon-2. Observe the difference between tropacocaine and cocaine. I'm not fully sure if any electrostatic interactions are involved in cocaine binding to MAT. The only possible electrostatic interaction that could occur is if the basic nitrogen got protonated, and then this forming an ionic bridge with an aspartate residue or something....



Not so:

Read this on heterocycles versus carbmethoxy (scroll past the table, the page number is correct)


----------



## aced126

Which particular heterocycles are you referring to? Most heterocycles are able to accept an H bond and can therefore be bioisosteric for the carbomethoxy.


----------



## Nagelfar

aced126 said:


> Which particular heterocycles are you referring to? Most heterocycles are able to accept an H bond and can therefore be bioisosteric for the carbomethoxy.



All of them.

Check the link: It's only two paragraphs and it basically shows why the H bond is not the factor of binding @ 2-beta; yes they can all accept them, but the discrepancies in binding affinities to variants containing the same heteroatoms do not account for binding changes between those, in fact it goes *inverse* to what would be expected if that were the case:

I quoted it below, but Greek characters like delta do not come across when speaking of quantum values, etc.:



> The oxadiazoles 32c and 32h contained the same number and types of heteroatoms in the 2‚-substituent  but  the  binding  potencies  were  8-folddifferent.  Similarly, 32g and 32i both  had  one nitrogen and one oxygen in the 2‚-substituent, but 32g was 15 times more potent at the DAT compared to 32i.
> 
> To explore the possibility that the differences inbinding  potencies  of  the  2‚-heterocyclic  phenyltropanes were due to electrostatic interactions, molecular electrostatic potentials (MEP) in the vicinity of the atoms at positions A-C in the model compound (34; Figure 9) were examined. In this model, phenyltropane moiety was replaced by a methyl group. The differences in the electrostatic potential minima near position A (¢Vmin(A)) were calculated using semiempirical (AM1) quantum mechanics calculations after superimposing the heterocyclic and the phenyl rings to  minimize  steric  and  conformational  effects.  A strong correlation between ¢V min (A) and affinity at the DAT was obtained. The ¢Vmin(A) values for 32c, 32g, 32h, and 32i were 0, -4, -50, and -63 kcal/mol,  respectively.
> 
> It  should  be  noted  that  an increasingly negative Vmin in the vicinity of hydrogen-bond acceptor atoms is correlated with an increase in the strength of associated hydrogen bonds.
> 
> Thus, higher affinity at the DAT appeared to be associated with relatively less negative ¢V min values. In other words,  the  observed  correlation  was  against  the hydrogen-bond  interaction  in  the  heterocyclic  analogues.
> 
> Thus, it can be stated that the binding of analogues  possessing  2‚-substituents,  which  arecapable of participating in electrostatic interactions, may be dominated by electrostatic factors rather than hydrogen bonding.


----------



## aced126

Nagelfar said:


> All of them.
> 
> Check the link: It's only two paragraphs and it basically shows why the H bond is not the factor of binding @ 2-beta; yes they can all accept them, but the discrepancies in binding affinities to variants containing the same heteroatoms do not account for binding changes between those, in fact it goes *inverse* to what would be expected if that were the case:
> 
> I quoted it below, but Greek characters like delta do not come across when speaking of quantum values, etc.:



The link takes me to the start of the pdf only. But yes, I'll have to look into this in more detail as it does seem that H-bond donation is playing a lesser role than steric factors.


----------



## Nagelfar

aced126 said:


> The link takes me to the start of the pdf only.



Wait until it loads. (or just enter "16" in the upper left corner once at the link if your browser has the integrated Firefox html *.pdf reader that this library computer has or similar)

Using RTI-126 as an example, I wonder if protonating the nitrogen at the heterocycle would benefit this interaction at all? Anyone with knowledge on electrostatic interactions care to say their piece?


----------



## aced126

You can't chose whether to protonate it or not. The protonated and unprotonated forms of the compound exist in equilibrium, depending on the pH of the medium they're in. Can't really find the pKa of 1,2,4-oxadiazole anywhere, so I don't even know if it'll get protonated at physiological pH at the transporter, but my guess is it will, although the tertiary amine also will be. If this is the case, it'll benefit the most in binding affinity if there's an aspartate residue somewhere nearby and it can form an ionic bridge. If not, positively charged drug residues can still form ion-dipole interactions with any amino acid residues bearing an electronegative residue.


----------



## Nagelfar

^interesting. Thanks aced.


----------



## DotChem

Nagelfar said:


> Wait until it loads. (or just enter "16" in the upper left corner once at the link if your browser has the integrated Firefox html *.pdf reader that this library computer has or similar)
> 
> Using RTI-126 as an example, I wonder if protonating the nitrogen at the heterocycle would benefit this interaction at all? Anyone with knowledge on electrostatic interactions care to say their piece?



wow! doubly protonated? only in highly (i mean REALLY highly acidic media that would happen.. something like concentrated oleum ie fuming sulfuric acid yes!. the pKa for the second nitrogen protonation(=N   =>   =NH+ ) is about -8! .. that of the first protonation is about 0.. so unless you immerse the target DAT in fuming sulfuric acid there's no way that molecule will exist along with anything resembling a protein called DAT. the mexican cartel used the method to make bodies disappears (Literally without a trace! ).


----------



## DotChem

Dissociatives opioid stims..








Bromadol (opioid)

metabolize into 








PCP and pyrovalerone 

how to get the plasma conc for both activities right about the same for maximum mu (w'out ODing) and stim/dissociatives?


----------



## Nagelfar

DotChem said:


> wow! doubly protonated? only in highly (i mean REALLY highly acidic media that would happen.. something like concentrated oleum ie fuming sulfuric acid yes!. the pKa for the second nitrogen protonation(=N   =>   =NH+ ) is about -8! .. that of the first protonation is about 0.. so unless you immerse the target DAT in fuming sulfuric acid there's no way that molecule will exist along with anything resembling a protein called DAT. the mexican cartel used the method to make bodies disappears (Literally without a trace! ).



What if you subtract the charge from the oxygen like is done in the common NO2 formula? ;-p


----------



## adder

Here's my piece of advice coming straight from the heart.  Go get some organic chemistry textbook with the very basics, start with McMurry or Wade, or even start with Clayden, there are some chapters discussing acid-base theory and conformations, and they're very good to start with. If you want to delve into drug design, you need to have a serious background in organic chemistry. Right now you're literally wasting your time in the library looking in the dark and I'm sure you could spend this time more productively. You can also find a lot of free resources on different levels of difficulty from various universities, however, at the very beginning I guess it's necessary for you to know what to look for, I suppose it's functional groups, acid-base theory, and conformations which you should look into, otherwise there's no point in playing with heterocycles and molecules with multiple functional groups.


----------



## aced126

Agreed


----------



## DotChem

Nagelfar said:


> What if you subtract the charge from the oxygen like is done in the common NO2 formula? ;-p


Hello @Nagelfar: But it doesn't work that way: just add or subtract  charge on atom whenever you feel like it.  There is rationale when you  see same molecule depicted sometime with =NH+ or sometime just =N.  Really just basic organic chemistry.  (acid+base <---> salt +  water) . The salt (in the case of imino =NH+ functional group) is a  positively charged specie and depending on the pH of the medium in which  your molecule is, the rx will go one way or the other depending also of the pKa of your molecule. example: cocaine tertiary amine (pKa~8.8) so  at pH7.4 (physiological) there will be 1 molecule free base for 10  protonated (salt form) with (+) charge. Now you put cocaine in the gut  (pH~3) then you'll have one neutral uncharged molecule(free base) of  cocaine for 100000 charged!..etc 
I tend to agree with preceding  posts: study basic functional groups including n-oxide, nitro, nitroso, sulfonyl sulfinyl, sulfoxyl...etc(since you like sulfo compounds in your design.) group and their chemistries including their  acidity/basicity reactivity ..etc. It is a must. Then everything will  make sense as far as drug design is concerned.


----------



## DotChem

Retro-DIPT ..







Retro-Methoxy


----------



## aced126

DotChem said:


> Retro-DIPT ..
> 
> 
> 
> 
> 
> 
> 
> Retro-Methoxy



How do you get the methoxy at that position?


----------



## DotChem

aced126 said:


> How do you get the methoxy at that position?



Good catch aced.. I forget to also "retro" the methoxy.. should be like that:






right? this way the 6-methoxy will occupy the 5-methoxy spot of foxy in the receptor? right?


----------



## DotChem

is that what you meant? or do you mean "how to get the methoxy in that position" in term of synthesis?? well you can.. ahem ahem!


----------



## aced126

DotChem said:


> is that what you meant? or do you mean "how to get the methoxy in that position" in term of synthesis?? well you can.. ahem ahem!



I meant exactly that; I know these molecules are purely hypothetical but it'd be nice if they could actually have some potentially real value. Your most recent molecule is interesting


----------



## Shamandrums

I'd like to draw random receptor sites...


----------



## roi

Lanicemine is a low-trapping NMDA receptor antagonist. However, with a N-ethyl group it would be fairly close to ephenidine.


----------



## Nagelfar

Shamandrums said:


> I'd like to draw random receptor sites...



Now if you had extant ones fully elucidated, we could make putative permutations as possible sub-ones for inclusion in genetically modified species. ;-p Goats create their own vitamin C, we don't; and yet the NMDAR is an orphan receptor in humans. hmmm


----------



## roi




----------



## DotChem

Bliss.. 







.. pure DRI piperazines with no SERT or NET .."me so horny"..


----------



## Incunabula

Many years ago, I tried mephentermine in Goa. You could buy it in vials for injection at the pharmacy, just like ketamine. Once it was crystalized we snorted it, and I swear that it was almost indistinguishable to the _"street"_ amphetamine we get in Europe. It's probably only half as potent as pure amphetamine, but as most amphetamine is cut anyway, it came out the same.

If I was an RC vendor, looking for the next mephedrone analogue, I'd make this:






Mephentermine+Mephedrone = Memephenterdrone

So memephenterdrone might be the most obvious name, even though 4-methyl-mephenterdrone would be more correct, but a bit too long. Imo, best would be to join the two Me's, and just call it *Mephenterdrone*. It has a nice sound to it. 

So to sum it up, I'm guessing it'd be less potent than mephedrone (maybe half the potency) But qualitatively probably identical.

Has this compound been thought of before?


----------



## roi

Probably closer to 4-methylbuphedrone (meh) than mephedrone.


----------



## Incunabula

lol, Yeah, probably. Snorted mephentermine powder was damn close to amphetamine in effects, I know that much. How that translates to a beta-ketone with a 4-methyl would probably have to be assayed in vivo for us to know. But yeah, chances of it being close to mephedrone are slim, I guess. 

I don't take stimulants or empathogens any more, so I don't really care. It was just a funny thought I had, and I thought I'd share it. I'd rather bet my money on this one being more worthwhile, than that mexedrone fail. (not that I've treid that one either, it's not my thing really)


----------



## aced126

I bet this has been drawn before, but does anyone know if open chain LSD analogues have been evaluated?


----------



## sekio

The phenethylamine/amphetamine open chain compounds have been investigated: they have effects on blood pressure but aren't hallucinogenic.


----------



## roi

Can't be much worse than mexedrone.


----------



## Incunabula

You forgot the ketone on your methylenedioxy-many-many-mexe-phenethylamine


----------



## aced126

Maybe that indole nucleus is required


----------



## Incunabula

Yeah. How about something like this? Could be interesting. Would it be easier to synth than LSD?


----------



## Midnight Sun

aced126 said:


> I bet this has been drawn before, but does anyone know if open chain LSD analogues have been evaluated?



If you're trying to increase potency I think it's a better bet to mess around with constraining the basic tryptamine amide ala 4-ho-mpmi and/or indazole substitutions in lieu of indole

pretty sure the pocket of 5ht2a that LSD's diethylamide docks in is rather unreasonable to try and reach with an open chain (would be just too floppy)

I'd really like to know what the rationale was that led to the discovery of 4-HO-MPMI cause it sure would be enlightening!


----------



## pharmakos

Incunabula said:


> Yeah. How about something like this? Could be interesting. Would it be easier to synth than LSD?



add a ketone on that methyl bridge, and tack a pentyl group onto the indolic nitrogen, and you'd have a potential cannabinoid


----------



## aced126

Midnight Sun said:


> If you're trying to increase potency I think it's a better bet to mess around with constraining the basic tryptamine amide ala 4-ho-mpmi and/or indazole substitutions in lieu of indole
> 
> pretty sure the pocket of 5ht2a that LSD's diethylamide docks in is rather unreasonable to try and reach with an open chain (would be just too floppy)
> 
> I'd really like to know what the rationale was that led to the discovery of 4-HO-MPMI cause it sure would be enlightening!



I wasn't really trying to improve potency. In fact the reason why LSD is so potent itself is probably because it is in a rigidified conformation.

Idk, dimethyl > pyrrolidine is a pretty obvious modification lol; I'm sure they synthesised molecules with much more complex modifications.


----------



## roi




----------



## clubcard

ftp://ftp.ensembl.org/pub/release-83/fasta/homo_sapiens/dna/


----------



## clubcard

sekio said:


> The phenethylamine/amphetamine open chain compounds have been investigated: they have effects on blood pressure but aren't hallucinogenic.



I think conformal rigidity might be an issue. The alkyls on the amide appear to be required for space-filling since some secondary amides also work. It's that N lone-pair that is the important bit. The NBOMe class overlays the O of the benzyl-methyl ether so I would look at the directions of the lone-pairs. Just a thought - I could be miles out.


----------



## Solipsis

Yeah but with the NBOMe class, IIRC even 25-NBOMe - the 2C-H analogue - is apparently just nasty and adrenergic let alone free phenyl or mono/dimethoxyphenyls (in terms to tolerating less substitution on the ring). Hans Meyer in PD is testing NDEPA compounds on himself that are based on more classical psychedelic PEAs with often a 2,4,5 substitution pattern. They apparently DO work, anecdotally.

Without a fully constrained lysergamide structure nor such a phenyl substitution pattern on a non-constrained open chain compound you are apparently missing too many binding sites incl. on both ends, for the molecule to both fit on the receptor AND activate it by doing something to the conformation of the receptor protein. An uncanny likeness on one side of the molecule but not the other just makes the above structures remote meth / stim neurotransmitter cousins that apparently are generic enough to do the job as a sympathomimetic drug.


----------



## aced126

Right then, new idea: what would happen if the indole was replaced with a benzene, like so: 
	

	
	
		
		

		
		
	


	




Look at the image for reference:


----------



## sekio

Dunno if it would be active as a hallucinogen, the 9,10 double bond is needed for psychedelic activity






But it's been made though,  refs
Horii et al. Chemical and Pharmaceutical Bulletin, 1966 ,  vol. 14, p. 1227-1234
Bulletin de la Societe Chimique de France, 1968 , p. 4463

Apparently it has oxytocic activity, so presumably it hits some of the serotonin receptors ?


----------



## aced126

sekio said:


> Dunno if it would be active as a hallucinogen, the 9,10 double bond is needed for psychedelic activity
> 
> 
> 
> 
> 
> 
> But it's been made though,  refs
> Horii et al. Chemical and Pharmaceutical Bulletin, 1966 ,  vol. 14, p. 1227-1234
> Bulletin de la Societe Chimique de France, 1968 , p. 4463
> 
> Apparently it has oxytocic activity, so presumably it hits some of the serotonin receptors ?



I meant to have the double bond there, but I couldn't manage to find a way to name it on Opsin. I have a feeling removal of the indole system will still retain activity to an extent. 

Anyway, if the double bond is needed for activity, what does that say about how the molecule interacts with the pocket? Even a small conformational change results in a massive drop in potency, implying that the rigid structure which LSD takes is crucial to not only binding to, but also activating it. Yet however other 5HT2a agonists which have a similar backbone to LSD (like DMT for example) are very active of course, only at 2 or 3 orders of magnitude higher. With that being said, would dihydro-LSD and lumi-LSD be active when administered in much higher doses?

On to a different question, is there a structural link I am missing between the 2C-X series and tryptamine series as they both hit the same receptors.


----------



## Dresden

The C=C is necessary to maintain the planarity of the LSD molecule.  Without that planarity, it is inactive.  But that doesn't mean that your molecule won't be active, just probably not as a psychedelic.  So yeah, basically what sekio said.


----------



## roi




----------



## Dresden

I could be wrong (as I often am), but that nitro-thiophenyl group looks unhappy.


----------



## Solipsis

The thiophene ring may open? 
(the thienodiazepine one to be exact)


----------



## DotChem

aced126 said:


> I meant to have the double bond there, but I couldn't manage to find a way to name it on Opsin. I have a feeling removal of the indole system will still retain activity to an extent.
> 
> Anyway, if the double bond is needed for activity, what does that say about how the molecule interacts with the pocket? Even a small conformational change results in a massive drop in potency, implying that the rigid structure which LSD takes is crucial to not only binding to, but also activating it. Yet however other 5HT2a agonists which have a similar backbone to LSD (like DMT for example) are very active of course, only at 2 or 3 orders of magnitude higher. With that being said, would dihydro-LSD and lumi-LSD be active when administered in much higher doses?
> 
> On to a different question, is there a structural link I am missing between the 2C-X series and tryptamine series as they both hit the same receptors.



apparently the indole NH is REQUIRED for agonist activity . Removing it decrease 5ht2a binding DRAMTICALLY (will post some sar when time permitted but you can run a quick search on http://ncbi.nlm.nih.gov  .


----------



## DotChem

methylphendate ..fully oxidized cousin piperidine=> pyridine .. US legal? its not piperidine ..UK for sure.. more potent than MPH! nice logP faster onset of action. Nootropic working on that..


----------



## Nagelfar

DotChem said:


> methylphendate ..fully oxidized cousin piperidine=> pyridine .. US legal? its not piperidine ..UK for sure.. more potent than MPH! nice logP faster onset of action. Nootropic working on that..



Good idea:






Restrict rotation, phenyl to naphthyl, bioisostere at the restricted descarbmethoxy place.

or:





Di-bromo; higher potency.

(P.S. I was supposed to be at a "retreat" of sorts, but am not. I learned the hard way that no-body here in the pharm. @ BL reads posts at The Lounge section; or anyone anywhere else on this board, for that matter.)


----------



## pharmakos

i saw that thread, actually =p


----------



## DotChem

Nagelfar said:


> Good idea:
> 
> 
> 
> 
> 
> 
> Restrict rotation, phenyl to naphthyl, bioisostere at the restricted descarbmethoxy place.
> 
> or:
> 
> 
> 
> 
> 
> Di-bromo; higher potency.
> 
> (P.S. I was supposed to be at a "retreat" of sorts, but am not. I learned the hard way that no-body here in the pharm. @ BL reads posts at The Lounge section; or anyone anywhere else on this board, for that matter.)



It might work @nagelfar except (naphthalene or dibromophanyl) are too  lipophilic. high lipophilic => high non specific protein binding  => slow distribution => slow to reach brain = no rush.  Plus  isoxazole biosteric will not metabolize easily like the carboxylic  ester. consequence: ultra long half-life (especially with the dibromo  since an alternative metabolic site is now blocked. I mean first-pass  para-hydroxylation of unsubstituted phenyls).  Now I dont even ask how  you go about synthesizing that! would cost you lot$..(but shhttt....
PS:  dibromo or  naphthalene derivatives (ie the more lipophilic the group at the phenyl  binding site) tend to be more serotonergic SERT inhibitor than DAT/MET  so you might end up with MDMA-like with less stim ..could be a good  thing: MDMA with 2-3 weeks half-life! the Lounge section? am I missing  something? ..I like to draw molecules..


----------



## DotChem

but that 







would make a potent MDMA like serotonergic (at least 10x more than MDMA just my opinion.. no data). reason: going from phenyl=>dibromophenyl or naphthyl jack up serotonergic 10x .. would be nice to try DB-BZP


----------



## pharmakos

how does the dibromo sub affect toxicity of related compounds?


----------



## DotChem

Good question! you mean neurotoxicity, right? as far I can tell there is  no similarly halogenated compound to compare to. But correct me if I am  mistaken. The closest I think will be 3-CPP:






or 5-BromoDMT






My guess dibromo-piperazines shouldn't be very different in term of neurotoxicity.. but caution as always!


----------



## aced126

pharmakos said:


> how does the dibromo sub affect toxicity of related compounds?



The parahalogenated amphetamines are neurotoxic. If 3,4-dibromobenzylpiperazine works in a similar fashion, I would expect it to display signs of neurotoxicity.


----------



## Nagelfar

DotChem said:


> It might work @nagelfar except (naphthalene or dibromophanyl) are too  lipophilic. high lipophilic => high non specific protein binding  => slow distribution => slow to reach brain = no rush.  Plus  isoxazole biosteric will not metabolize easily like the carboxylic  ester. consequence: ultra long half-life (especially with the dibromo  since an alternative metabolic site is now blocked. I mean first-pass  para-hydroxylation of unsubstituted phenyls).  Now I dont even ask how  you go about synthesizing that! would cost you lot$..(but shhttt....
> PS:  dibromo or  naphthalene derivatives (ie the more lipophilic the group at the phenyl  binding site) tend to be more serotonergic SERT inhibitor than DAT/MET  so you might end up with MDMA-like with less stim ..could be a good  thing: MDMA with 2-3 weeks half-life! the Lounge section? am I missing  something? ..I like to draw molecules..



Restricted rotation, if MPH (i.e. methylphenidate) SAR trend is anything like PT (i.e. phenyltropane) then " decreased conformational flexibility" = better binding. (forgot to mention as much in my original post, as per: cited page 25, end of left column)

paroxetine (pg. 22) + benztropine in a phenyltropane,

_a la_:





Reminds me of (check third one down; honeycomb benzene side-chain)


----------



## DotChem

aced126 said:


> The parahalogenated amphetamines are neurotoxic.  If 3,4-dibromobenzylpiperazine works in a similar fashion, I would  expect it to display signs of neurotoxicity.


@aced126: It seems the neurotoxicity of para-Halo-amphetamines  (p-halo-PEAs in general and even the rat-aphrodisiac  para-chloroPhenylalanine) is because they are potent irreversible  inhibitors of Aromatic Amino Acid hydroxylase. the enzyme that convert  phenylalanine into tyrosine and further to dopamine and to NE.  also  Tryptophan to 5HTP to serotonin...etc

Blocking this enzyme =>  build-up dangerous level of precursors  => kill neurons especially serotonergic.  Question  is: would para-halobenzyl-Piperazines also act as AAH inhibitors? IMHO  probably not since a phenyethylamine(arylethylamine) skeleton will be  required for AAH enzyme recognition else lots of drugs containing  halophenyl would have similar neurotoxicities..one Bromopipearzine 2C-B-BZP seems to be fine ..but who knows?


----------



## aced126

DotChem said:


> @aced126: It seems the neurotoxicity of para-Halo-amphetamines  (p-halo-PEAs in general and even the rat-aphrodisiac  para-chloroPhenylalanine) is because they are potent irreversible  inhibitors of Aromatic Amino Acid hydroxylase. the enzyme that convert  phenylalanine into tyrosine and further to dopamine and to NE.  also  Tryptophan to 5HTP to serotonin...etc
> 
> Blocking this enzyme =>  build-up dangerous level of precursors  => kill neurons especially serotonergic.  Question  is: would para-halobenzyl-Piperazines also act as AAH inhibitors? IMHO  probably not since a phenyethylamine(arylethylamine) skeleton will be  required for AAH enzyme recognition else lots of drugs containing  halophenyl would have similar neurotoxicities..one Bromopipearzine 2C-B-BZP seems to be fine ..but who knows?



Interesting hypothesis. Do you have a source for this? I can see why they could be potentially reversible AAAH inhibitors, but how can they irreversibly inhibit the enzyme? The only possible thing that could happen is a nucleophilic residue attacking the aromatic carbon and the halogen leaves; unlikely seeing as there are no EWGs to stabilise the intermediate. Maybe there are downstream cellular changes which cause irreversible inhibition. Lastly, why is inhibition of AAAH more neurotoxic to 5HT neurons? 

With these thoughts in mind, I have the following questions: why are 3-haloamphetamines less selective for 5HT neurons? 

Would this be a potent SRA and neurotoxin: 






I'm not fully sure whether 3-FPM itself is a releasing agent or simple a reuptake inhibitor. 

Are there any examples of reuptake inhibitors with a high affinity for SERT causing the typical physiological changes that are observed with SRAs like MDMA (empathy mainly)?

Finally, to what extent do reuptake inhibitors like methylphenidate enter neurons? Is it that a small proportion of them do actually get transporter into the neuron through DAT but then cannot either cause DA vesicle release or DAT reversal?


----------



## roi

Fluorinated amphetamines aren't neurotoxins. Same should apply to fluorinated phenmetrazines. And 3-FPM, just like phenmetrazines itself, is a releasing agent. 4-MPM is somewhat selective for serotonin (by far not as much as MDAI though), 4-FPM should be a slightly more balanced releaser. It's sold in Sweden, but apparently it's not very good and also less potent than 3-FPM.


----------



## aced126

roi said:


> Fluorinated amphetamines aren't neurotoxins. Same should apply to fluorinated phenmetrazines. And 3-FPM, just like phenmetrazines itself, is a releasing agent. 4-MPM is somewhat selective for serotonin (by far not as much as MDAI though), 4-FPM should be a slightly more balanced releaser. It's sold in Sweden, but apparently it's not very good and also less potent than 3-FPM.



Where is your source for fluoroamphs being non-neurotoxic?


----------



## Solipsis

Nothing beats an actual source, but I wanna mention that 4-FA was tested along with 4-CA (pCA) and 4-IA (pIA) and found to have very limited potential as serotonergic neurotoxin (which seems to be the type the fuss of halogenated amps and also 4-MA has always been about: their extreme affinity for serotonergic transporters IIRC and lasting damage done to them). Whether that potential is still any bit significant for 4-FA I don't know, what it means for one time use, frequent use, or doses considered safe. I'm too lazy to get the source for that study but it's been discussed many times - unless i am mistaken the consensus was that 4-FA neurotoxicity wasn't comparable to the serious and concerning 4-CA.

When going from 4-FA to 3-FA and 2-FA, I think the affinity for SERT drops in favor of DAT (if not others) and the assumption is that the neurotoxicity is kinda relying on that high SERT affinity - and a similar toxic mechanism for DAT or NET would be something I never even heard of before.
Are super agonists for DAT neurotoxic?

I believe all that is on the opposition of the fluoroamp neurotoxicity concern? My impression that is what makes roi kinda confident about the matter.


----------



## Incunabula

Hasn't the flourinated amphetamines (aswell as the meth analogues too) been available as RC's for ages? I don't take that stuff, but I'm sure I've been seeing vendors stocking it for a long time now.


----------



## Solipsis

Yes, for an RC stim 4-FA has been around for quite a while (even been sold in smartshops next to methylone in my country - no idea about that currently). Then after a while 2-FA als became available and 3-FA as well as 4-FMA and 2-FMA. Don't know about others and never seen 3-FMA.

Availability doesn't inherently say anything about safety or toxicity. A history of availability at the most would show a good sign, if on the whole people have not noticed acute or correlated chronic health effects that they link to it. Often RC users don't stick to one compound, but 4-FA pretty much went mainstream here.

Still, it doesn't really prove anything technically.

I don't think that serotonergic neurotoxicity is usually noticed as a side-effect during the main effects of the drug, it's noticed afterwards as problems with mood and certain functionalities - even personality on some level, something also observed after chronic cocaine abuse, but different probably. 4-MA sounds scary like that ^ from a few reports. Never heard much about fluorinated amps, but if damage is subtle enough people may not notice it enough to make the link to begin with (not enough damage to induce a disorder or real dysfunction..).
Personally I'm very interested to hear about any problems from 4-CMC or 4-BMC solely. It's claimed they are not toxic like the amps.

There's always a few people who start abusing insanely. A close friend of mine had a 4-FA problem, but alas no clear case there.

Sorry for not drawing random molecules - moderate as you see fit of course? 

Hey... are 3,4-chlorophenyl pea based stims dangerous? That seems to be such a typical moiety like in AH-7921 or U4 (I think), and the methylphenidate analogue. (Ah.. I see DCA is neurotoxic also) - So DCFPM would be a pretty tricky plan : P  So, make the para a fluoro then - 3-chloro-4-fluorophenmetrazine.


----------



## Nagelfar

THIS IS IT!!! THE MOLECULAR MASCOT FOR BL.RU!!!!
=





9,10-Diphenylanthracene + MDMA

It's literally blue light, with a methylenedioxy, and an amphetamine tail. ;-P



aced126 said:


> The parahalogenated amphetamines are neurotoxic. If 3,4-dibromobenzylpiperazine works in a similar fashion, I would expect it to display signs of neurotoxicity.







??


----------



## DotChem

QUOTE=aced126;13480853]Interesting hypothesis. Do you have a source for this?[/QUOTE]
paraChloroPhenylalanine is a known irreversible inhibitor of AAAH especially TrypHydroxylase.

here is one ref for TPH: http://www.ncbi.nlm.nih.gov/pubmed/8015380 (you can find lots of refs for other AAHs.


> .......PCPA is a potent, specific and irreversible inhibitor of TPH activity which drastically reduces 5-HT concentration in the 5-HT neurons and terminals. When PCPA was administered, TPH activity in both cell bodies and nerve terminal areas, was reduced to 10% of control values and recovered to the control levels by day 7 in raphe nucleus, and within 14 days in the hypothalamus. In serotonergic terminal areas, 5-HT could not be detected immunohistochemically at day 1, but slowly recovered within 2 weeks......


Now to my knowledge much less serious studies have been done on ParachloroAmphetamine: the US gov wont give you research $$ to make better stims for the sake of getting wired! but replace the CO2H of PCPA by a methyl and you get PCA.

















I dont see why they souldn't act similarly to PCPA ie inhibitor of AAAH (may be less efficiently but still enough to fry some serotonergic neurons!). Am not sure if anybody has specically study neurotoxicities of PCA but if you dig a bit, am sure you'll find papers on that..




aced126 said:


> ..but how can they irreversibly inhibit the enzyme? The only possible thing that could happen is a nucleophilic residue attacking the aromatic carbon and the halogen leaves; unlikely seeing as there are no EWGs to stabilise the intermediate. Maybe there are downstream cellular changes which cause irreversible inhibition.




Not quite!  it is a bit more complicated: AAAH enzymes used Fe and a cofactor(biopterin) and the mechanism is radical (not nucleophilic attack..etc). the enzyme grab the para H (in the form of free radical) and replace it with OH via a radical H tranfer mechanism with the help of iron Fe and cofactor (too complicated to elaborate here on PD but important thing is: apparently the enzyme generates DEADLY chloro or bromo free radicals that then kill itself) Much more complicated than that but you get the idea.




aced126 said:


> why is inhibition of AAAH more neurotoxic to 5HT


I don;t know. It could be probably as simple as distribution of the molecules ie if it tends to accumulate preferably in 5HT rich brain regions.  Another reason may be depletion of 5HT by irreversibly blocking TPH lead to cells death.. but who knows? 



aced126 said:


> why are 3-haloamphetamines less selective for 5HT neurons? </QUOTE>
> ?? in terms of what? if anything 3-halo should not have similar neurotoxicity while beeing as potent as the 4-halo (see bupropion )
> 
> more ...later


----------



## DotChem

but 6-CAT is non-neurotoxic according to Pr Dave Nichols:

wiki: 6-CAT


> 6-Chloro-2-aminotetralin (6-CAT) is a drug which acts as a selective serotonin releasing agent (SSRA) and is a putative entactogen in humans.[1][2] It is a rigid analogue of _para_-chloroamphetamine (PCA).[1]
> 
> According to Nichols _et al._,[3] 6-CAT is a non-neurotoxic analog of PCA.


----------



## Nagelfar

DotChem said:


> here is one ref for TPH: http://www.ncbi.nlm.nih.gov/pubmed/8015380 (you can find lots of refs for other AAHs.



Added info to WP, thanks for that one Do(t)C.


----------



## aced126

DotChem said:


> QUOTE=aced126;13480853]Interesting hypothesis. Do you have a source for this?


paraChloroPhenylalanine is a known irreversible inhibitor of AAAH especially TrypHydroxylase.

here is one ref for TPH: http://www.ncbi.nlm.nih.gov/pubmed/8015380 (you can find lots of refs for other AAHs.

Now to my knowledge much less serious studies have been done on ParachloroAmphetamine: the US gov wont give you research $$ to make better stims for the sake of getting wired! but replace the CO2H of PCPA by a methyl and you get PCA.

















I dont see why they souldn't act similarly to PCPA ie inhibitor of AAAH (may be less efficiently but still enough to fry some serotonergic neurons!). Am not sure if anybody has specically study neurotoxicities of PCA but if you dig a bit, am sure you'll find papers on that..





*Not quite!  it is a bit more complicated: AAAH enzymes used Fe and a cofactor(biopterin) and the mechanism is radical (not nucleophilic attack..etc). the enzyme grab the para H (in the form of free radical) and replace it with OH via a radical H tranfer mechanism with the help of iron Fe and cofactor (too complicated to elaborate here on PD but important thing is: apparently the enzyme generates DEADLY chloro or bromo free radicals that then kill itself) Much more complicated than that but you get the idea.*



I don;t know. It could be probably as simple as distribution of the molecules ie if it tends to accumulate preferably in 5HT rich brain regions.  Another reason may be depletion of 5HT by irreversibly blocking TPH lead to cells death.. but who knows? 



aced126 said:


> why are 3-haloamphetamines less selective for 5HT neurons? </QUOTE>
> ?? in terms of what? if anything 3-halo should not have similar neurotoxicity while beeing as potent as the 4-halo (see bupropion )
> 
> more ...later



Where can I find more about the mechanism? Wikipedia has nada.


----------



## DotChem

Exact same thing for phenylalanine => tyrosine and tyrosine => l-DOPA (the heterocylcle on top is the biopterin co-factor. 
Mechanisms of tryptophan and tyrosine hydroxylase http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270200/ 



> The aromatic amino acid hydroxylases tryptophan hydroxylase and tyrosine  hydroxylase are responsible for the initial steps in the formation of  serotonin and the catecholamine neurotransmitters, respectively. Both  enzymes are nonheme iron-dependent monooxygenases that catalyze the  insertion of one atom of molecular oxygen onto the aromatic ring of  their amino acid substrates, using a tetrahydropterin as a two electron  donor to reduce the second oxygen atom to water. This review discusses  the current understanding of the catalytic mechanism of these two  enzymes. The reaction occurs as two sequential half reactions: a  reaction between the active site iron, oxygen, and the tetrahydropterin  to form a reactive FeIVO intermediate and hydroxylation of the amino acid by the FeIVO. The mechanism of formation of the FeIVO is unclear; however, considerable evidence suggests the formation of an FeII-peroxypterin intermediate. The amino acid is hydroxylated by the FeIVO intermediate in an electrophilic aromatic



(the full review paper is free! and very up to date) .. good luck


----------



## DotChem

more details (from same paper)....


----------



## Incunabula

I know we don't do synth talk here, but how difficult would it theoretically be to remove the acetic acid from the β carbon? And am I correct in thinking, that it would be a substitution reaction?






Edit: I guess it's a decarboxylation. How difficult and dangerous is it. (theoretically, I'm not about to blow myself up just yet)


----------



## Nagelfar

Altinicline + Fenclonine

(for some reason, no clue why, just random association inspired me)


----------



## roi




----------



## Dresden

DotChem said:


> but 6-CAT is non-neurotoxic according to Pr Dave Nichols:
> 
> wiki: 6-CAT



I wouldn't touch that with a ten foot pole.


----------



## Solipsis

Yea 2-aminotetralin itself appears dangerous and nasty in humans from anecdotes (secondhand from nuke), so it's not even the pCA analogy alone warranting that wide berth..

I really like the phenidates vs modafinils hybrid / analogues - tickling structures roi


----------



## DotChem

any idea why the tetralines so nasty.. not very different from simple PEA at first glance!


----------



## DotChem

talking about tetralines...Dissociatives Stims


----------



## Solipsis

Not bad, in morphinans including DXM there is the same 2-aminotetralin configuration. In that tetraphenidine the phenyl is perhaps not necessarily as optimal for PCP-site binding as the phenyl in PCP itself, because the one side of the aromatic ring in the tetralin would fulfill that role mimicking the carbonyl function of glutamate. Demonstrated by DXO's structure I guess.
For mimicking glycine there is one less spacer... I wonder if you can make the drug more selective that way. It might mean that diphenidine type structures are dirty that way overlaying with glutamate and glycine?

Might not be such a bad idea to simplify and modify DXO to make it optimal as a recreational drug (as opposed to a metabolite of cough suppressant medication), in a similar way as MXE was an ingenous design starting from ketamine as the ACH template.

Log p yeah not to ignore, but I'm not sure if slapping phenyls on drugs is such a great idea if they don't actively play a role in binding... The stupidly long durations of many popular dissociatives are to me one of the banes.
Instead add some polar groups that besides facilitating excretion improve on the drug's effects, like perhaps borrowing the idea from -OH on DXO to make a 6-tetralinol.


----------



## DotChem

Solipsis said:


> ..in morphinans including DXM there is the same 2-aminotetralin configuration...



You're right! actually that may explain problems with tetralines!! If they get para-hydroxylated in first pass metabolism (a real possibility),then you might end up with a potentially potent morphinan like structure with the 6-phenolic OH in the right position ala DXM. At least for the unsubstituted ones.  So stims/nmda doses would certainly correspond to mortal opioid ods.  If that is the case though, then the 6-chloro-2-amino tetralines may also be toxic in that sense; not necessarily neurotoxic...

On the other hand, 2-amino-indanes seems to be ok...(not sure about the corresponding 6-chloro-2-aminoindane!) 








Solipsis said:


> In that tetraphenidine the phenyl is perhaps not necessarily as optimal for PCP-site binding as the phenyl in PCP itself, because the one side of the aromatic ring in the tetralin would fulfill that role mimicking the carbonyl function of glutamate..



Very true! the question is how much can the cyclohexyl (the PCP cyclohexyl) binding site accomodate?  I guess one can tinker around with this part of PCP and still retain some Glu-site activity but yeah, tetraline seems too big.  cf benocyclidine where the Ph of PCP is replaced by 2-thiophenyl gives 0 NMDA activity but potent and pure DRI with no SERT or NET!! 




Solipsis said:


> For mimicking glycine there is one less spacer... I wonder if you can make the drug more selective that way. It might mean that diphenidine type structures are dirty that way overlaying with glutamate and glycine?



may be an aminoindane like this?







But they're harder to synthesize..(almost always catalytic hydrogenation step! I always hated Parr hydrogenators lest you're trying to bl0w the lab up!)



Solipsis said:


> Might not be such a bad idea to simplify and modify DXO to make it optimal as a recreational drug (as opposed to a metabolite of cough suppressant medication), in a similar way as MXE was an ingenous design starting from ketamine as the ACH template.




Can't diphenidine really be looked at as a simplified version of DXO with the 1-phenyl mimicking the cyclohexyl of DXO? like this:










Solipsis said:


> Log p yeah not to ignore,




logP are pretty decent. a bit on the lipophilic side but not very different from diphenidine(1.5-1.8 @pH7.4). 




Solipsis said:


> but I'm not sure if slapping phenyls on drugs is such a great idea if they don't actively play a role in binding... The stupidly long durations of many popular dissociatives are to me one of the banes.
> Instead add some polar groups that besides facilitating excretion improve on the drug's effects,




Now that's serious PK issues you raised: ridiculously long half-life of hydrophobic molecules. 

How about Ph ----> CO2Et replacement? which bring me back to some structures related to methylphenidate I suggested earlier. will the CO2ET mimick the CO2H of Glu at NMDAr site?! 





or







extremely easy synthesis .. half life probably similar to MPH (the ester.. the ketone a little longer!). potential dissociatives stim?



Solipsis said:


> like perhaps borrowing the idea from -OH on DXO to make a 6-tetralinol.


 

Caution though with 6-hydroxy tetralines: lest you end up with morphinan-like opiods. But with a little luck the piperidine ring (instead of simpler amino) might make them ANTAGONISTS rather than agonists at opiates receptors if they happen to have any affinity at all for OPs.. but who knows?


----------



## aced126

Aminotetralins aren't toxic in the fact that they cause respiratory arrest. Rather, they reduce the seizure threshold, something which is not caused by opioids.


----------



## crmt28

2C-iP with a "ButterFLY" structure, but on the 4 and 5 positions instead. Pretty interesting molecule, looks kinda like THC!






EDIT:

Oops, Shulgin already did it with the F-x series, with a furan ring instead. 
But he didn't seem to try the alpha unmethylated versions.


----------



## Nagelfar

^This reminds me of a methylphenidate methylenedioxy version of cocaine; inasmuch as cocaine has a methyl acetate (to the phenyl, the benzoate) and a carbmethoxy which is basically the inverse of the other: it is much likewise with the cyclopentane methylenedioxies in the above MPH derivative.


----------



## Pomzazed

^
That "1,3-dioxolane" (the five member ring with 2 oxygen) will RAPIDLY hydrolyses in contact with water (catalysed by H+ also, and will be alot faster) into aldehyde group plus ethylene glycol (very toxic to kidney forming oxalate kydney stone rapidly)

I wont touch this molecule also...


----------



## aced126

Pomzazed said:


> ^
> That "1,3-dioxolane" (the five member ring with 2 oxygen) will RAPIDLY hydrolyses in contact with water (catalysed by H+ also, and will be alot faster) into aldehyde group plus ethylene glycol (very toxic to kidney forming oxalate kydney stone rapidly)
> 
> I wont touch this molecule also...



Why so? Cyclic acetals are more stable than normal acetals and anyway doesn't acetal hydrolysis occur slowly unless catalysed by H+. By the same argument you could say that methylphenidate will rapidly hydrolyse to ritalinic acid and methanol (which might blind you...not, not at that dose anyway). Ethylene glycol is not toxic in milligram range.


----------



## sekio

> Why so?



no/very little steric hindrance around the two outer carbons (if you count from the top as #1 they are the 3rd and 4th members of the ring)

look up the mechanism of acetal hydrolysis

also enzymes in biological systems can catalyse this rxn just as well as H+, presumably also certain metals/ions, etc

you are right that the ethylene glycol generated wouldnt be toxic but the hydrolysis of the ring would destroy the activity

a better analog for the ester group (die Ester-Gruppen??) would be an oxazoline or whatever is present in that one RTI compound - a ring just like that acetal except with a nitrogen with a double bond in it present in the place of one of the oxygens


----------



## Pomzazed

aced126 said:


> Why so? Cyclic acetals are more stable than normal acetals and anyway doesn't acetal hydrolysis occur slowly unless catalysed by H+. By the same argument you could say that methylphenidate will rapidly hydrolyse to ritalinic acid and methanol (which might blind you...not, not at that dose anyway). Ethylene glycol is not toxic in milligram rangeff.



1.well, I retract the kidney stone i said above then, I forget about the dosage range which is small, even a gram of that hydrolyse to only milligrams range, so you are right on this part.

2.I still stand about hydrolysis. It is tru that the oxazolidine is stable in neutral and basic media, but in biological environment, if you eat it, with pH 2 in the stomach, it breaks to aldehyde and MEG rapidly, even when smoked/evaporate/snorted or injected, there are several enzymes in bloodstream that catalyse the breakdown of this acetal. The rate will be diminished by steric hindrance of carbon4,5, which in this case is no steric at all (all 4 substituents there are H's)

3. Ester is harder to hydrolyse than (aliphatic) cyclic acetals. Thats why acetals are often used as protecting group in org syn. 

4. I do not say that acetals can be used in bioactive compounds, yes there are several, for example: topical steroidal drug: Triamnicolone Acetonide. But this wont hydrolyse so easily, look at how C4 and C5 steric demands are.



> better analog for the ester group (die Ester-Gruppen??) would be an oxazoline or whatever


Oxazoline would be much more stable and mimics ester better with that p-orbital.
Exchange MEG to MEA and additional dehydrating base and you form oxazolidine from aldehyde, then You can make it from oxazolidine to oxazoline by [snip]No synthesis discussion[/snip]
(*hint: strong halogenated oxidizer)


----------



## crmt28

A little more info on the last compound I posted. It may have lot of potential!

Let's look at F (pretty unknown compound buried in PiHKAL):









It's 15x less potent than DOM, but it was never tested. Probably active near 70mg or so. 
Then we have F-2 and F-22, which add methyl groups on the 2 position of the furan ring, and are noticeably weaker. (40x weaker than DOM)

Shulgin was planning to try F-3 and the benzopyran analogues, but he gave up due to the hard synthesis and loads of chiral centers.
This seems to be a much better idea, since it's basically extending the chain on the 4-position. Real shame he gave up.

Here are some more compounds expanding on that:

F-(2-HemiFLY) - Adding a HemiFLY structure to F. This one could probably be very close to DOM in activity by weight.






F-3-(2-HemiFLY) - Changing the 3rd position instead of the 2nd. If this could increase potency (look at the molecule and think of 2C-D vs 2C-E) it would be a winner! 







Let's get crazy here with not so serious compounds:

 2C-G-4 and 2C-G-5 analogues:










Bonus semi-related compound:

3-Me-6-APB (3-methyl-6-(2-aminopropyl)benzofuran)


----------



## Incunabula

Nice molecules, crmt28. Your 2C-G-4 and 2C-G-5 analogues looks a little too bulky, but they are very interesting. 

They remind me a bit of some molecules I drew a year ago or so. They are kind of a mix-up of the fly's and indanes (Like 2CB-ind or Jimscaline) I think there's a they could potentially be active according to the psychedelic phenethylamine SAR we know. If there is a way to synth them, that is.

I like the symmetry.


----------



## aced126

3-methyl on the furan ring might cause too much steric hindrance. SERT is tight. A methyl group on the methylene carbon of MDMA (ethylidenedioxymethamphetamine) halves potency. 2 methyl groups (isopropylideneMA) and activity is abolished.


----------



## DotChem

Valeroxamine ... 





what you guys think about these?? MXE open-chain


----------



## pharmakos

almost looks like gabapentin or pregabalin when you open it up





gabapentin





pregabalin


----------



## Nagelfar

Spoiler: Cruft you don't need to see









Don't you dare say it's fatuitous ;-p

"Cleaned up":






*You* clicked on it.








Stimulant?


----------



## crmt28

^ Looks like a Harmaline/Phenethylamine hybrid! 

"Closer" versions:


----------



## Nagelfar

_meta_-bromo-(2-methyl-2-butanol)-naphthidate (would that still be "_meta_" on a naphthyl or is the nomenclature different?)

Perhaps simplify it as thus:






Should have good affinity unless one 3'/_meta_ position need be free for optimized binding.

For curiosities sake:











From a doodle at my out-patient group:


----------



## Nagelfar

crmt28 said:


> ^ Looks like a Harmaline/Phenethylamine hybrid!
> 
> "Closer" versions:



Speakin' o' hybrids check this one out, epiphany inspired just moments ago:






Amylocaine (the very first synthetic topical anesthetic based on cocaine, residual stimulant properties?)  + dimethylaminopivalophenone (simplest opioid)

Simplest uni/mono-molecular speedball?

EDIT: I can get it even closer; containing all the constituents of both (OK, minus an oxygen), if I just make it the salt:


----------



## Solipsis

Oh awesome, after PV type stuff finally another stim that promises to reek of semen ;p


----------



## DotChem

DXM ..






Open-chain ..






look like Tramadol ???


----------



## DotChem

pharmakos said:


> almost looks like gabapentin or pregabalin when you open it up
> 
> 
> 
> 
> 
> gabapentin
> 
> 
> 
> 
> 
> pregabalin





Nice observations! also like phenibut.. who knows they might be GABA-ergic altho they're Alfa AA analogs instead of Gamma!


----------



## pharmakos

DotChem said:


> DXM ..
> 
> 
> 
> 
> 
> 
> Open-chain ..
> 
> 
> 
> 
> 
> 
> look like Tramadol ???



interesting.


----------



## Nagelfar

Mini-phenyltropane






MPH variant:


----------



## Solipsis

DotChem said:


> DXM ..
> 
> 
> 
> 
> 
> 
> Open-chain ..
> 
> 
> 
> 
> 
> 
> look like Tramadol ???



Sure, cause the clarifying comparison would be not with DXM but with the other stereoisomer of methorphan:

https://en.wikipedia.org/wiki/Levomethorphan

An opioid roughly as potent as hydrocodone.


----------



## aced126

Nagelfar said:


> Speakin' o' hybrids check this one out, epiphany inspired just moments ago:
> 
> 
> 
> 
> 
> 
> Amylocaine (the very first synthetic topical anesthetic based on cocaine, residual stimulant properties?)  + dimethylaminopivalophenone (simplest opioid)
> 
> Simplest uni/mono-molecular speedball?
> 
> EDIT: I can get it even closer; containing all the constituents of both (OK, minus an oxygen), if I just make it the salt:



Charged species won't cross BBB.


----------



## roi




----------



## DotChem

Solipsis said:


> Sure, cause the clarifying comparison would be  not with DXM but with the other stereoisomer of methorphan:
> https://en.wikipedia.org/wiki/Levomethorphan
> An opioid roughly as potent as hydrocodone.



You're right! I drew the "wrong" stereoisomer or shall we call it the "opioid-like stereoisomer" around the C -Ph carbon?

Yes the Cis (that is the 3MeOPhe and CH2NHCH3 in cis, Zusammen in German) overlay with dextro-metorphan (DXM) like this:








----->DXM-like dissociative 



and the (+/-) trans with levo-metorphan and (+/-)tramadol..







"Cis-Tramadol"
--->Levomethorphan-like opioid .. 

so  in theory then "cis" Tramadol should have dissociative but not opioid  .. would be an interesting RC if it is easily accessible synthesis-wise!  (from tramadol I guess it should be possible...   ) "pure" DXM-like dissociative with no opioid to worry about! may be some stim?? but pretty safe I would imagine!


----------



## DotChem

roi said:


>


Nice but are alfa-aminosulfones stable? ..would they not behave like alfa-acetoxy amines! hydrolyze very easily in solution into sulfinic acid and amide?


----------



## Nagelfar

aced126 said:


> Charged species won't cross BBB.



What's the specific rationale; just because I'd like to educate myself on the simple 'ring-pass-naught' rules of the BBB. Not just *that* it is charged, is it? Is Deprotonation prior to BBB always the case in salt drugs?

How 'bout:






which is (the aforementioned) combination of these two:






^Top = anesthetic(/stimulant?) + ^bottom = analgesic/mu-agonist-opioid


----------



## Pomzazed

Nagelfar said:


> What's the specific rationale; just because I'd like to educate myself on the simple 'ring-pass-naught' rules of the BBB. Not just *that* it is charged, is it? Is Deprotonation prior to BBB always the case in salt drugs?
> 
> How 'bout:
> 
> 
> 
> 
> 
> 
> which is (the aforementioned) combination of these two:



imposiburu molecule; stop snapping a CH2 in-between electronegative heteroatoms like N, O, P, S in aliphatic compounds, especially in non-ring molecule!
It breaks down to corresponding carbonyl; eg. That N-CH2-N will break down to two amines and formaldehyde,
This is aloso true for that N-CH2-OR shown in your pic will go to ethylamine, methyl alcohol, and ketone

The breaking will be more prominent in charged N molecules.

Aromatic ring greatly stabilize this so it is "ok" (ala MDMA), aliphatic ring wont be much so, so not-ok (eg MD-propylhexedrine; isolatable, but decompose near sudden) non-ring is even worse, snip it when you see. (it also breaks either when you 'look at' it or not)

I dont directly target against your molecule, but I see it too often now in this thread. Just need to make ppl realise before designing


----------



## roi

Now that 4-Fluorophenibut and 3,4,5-Trimethoxyphenibut are available, we need some proper analogues. You know what to do bluelight.


























and of course


----------



## Dresden

You got me thinking about pregabalin, and this came out.


----------



## Dresden

That last one, roi, is a methylating agent and is supertoxic.


----------



## Dresden

And this.


----------



## Dresden

Those oxygens should liven things up compared to the first two.


----------



## Dresden

At least I think it is a methylating agent.


----------



## Dresden

Finally, somebody backs up my claim that N-CH2-O's are impossible!


----------



## pharmakos

Dresden said:


> Those oxygens should liven things up compared to the first two.



i'm surprised that 4-cyclopropyl phenethylamines haven't been tried.  i can't dig up anything about them, at least.  anyone have any guesses as to why these haven't been done?  or is it just that no one's gotten around to them yet?

that cyclopropyl group would be perpendicular to the plane of the benzene ring, right?  might kill potency.


----------



## Dresden

Idk but I bet this would be cool.






I love propanes!

As for the cyclopropanes, Ann Shulgin took this one and felt "like a goddess."






?


----------



## Pomzazed

Dresden said:


> Finally, somebody backs up my claim that N-CH2-O's are impossible!



Yeah, most are imposiburu except in very special case, 
I have been seeing that "breaks into formaldehyde and amine" periodically, but i just ignore it.
Now i see it more and more, really, ppl need to look at "aminal"(not animal!) hemiaminal, hemiaminal ether
And see their formatiion and breakdown mechanism and conditions required for that.

TLDR:
Dont design aliphatic noncyclic X-CR2-X drugs, where X is N,O,S,P , and R is alkyl!


----------



## Dresden

This one is a longshot for sure, but heck, here it is anyway...


----------



## Dresden

Here's a nightmare drug.


----------



## Dresden

And another.


----------



## clubcard

I hope you're using Marvin-sketch to check cLogP (calculated LogP - who has actually taken a vessel filled 50/50 with N-octanol & water to see what % ended up where?) and pKa at blood pH. Follow Lipinski's rules of 5 and give values - in the name of learning. I think anyone without a formal education (learning how to perform an AMES test, testing blood % urine and the 1001 thing before STAGE I). I had a VERY simple STAGE I and I'm still posting. Until the 60s, this was standard test - I mean, Bentley and other bit-hitters did it.


----------



## Nagelfar

Nagelfar said:


>





Pomzazed said:


> imposiburu molecule; stop snapping a CH2 in-between electronegative heteroatoms like N, O, P, S in aliphatic compounds, especially in non-ring molecule!
> It breaks down to corresponding carbonyl; eg. That N-CH2-N will break down to two amines and formaldehyde,
> This is aloso true for that N-CH2-OR shown in your pic will go to ethylamine, methyl alcohol, and ketone
> 
> The breaking will be more prominent in charged N molecules.
> 
> Aromatic ring greatly stabilize this so it is "ok" (ala MDMA), aliphatic ring wont be much so, so not-ok (eg MD-propylhexedrine; isolatable, but decompose near sudden) non-ring is even worse, snip it when you see. (it also breaks either when you 'look at' it or not)
> 
> I dont directly target against your molecule, but I see it too often now in this thread. Just need to make ppl realise before designing








??



Pomzazed said:


> Yeah, most are imposiburu except in very special case,
> I have been seeing that "breaks into formaldehyde and amine" periodically, but i just ignore it.
> Now i see it more and more, really, ppl need to look at "aminal"(not animal!) hemiaminal, hemiaminal ether
> And see their formatiion and breakdown mechanism and conditions required for that.
> 
> TLDR:
> Dont design aliphatic noncyclic X-CR2-X drugs, where X is N,O,S,P , and R is alkyl!



You callin' my compound aliphatic, man? "I Auummm Nottt An Aminal!!!"


----------



## Dresden




----------



## Dresden

Form the necessary, not for


----------



## Nagelfar

Dresden said:


>



Interesting. Many quaint changes to m-amp that are being overlooked IMHO, good aim/eye, Dres.

EDIT:






_N_-_cis_ (methyl = *R-one*, hydrogen = R-two) or _trans_: (methyl=* R-two*, hydrogen = R-one) propenyl-amphetamine



Nagelfar said:


>



A username "The Aliphaticman" with this avatar and the signature "I Am Not An Aminal" would be a great one for BL

(over at opiophile I made a thread with such suggestions: one was a little orphan Annie avatar with an arm holding a gun to her head and the username "End-orphans" ;-p)

...Well, anyhow, The Elephant man is an apt metaphor for my molecular catastrophes I'd wager.


----------



## Solipsis

Too late, Annie has already been serial-massacred by Dexter the meth orphan.
Orphans are so curious among each other. Cf orphan black (= surprisingly NOT batman).

I smiled at the aliphaticman but you do realize that hemiaminal ether is aliphatic, right? It's just not alicyclic.









_(RS)4-fluoro-N,α-dimethyl-cyclohexylethylamine

SMILES = FC1CCC(CC1)CC(C)NC_






_(2S)2-ammonio-3-(piperidinon-3-yl)propanoate

SMILES = [NH3+][C@H](C(=O)[O-])CC1C(NCCC1)=O_

Looks cooler ring-closed and lactams aren't so common in drugs I know of, ring opened hopefully still carried by amino acid transporter, you can guess what this is modeled after and on what system it may have effect, though perhaps only in ring-closed form? *Edit: sorry mistaken, ring closure doesn't apply*

Possibly a form of nylon could be made from it.. : p
Though not in vivo, otherwise someone should write a paper on mending internal wounds by injecting a patient with lactams, and glueing the stuff together with acrylfentanyl.
(speaking of materials like that)






_1-propionyl-3-[2-(Dipropylamino)ethyl]-1H-indol-4-yl propanoate

SMILES = C(CC)(=O)OC1=C2C(=CN(C2=CC=C1)C(CC)=O)CCN(CCC)CCC_

This drug was the runner up in the competition for the name 'substance P'


----------



## clubcard

Hey people - images are a BULKY way to exchange images. I feel certain that whatever editor you're using will give you the SMILES data &/or the IUPAC naming convention. With these, you can quickly search for the name in patents, Google Scholar or Reaxys. It's about 20x faster to swap data AND their is java SMILES ->Image. 

This means that the image above 6.83Kb (rounded up to 8Kb because of HD formatting)is, in SMILES CCCN(CCC)CCC1=CN(C(=O)CC)C2=CC=CC(OC(=O)CC)=C12 into 47 characters which could be physically stored even smaller by a simple Huffman tree (or an arithmetic tree now patent expired). Don't generate a tree for each image, just the best-fit from 255 trees themselves chosen by scanning through chemicalize.org. I would expect to get at least 70% compression since we virtually only use a set containing a small number of elements (11 give or take) and a small number of bonding types (about a dozen). I mean, everyone can SEE the image & copy and paste it into some other software. I have never had the need to use InChI or InChI key but that needs a straw poll.

I know I keep going on about it but if the software is available but their are Python scripts to do this. 6K seems nothing, but if the site generates the images, they won't disappear when a link breaks or the thread is archived. I've not seen the PHP running the site or how complex inclusion would be, but I think if people had it & could export it, it leads on to people buying the Student edition of ChemOffice and all you guys in collage can throw it in Reaxys.

If I'm just the 1 person who can see the importance, I can also add that when it's used in Marvinsketch (or Chemoffice) then the cLogP & pKa at blood pH can quickly edit a compound that fulfil's the rules of 5 so you're learning by doing, While we cannot give any synthesis information, so often the answer is in a patent or a paper so adding on the source data also cuts a pathway for all who follow,


----------



## Solipsis

While some ideas are definitely titillating, I think one reason why this thread exists is because amateurs also like coming to this forum to share wacky ideas, hence the 'random molecules' in the title rather than 'amazing novel psychoactives that should theoretically work and everything!', well yeah also the latter is too long.

I added SMILES for the hell of it ^ but for your fine idea to work I think this first would have to split into an amateur / entertainment thread and a serious new ideas thread - like differentiating between business and pleasure at the airport, or social talk from drug addled ramblings in PD. 
I don't think splitting them isn't particularly desirable, though I understand if it's annoying if you strictly love the nonsense or the sensical here.
And often people here react to fun ideas from less than educated people as if they were submitted to be analyzed as a candidate for actual synthing or assaying. Which is a little like completely missing someone's sarcasm on a forum for some reason.. 

The lines are a bit blurry, and I think it's fun that way, I like the entertaining ideas as much as the serious possibilities that appeal to the imagination.

Otherwise any change like that, which ignores half of the public, would be pretty unfair?


----------



## DotChem

Dresden said:


> Here's a nightmare drug.



what's the pb with it? ..it looks so similar to foxy!


----------



## Solipsis

'spirobarbital'
(RS)-12-methyl-2,4-diazaspiro[5.6]dodec-8-ene-1,3,5-trione
CC1CCC=CCC12C(NC(NC2=O)=O)=O

Let's LSZ-tidize that bastard and get the constrained winner..

Or another avenue below - doesn't even have to be 'symmetrically' bridged..
Omitted the terminal methylene this time cause it doesn't really look right to me (polymerization? alkylation?)
But perhaps chloro is more of a sub






3-fluoro-1,2-dimethyl-7,9-diazaspiro[4.5]decane-6,8,10-trione
FC1C(C(C2(C1)C(NC(NC2=O)=O)=O)C)C



DotChem said:


> what's the pb with it? ..it looks so similar to foxy!



https://www.erowid.org/library/books_online/tihkal/tihkal52.shtml
https://www.erowid.org/library/books_online/tihkal/tihkal43.shtml

It actually kinda shows that sometimes 'constraining'  (bridging really) two chains together gives you a weird acting compound... although the dimethylazetidine is still exciting to check out, again a la LSZ probing research.

I submit this (maybe as IP injection?) for nightmares:






_diphenyl(piperidin-2-yl)methyl palmitate_

maybe the adamantane dicarboxylate bis pipra is twice as 'good'


----------



## DotChem

Solipsis said:


> https://www.erowid.org/library/books_online/tihkal/tihkal52.shtml
> https://www.erowid.org/library/books_online/tihkal/tihkal43.shtml
> 
> It actually kinda shows that sometimes 'constraining'  (bridging really) two chains together gives you a weird acting compound... although the dimethylazetidine is still exciting to check out, again a la LSZ probing research.



Horrible compound! light-years away from foxy glow. amazing how small changes can have big impacts! Dimethylazetidine seems good alternative.. or even the dimethylpyrrolidnyl? I guess it will be closer to 5MeODIPT in terms of steric, electronic logP..etc..but who knows how they'll behave once they cross BBB!


----------



## Midnight Sun

DotChem said:


> what's the pb with it? ..it looks so similar to foxy!



https://en.wikipedia.org/wiki/5-MeO-pyr-T

it's barely even active

@ solipsis - curse you, I was coming in here to post a pipradrol ester


----------



## Dresden

It caused one of Sasha's subjects to wander the streets for I forget how long in a fugue state replete with amnesia, so how can you call it "barely active"?


----------



## Midnight Sun

Dresden said:


> It caused one of Sasha's subjects to wander the streets for I forget how long in a fugue state replete with amnesia, so how can you call it "barely active"?



sum total of effects: nausea, vomiting, amnesia (?) 

ok, that's about as active as the shit I took this morning would be if I loaded it into a pipe and smoked it


----------



## Nagelfar

early never-marketed/discontinued anti-depressants with interesting skeletons:


Tranylcypromine


Carbenzide


Isocarboxazid


Iproniazid


Metfendrazine


Domoxin


Cimemoxin








Solipsis said:


> Cf orphan black (= surprisingly NOT batman).
> 
> I smiled at the aliphaticman but you do realize that hemiaminal ether is aliphatic, right? It's just not alicyclic.



Humans are animals, taxonomic genus "Homo", I am as right/correct as the Elephant Man; but I'm not his clone (I hope, my mirror is the same as Shallow Hal's if not)


----------



## sekio

tranylcypomine is still in active use


----------



## Nagelfar

sekio said:


> tranylcypomine is still ina ctive use



Interesting. The cyclopropane on it. Wonder what modification'd be needed to make a dopaminergic instead of an MAOI


----------



## roi




----------



## Solipsis

There are RCs available that are close analogues of tranylcypromine:

the 4-methyl (or rather 4'-methyl with the cycloprop being main ring) - so a mephedrone tolyl style compound, and
the 3,4-fluoro (3',4') - cause 3,4-fluoroamph is so well known and popular 

Both of which are scary as they are about half as potent MAOIs as the parent and I don't know what other activity they possess that would contraindicate with MAOI.

I really don't like seeing analogues like that.


----------



## aced126

Tranylcypromine is a DRA. It would have to be a dopaminergic because has to enter dopaminergic neurons for its mechanism of action (inhibiting cytosolic MAO-b) to take place. Once in the neuron it needs to release DA from vesicles as well as reverse the function of DAT, which it does but only 10% as efficacious as amphetamine itself.


----------



## crmt28

I'm too lazy to draw the structure, but is there any reason we've never seen any benzodiazepines with iodine atoms? 

The only thing close is iomazenil, but that's a Flumazenil (antagonist!) analogue with an iodine atom instead of fluorine.


----------



## Dresden




----------



## Solipsis

Funny hybrid of methamp and arylcyclohexylamines.. 
Looking at beta-methylamphetamine putting more on the beta may just really weaken it to the point of nothingness or even do strange things for blood pressure?
As a dissociative... it's not an n-methyl aspartic acid analogue but if anything a step in the direction of glutamic acid? Glutamate agonists could be neurotoxic so thatd be awkward, but its missing a lot of similarity for that. Also then I'd expect the diphenidines to be risky as well in that sense, plus many more compounds.
Nothing to do with that spacer really, but put a 2'-oxo on there while you're at it? :D overlap with glutamate would be extra funny

@iodo benzo's:

Should work as electron withdrawing groups on the 7- and 2' position increase potency, and 2'-iodo diazepam has 9x affinity of diazepam - even higher than of flumazenil.
I've had a highly 7 / 2'-position electronegative diazepam analogue I cannot name and it was active in the 100 µg range but also seemed to precipitate withdrawal symptoms a little, making me suspect it's a mixed agonist/antagonist which is not atypical for high affinity ligands. When a drug binds very strongly, it doesn't continue to keep increasing net activation just like hugging someone is not always the more pleasant the longer they continue to hang on. For an antagonist there may not be activation at all, or even if there is for some drugs - the drug may occupy the site for so long that endogenous ligands would have caused more activation per saldo. Correct me if I'm wrong.

I don't know if the actual action of those super benzo's have been explored or if this tendency is understood by drug designers and psychopharmacologists... but it could be why 7,2'-diiodo benzos might be absolute monsters. Then again, there exist ultra potent agonists without having that mixed agonism/antagonism or plain antagonism.
Do they keep the receptor in an activated conformation? Are they just that 'good' ?


----------



## crmt28

*Triazolos*

Iobromazolam / Ionazolam / Diiodotriazolam














*2-Keto*

Iobromazepam / Ionazepam










*1-Methyl-2-Keto


*Diiodazepam / Iodiazepam


----------



## Nagelfar

This started as a phenyltropane, would you believe it? I sketched it at home freehand, turned what the aryl became into a replacement for the tropane base, and with what remained attempted to make it overlap (in 2D mind you, probably not in 3D) with a phenyltropane (in a back-formation of the original)






Comments would amuse me. Humor me.


----------



## aced126

Nagelfar said:


> This started as a phenyltropane, would you believe it? I sketched it at home freehand, turned what the aryl became into a replacement for the tropane base, and with what remained attempted to make it overlap (in 2D mind you, probably not in 3D) with a phenyltropane (in a back-formation of the original)
> 
> 
> 
> 
> 
> 
> Comments would amuse me. Humor me.



So many comments to make...so many

I will resist the urge.


----------



## DotChem

Dresden said:


>



Interesting molecule.


----------



## DotChem

Methylphenadil 






would make you very smart


----------



## DotChem

Nagelfar said:


> early never-marketed/discontinued anti-depressants with interesting skeletons:
> 
> Tranylcypromine
> 
> Carbenzide
> 
> Isocarboxazid
> 
> Iproniazid
> 
> Metfendrazine
> 
> Domoxin
> 
> Cimemoxin
> 
> 
> 
> 
> 
> 
> 
> 
> Humans are animals, taxonomic genus "Homo", I am as right/correct as the Elephant Man; but I'm not his clone (I hope, my mirror is the same as Shallow Hal's if not)




Hydrazides ( molecules containing -NH-NH-CO- group) were withdrawn from market because pretty much all the hydrazides and the hydrazines give you liver cirrhosis at low doses. like a drinker of a pint of scotch every day for 50 years!


----------



## Nagelfar

DotChem said:


> Hydrazides ( molecules containing -NH-NH-CO- group) were withdrawn from market because pretty much all the hydrazides and the hydrazines give you liver cirrhosis at low doses. like a drinker of a pint of scotch every day for 50 years!



How long with the indicating dosing did the hydrazides = the affect on the liver of a pint of scotch daily for a half-century? or is this a rhetorical summation of a comparison?



DotChem said:


> Methylphenadil
> 
> 
> 
> 
> 
> 
> would make you very smart



The ethyl is a "v.(ery)" and the sulfur means "smart". I think I've discovered a hidden truism, rhyme and reason, behind chemistry.



aced126 said:


> So many comments to make...so many
> 
> I will resist the urge.



That counts. Taken. (now, if someone can shoot some holes in it, I'll be indebted. I learn through my immense capacity for folly and blunders of large magnitude and the attention they draw. I read in Utah it is illegal to "cause a catastrophe", within the midst of the abstract professional field of academics: I'm glad I live in WA state.


----------



## roi




----------



## Solipsis

hehe

jimmy! stop making sufent propethidine analogues!

I wasnt mom! its just an mpa analogue!

[would generate less nor metabolite?]


----------



## roi

Should be at least 50x fentanyl.


----------



## DotChem

roi said:


>



Word of Caution: Reverse esters of pethidine (OCOEt instead of  -COOEt) easily (ie normal physiological conditions) give rise to  neurotoxic MPTP and MPP+  via elimination(of OCOEt)/oxidation of the methylpipiperidine... The RC  chemists back in the 80s who tried it found out the hard way: they ended  up "frozen" with permanent irreversible Parkinson!





MPPP



> The neurotoxicity of MPTP was hinted at in 1976 after Barry Kidston, a 23-year-old chemistry graduate student in Maryland,  US, synthesized MPPP with MPTP as a major impurity, and self-injected  the result. Within three days he began exhibiting symptoms of  Parkinson's disease. The National Institute of Mental Health found traces of MPTP and other pethidine analogs  in his lab. They tested the substances on rats, but due to rodents'  tolerance for this type of neurotoxin nothing was observed. Kidston's  Parkinsonism was treated with levodopa but he died 18 months later from a cocaine overdose. Upon autopsy, destruction of dopaminergic neurons in the substantia nigra was discovered.[6]
> 
> In 1982, six people in Santa Clara County, California, US, were diagnosed with Parkinsonism after having used MPPP contaminated with MPTP. The neurologist J. William Langston  in collaboration with NIH tracked down MPTP as the cause, and its  effects on primates were researched. The motor symptoms of two of the  seven patients were eventually successfully treated at Lund University Hospital in Sweden with neural grafts of fetal tissue.[7]
> Langston documented the case in his 1995 book _The Case of the Frozen Addicts_, which was later featured in two NOVA productions by PBS, re-aired on the UK on the BBC programme Horizon.[8]


 https://en.wikipedia.org/wiki/MPTP


more from wiki entry:



> Injection of MPTP causes rapid onset of Parkinsonism, hence users of MPPP contaminated with MPTP will develop these symptoms.
> MPTP itself is not toxic, and as a lipophilic compound can cross the blood–brain barrier. Once inside the brain, MPTP is metabolized into the toxic cation 1-methyl-4-phenylpyridinium (MPP+) by the enzyme MAO-B of glial cells. MPP+ kills primarily dopamine-producing neurons in a part of the brain called the pars compacta of the substantia nigra. MPP+ interferes with complex I of the electron transport chain, a component of mitochondrial metabolism, which leads to cell death and causes the buildup of free radicals, toxic molecules that contribute further to cell destruction.....etc


 https://en.wikipedia.org/wiki/MPTP


----------



## DotChem

Nagelfar said:


> How long with the indicating dosing did the hydrazides = the affect on the liver of a pint of scotch daily for a half-century? or is this a rhetorical summation of a comparison?


Enough to inhibit their target MAO because they're irreversible MAO inhibitor. If I recall even a single dose make small holes in the liver which of course the Pharma companies developing the drugs didn't tell anybody till they recoup the $$ they've invested (including class action laywers cut$$ too!





Nagelfar said:


> The ethyl is a "v.(ery)" and the sulfur means "smart". I think I've discovered a hidden truism, rhyme and reason, behind chemistry.


Not that the sulfur make smart .. but it looks (and i think will behave) like nootropic Modafinil (with the sulfoxide somehow off tho ..) AND methylphenidate (with methyl ester of MPH bioisosteric replacement by SOEt).... easy to synthesize (just need testers ala Shulgin!!


----------



## Solipsis

So piracetam hydrazide is very dangerous? Seems worth putting a warning in the nootropics thread?


----------



## roi

Both piracetam hydrazide and phenylpiracetam hydrazide have been sold for quite a while and there aren't any "harmful" reports on it afaik.


----------



## DotChem

Carbohydrazides like isoniazid are known to be hepatotoxic since 80s.  here is a ref and a proposed model of how they wreck havoc in the liver where they get metabolized by oxidases.  you can find lots of other refs.





"Direct Oxidation and Covalent Binding of Isoniazid to Rodent Liver and Human Hepatic Microsomes: Humans Are More Like Mice than Rats"
Uetrecht et al (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501148/)



> soniazid (INH) is associated with serious liver injury and autoimmunity. Classic studies in rats indicated that a reactive metabolite of acetylhydrazine is responsible for the covalent binding and toxicity of INH. Studies in rabbits suggested that hydrazine might be the toxic species. However, these models involved acute toxicity with high doses of INH, and INH-induced liver injury in humans has very different features than such animal models. In this study, we demonstrated that a reactive metabolite of INH itself can covalently bind in the liver of mice and also to human liver microsomes. Covalent binding also occurred in rats, but it was much less than that in mice. We were able to trap the reactive metabolite of INH with _N_-α-acetyl-l-lysine in incubations with human liver microsomes....blablabla




Later hydrazides (me-too drugs related to isoniazid, like the one cited by @nafelgar) were also found to be as bad or worse in humans and mice (but NOT RATS!!). Rats metabolize them differently.


Even though one cannot generalize to EVERY SINGLE HYDRAZIDE containing drug, chances are they can be expected to get metabolized similarly to isoniazid at least the one containing the Aryl-CO-NH-NH2 type..(good substrate for liver oxidase)


As for phenylpiracetam hydrazide I wouldn't be surprised if it too gives the same type of hepatotoxcity.  As far as one can tell, no formal study of users of this drug has been done (corretc me if I am wrong).  So one cannot exlude liver problem.  This kind of problem may not be as obvious as say problem with opiates (YOU DROP DEAD if something do wrong!) so it is hard to tell your liver is getting chewed by the drug.  Advanced clinical investigations such as liver biopsy to detect it will be needed or like alcohol cirrhosis only when it is too advanced that anything pain will be felt (by then its too late..you may need a new liver!). + if you're heavy drinker it will make it worse and complicated the picture further.


So I think until more is known on phenylpiracetam hydrazide and Liver issues, one must avoid at the very least chronic use of this molecule just to be cautious.  But it may be metabolized differently from isoniazid ..who knows?  


PS: that article title? (I personally believe humans are more like rats. I know lots of them! rats..


----------



## Bagseed

Nagelfar said:


> This started as a phenyltropane, would you believe it? I sketched it at home freehand, turned what the aryl became into a replacement for the tropane base, and with what remained attempted to make it overlap (in 2D mind you, probably not in 3D) with a phenyltropane (in a back-formation of the original)
> 
> 
> 
> 
> 
> 
> Comments would amuse me. Humor me.


lol


----------



## Dresden

3-Chloro


----------



## Dresden

3-Methyl-MXE


----------



## Dresden

A (potentially genius) hybrid of methamphetamine and Strattera.


----------



## adder

> When a drug binds very strongly, it doesn't continue to keep increasing net activation just like hugging someone is not always the more pleasant the longer they continue to hang on.



I understand that affinity is just a measure of at what concentration 50% of radioligand molecules are displaced by a ligand of interest from the receptor, so this has nothing to do with dissociation time from the receptor, right? I suppose both etorphine and buprenorphine fit well into your hugging analogy even though one is a full mu agonist and the other only a partial agonist, but they both have long dissociation times.


----------



## Solipsis

Yeah I think it will depend on whether it keeps a receptor in activated conformation while occupying?

I wasn't really trying to in a general sense define any singular pharmacology term but mentioned mixed agonists / agonist-antagonists, and was musing on those peculiar drugs that are very potent agonists but have slightly modified analogues that are potent antagonists. Not that I have an actual proof that the novel benzo I tried is an agonist-antagonist but it's certainly interesting how it is a very close analogue to known potent benzo agonists, and exhibited agonist-antagonist effects. Pretty consistently, but it remains my subjective experience.

Also I wouldn't think that affinity has nothing to do with dissociation time, because if there is more optimal binding energy (difference between intermediate state with bound/unbound state) doesn't that lead to longer dissociation time since that energy is not so easily overcome? It seems like that would mean that it would at least be one of the factors if not the only one in net displacement since even if one or the other ligand does bind 'better' than the other one, when the long-occupying one IS actually bound to it, during that time there is no competition possible.
I don't know that it's possible for the better binding one not to be the long occupying one by definition.
And I don't really know the time scales for binding of high affinity drugs, the period of time bound compared to the receptor being free (though I randomly heard numbers like 60 or 80% of receptor occupancy being possible with some drugs, not even being a limit?)... but unless dissociation time is actually insignificant in this perspective, it seems like it would come into picture?

edit:
Hopefully I am not taking anything out of context, but if the well versed mr serotonin2a says:



> Opioids that bind with high affinity (slow dissociation)


http://www.bluelight.org/vb/threads...-Acid-in-solution-with-Acetylfentanyl-Acetate

it seems my thinking is on the right track?


----------



## roi

Inspired by pregabalin


----------



## adder

@Solipsis

Your reasoning with binding energy sounds right. I later saw the comment by serotonin2a you're quoting and that made me thinking as well. 



> Also I wouldn't think that affinity has nothing to do with dissociation time, because if there is more optimal binding energy (difference between intermediate state with bound/unbound state) doesn't that lead to longer dissociation time since that energy is not so easily overcome? It seems like that would mean that it would at least be one of the factors if not the only one in net displacement since even if one or the other ligand does bind 'better' than the other one, when the long-occupying one IS actually bound to it, during that time there is no competition possible.



So now I'm wondering what makes fentanyl have a higher affinity than buprenorphine but at the same time dissociate much faster from mu receptors. I suppose you can explain everything in terms of energy, but affinity then can't be just the only thing affecting dissociation time, there must be a way for molecule A to bind with a higher energy but at the same time unbind more easily than molecule B which binds with somewhat lower energy and stays bound for longer, and that might be dictated by the nature of component interactions and conformation changes they cause, though I don't really know how it would work out with such big systems like receptors.


----------



## Solipsis

Reading up on it, I think that the reason for that is that it's not a first order process of ligand and receptor forming a complex in one reaction process, but an induced fit: the initial binding of the ligand to the receptor causes an isomerization, a change in the conformation that changes it into a usually higher affinity final complex, that causes the ligand to have an extended residency time (occupation).

In such cases affinity is not a simple = (1 / dissociation time), but becomes a multivariable of association time and dissociation time, which are functions of the energy of more than one state of the complexed or not receptor.

VVV  the induced fit causes the thermodynamics to shift, which would explain different energies and times for association and dissociation

I am not positive if the below example applies exactly in terms of how the shift occurs.


*NSFW*:


----------



## Bagseed

I was thinking about this recently. I have no clue about this though, any thoughts?


----------



## Nagelfar

^
RTI-(4229)-163/157 + 220c + ebati, _p_-azido,_m3′_-nitro,_m5′_-nitrile-phenyltropane



Solipsis said:


> In such cases affinity is not a simple = (1 / dissociation time), but becomes a multivariable of association time and dissociation time, which are functions of the energy of more than one state of the complexed or not receptor.



I've been wondering about the variable of entropy of binding kmol values recently in terms of how that effects abuse potential, _e.g._ between cocaine & methylphenidate. Is there no known predictor for such a thing besides direct observation comparing two ligands?


----------



## blueberries

Ok, I've got a bit of a mash-up here; 5-Fl-a,N,N-TMT






The base compound a,N,N-TMT is active at 80-120mg, 5-Fl-aMT is supposedly quite a powerful compound in itself, being an SNDRA and 5-HT2a agonist, plus 5-Fl-DMT has little effect on the base compound's psychoactive effects, so the addition of the dimethyl would have no effect upon the 5-Fl-aMT. Altogether it should be quite an impressive compound...if not for the MAOI properties of aMT. So you'd need to be careful but I was thinking that either a 5-Tri/Fluoromethyl or 5-Fluoro-methoxy group would serve to first off increase potency and secondly perhaps reduce the MAOI properties but the latter is a complete guess!


----------



## Nagelfar

Bagseed said:


> lol



This one I didn't even make up, puts mine to shame:






A methylphenidate cross between Adiphenine & Dicycloverine (possible inhibitor of nicotinic or muscarinic receptors + inhibitor of DAT?)


----------



## blueberries

I just thought of this too:






4-Acetylthio-DMT; I'm very doubtful it would work at all but it's an interesting thought nonetheless.


----------



## Midnight Sun

Pretty sure something just like this has been posted already a few pages back, but whatever...





As far as this thing goes, I was paging through aced's thread about DRI pharmacophores and I could've *sworn* I read once upon a time that esters were more critical to DAT binding than anything else... but now I can't find anything referencing that.  shit looks more like a weird reverse-o-matic take on meprobamate  I'm not even sure if that structure is permissible anyway


----------



## Bagseed

Nagelfar said:


> This one I didn't even make up, puts mine to shame:


the main problem with your compound is that sp2 hybridized carbon atoms have all their bonds lying in a plane. so you cannot have this nitrogen sticking over the ring plane being bonded to it.

ps: I'd really like some feedback on my molecule.. has this been tried before? I thought since beta-keto doesn't destroy activity, replacing the beta carbon with an ether might be something worthwhile...


----------



## aced126

I think the amine has to be in the plane of the phenyl ring for greatest efficacy at DAT. This is how it is in dopamine and in amphetamine (antiperiplanar conformation) but I don't know if this is the case with this molecule. There's a good chance it'll work well as a dopamine releaser though with a shorter half life (the ether is an alright metabolic handle).


----------



## Bagseed

I think the main difference between C-O-C and C-C-C is the bonding angle, the rest should be fairly similar (regarding configuration).

I also thought about metabolism: should give phenol (yuck) and 1-Aminoethanol, no?


----------



## pharmakos

seems like a pretty easy group for enzymatic attack in your body.  but idk enough to say for sure... anyone else?


----------



## Bagseed

yeah I am no good at pharmacology, that's why I posted it here


----------



## pharmakos

just judging based on my layman's feels, tho, any simple group like that aminoethanol group is going to be pretty easy for one of your body's enzymes to hit.  if it even needs to hit an enzyme before separating from the benzene... maybe just acidic conditions could do it?  idk.  still just *looks* fragile to me.  like it's barely holding on.  =p


----------



## Bagseed

:D

but to be fair, you find plenty of ether groups in very active compounds (methoxy groups), and they don't seem to fall apart very quickly.


----------



## pharmakos

true story.  i had half a thought typed up about that, i think the nitrogen makes a pretty big difference, but i typed half the thing calling aminoethanol an amino acid and only realized at the end that it isn't in fact a true amino acid, so i scrapped that whole train of thought.  =p


----------



## aced126

When considering metabolic products, it's good to take into account what the likely dosage of the compound will be. Given that the ether is active sub 100mg, the amount of phenol generated from metabolism shouldn't be enough to cause harmful effects like DNA alkylation etc.


----------



## aced126

Ethers are strong bonds. I didn't mean to say that the compound would be easy to metabolise when I said the ether could function as a metabolic handle. I meant to say that it gives the compound another possible place of metabolic attack, which in general is good for the safety of the drug as the liver can attack it in many ways. A straight carbon-carbon alkyl bond will not be metabolised at all (unless it's got electronegative substituents of course) but ethers can be metabolised slowly.

What is a weak bond is an ester bond, which is easily hydrolysed in water along with acid or alkali as a catalyst. This is why drugs like cocaine have a very low oral bioavailability.


----------



## blueberries

Sorry to interrupt but I had an idea based on Shulgin's statement that fluorine atoms are essentially "fake" hydrogens, so if that were true, would NFl2 be able to replace amine groups? I always saw them as "fake" methyls, so I'm quite skeptical, but imagine the difference in affect, and this could apply to /any/ compound, perhaps changing it significantly.

Also could you take a quick look at my above compounds; I'm really interested in that acetylthio bit and the aMT one..well, it could be beautiful!
Thanks!


----------



## Solipsis

No, fluorines are relatively quite small and in that sense (sterically) substitute for hydrogens somewhat. But assumed that the fluorine is on a carbon.

Electronically fluorine is very negatively charged (δ-). Bound to carbon which is a little positively charged (δ+) this forms a stable, balanced covalent bond. This δ is a partial charge, not like a full (+) or (-) electron charge that makes an ion.

But nitrogen is not δ+ its moderately δ- making N-F bonds not so stable. Especially -NF2 (not Fl) which would be that much harder to make (they don't want to be together like that  ), and is I expect a good fluorinating agent, using any possible chance to give that fluoro in a nucleophilic attack. If not oxidative or violent like noxious or explosive.
Donating fluoros is good for making teflon but not for a drug..

The acetylthio perhaps gets thioester transfered by enzymes giving the indolic thiol... probably very nasty and may be toxic. As 4-MeO tryptamines show an ether there isn't so great for creating powerful psychedelics so it's doubtful a 4-thioether tryptamine is. But anyway that wouldn't be so metabolically problematic which is why we do see the 2C-T-x series and IIRC 5-MeS-DMT (yes https://www.erowid.org/library/books_online/tihkal/tihkal46.shtml ).

5-F-a,N,N-TMT could be good, yea.. but I have never seen a,N-N-TMT itself and have no idea if it's worth giving up half the potency for little change in effect. But yeah if a,N,N-TMT is found to be very nice and worth the hassle over aMT by all means..   Please if you have the awesome power to 5-fluorinate shizzle start with the proven stuff like DMT, DPT etc and clarify if 5-F-psilocin is active.. :D



Nagelfar said:


> I've been wondering about the variable of entropy of binding kmol values recently in terms of how that effects abuse potential, _e.g._ between cocaine & methylphenidate. Is there no known predictor for such a thing besides direct observation comparing two ligands?



Docking software?


----------



## Dresden

It won't exist.


----------



## Dresden

Talking about the oxa-amphetamine


----------



## Dresden




----------



## aced126

I wouldn't really call them "fake hydrogens". Yes, they have a very small radius but that might be about it in terms of similarities. They are able to form weak hydrogen bonds due to their lone pairs, are more lipophilic than C-H bonds and they are also very electronegative. These properties have big results and consequences on molecules, both in terms of pharmacodynamics and pharmacokinetics. I'll give a few examples:

1) Trifluoroacetic acid has a sub-zero pKa (it is extremely acidic) compared to the acetic acid (which has a pKa of about 5) meaning TFA is about hundred thousand times more acidic than its non-fluorinated counterpart. This is because the fluorines are so electronegative that they are able to stabilise very well the carboxylate ion's negative charge. 

2) They can have big impacts on the drug's pharmacodynamic profile. Fluoroacetate can enter the Krebs cycle as acetate and halt the cycle at one of the stages because the one of the intermediate fluorine compounds can almost irreversibly bind to an enzyme (acotinase). Norfenfluramine has different pharmacology to amphetamine, and most notably is a 5HT2b agonist whereas amphetamine is not, only due to the 3-trifluoromethyl moiety. Similarly, 4-FA has a completely different mode of action to amphetamine resulting in empathogenic effects rather than just dopaminergic stimulation. Take a look at this excerpt from Traschsel's paper on fluorine in psychedelic phenethylamines: "For example,in contrast to the psychoactive escaline (70), it was observed that its fluoroescaline (76) counterpart was almost devoidof psychoactive effects. Difluoroescaline (77), on the other hand, retained, and trifluoroescaline (78) showed increased humanpotency of escaline (70). Difluoromescaline (72) and trifluoromescaline (73) increasingly surpassed human potency and durationof mescaline (22) effects."

3) The pharmacokinetic profile of drugs can be modified with fluorine. Most notably, substitution onto an aromatic ring will increase its half life due to the electron withdrawal of fluorine decreasing the ring's ability to act as a nucleophile and form epoxides. 

With this in mind, O-F bonds very reactive. Sekio mentioned this compound: https://en.wikipedia.org/wiki/Trifluoromethyl_hypofluorite. The only reason it is stable I would speculate is because the TFM group withdraws electron density from O-F, stabilising it. Other compounds which aren't so lucky are extremely reactive (e.g. https://en.wikipedia.org/wiki/Dioxygen_difluoride). That being said, I would say N-F bonds would have the same problem; there's too much electron density in too little space and they just wouldn't be stable.

After a brief thought about the aMT analogue, I would most likely be active reasonable dosages and could possibly be quite potent. I'm not that well versed in tryptamine SAR to comment anymore. As for the sulphur molecule, I just skimmed the wikipedia page on organosulphur compounds and I couldn't seem to find any amide equivalents (-S-(C=O)-C-). Sulphur is a soft nucleophile and normally the carbonyl carbon of an aldehyde or ketone is a hard electrophile, which will be attacked by hard nucleophiles (small, high charge density nucleophiles), so maybe that is why we don't have sulphur equivalents of amides.

2 molecules from me:


----------



## aced126

Dresden said:


> Talking about the oxa-amphetamine



Why?


----------



## Dresden

N-C-O's are unstable.

Imines are hydrolyzed by H2O (or saliva).  So yours will be turned into:


----------



## Dresden

Midnight Sun, one of your structures is alpha-PVP.  I did it and liked it.  Lately it has been showing up as meth on the streets.

This one was inspired by 5-MeO-DMT (obviously) and DOB:


----------



## Dresden




----------



## Dresden




----------



## Midnight Sun

Dresden said:


> Midnight Sun, one of your structures is alpha-PVP.  I did it and liked it.  Lately it has been showing up as meth on the streets.
> 
> This one was inspired by 5-MeO-DMT (obviously) and DOB:



Yeah I realize that, the other one next to it is plain ol' methylphenidate.  Bottom one is the novelty w/ ethyl ester and the carbon chain of a-pvp bound back to the nitrogen (while maintaining geometric positioning of the amide) -- decent enough exercise in messing around with the least common denominators of DRI pharmacophores

The shitty thing about pyrrolidines is how fast they lactamize into inactive metabolites


----------



## Dresden

Sorry, it can be hard to determine what page ppl are on here, as they come from all levels.


----------



## Bagseed

Dresden said:


> N-C-O's are unstable.


then how about a thioether instead?


----------



## DotChem

SSRI + SRA + NMDA antagonist:






Thiocyclidine (Thienocyclidine sounds better!) thio analog of MXE






SRA ala MTA:


----------



## roi

Derived from a series recently identified in China:


----------



## Midnight Sun

U-4 meets CB-13

can't ignore the resemblance of u-47700 to classical syncans any longer


----------



## roi




----------



## Solipsis

Midnight Sun said:


> U-4 meets CB-13
> 
> can't ignore the resemblance of u-47700 to classical syncans any longer



Or turns out to be sunifiram-esque?  surprise


----------



## Midnight Sun

Solipsis said:


> Or turns out to be sunifiram-esque?  surprise



well shit!

now I'm curious what just the ethylene bridge btwn the 2 nitrogens would do to u-47700 itself, anyone know if upjohn messed around with that in the patent?  Suppose I should look through it when I have the time


----------



## Nagelfar

Attempting a tropane-cyclized amphetamine. Amphetatropane?






If a charge is exchanged from one heteroatom to another (_e.g._ a nitro group) can two such changes exist without it being considered double-protonated or equally untenable?

For instance:






2-beta azido-di-nitro-amino-phenyltropane


----------



## Dresden

Nagelfar, 

Your many cocaine analogues tend to border on the monstrous, bizarre, and impossible.  Just saying, that's all.


----------



## Solipsis

Protonated means having a proton, H+
Doesn't seem relevant here? So it makes your question very 

A charge is not *really* exchanged in nitros, it's balanced over the oxygens. https://upload.wikimedia.org/wikipe.../Nitro-group-2D.png/1024px-Nitro-group-2D.png https://en.wikipedia.org/wiki/Formal_charge
They just want to stick to the octet rule, but for the heteroatoms in nitro groups there isn't a more optimal spread of electrons possible than the one in that img ^

Anyway dinitroamines exist but may be explosive, esp certain derivatives. The nitro groups much rather want to leave and jump ship as gases like nitrogen - which as gas is so much more voluminous that the sudden increase yields an explosion.

and yea in some cases where there's a bunch of electrons (in bonds or lone pairs, esp with formal charge) it's worth paying attention whether they can conjugate / find a balance to flipflop, domino in a molecule towards other groups. With nitro's even dinitroamines there isn't really a possibility of what they call intramolecular interaction (look it up).. i dont think so

The drawn structures are kinda like doodles yeah. I don't think drawing outrageous strings of atoms together and slowly learning why that is a faux pas is the way to learn org chem as others said.

If it floats your boat, cool... but don't fool yourself, pick up that org chem textbook if you wanna really get it better.


----------



## Dresden

Better yet, go to college and take years of chemistry and other science classes like the rest of us.


----------



## Solipsis

Well, you're definitely going to need to invent that new amazing coke analogue if you have student debts.


----------



## Bagseed

Nagelfar said:


> Attempting a tropane-cyclized amphetamine. Amphetatropane?


once again, you cannot have bonds like that sticking from an aromatic ring. maybe learn about orbital hybridization (in this case sp2 on the carbon)


----------



## DotChem

Bromadol








DotChemtanyl


----------



## Dresden

If I get into graduate school, I plan to start collecting some serious antibiotic royalties starting in around 12 to 15 years.  I would say that's a more likely scenario than my successfully completing the 8 year Ph.D program that comes along with it.  But first I have to somehow apply and be accepted to the program, which is at Emory University in Atlanta.

"I took too much NBOMe, now I'm at ICU at Emory!"--Rehab.


----------



## Dresden

Actually, Rehab said LSD, but I didn't want to be lectured on the low likelihood of an actual LSD overdose.


----------



## roi

U-47700 analogue that smells like basmati rice.


----------



## Nagelfar

Dresden said:


> Nagelfar,
> 
> Your many cocaine analogues tend to border on the monstrous, bizarre, and impossible.  Just saying, that's all.



I prefer to call them unconventionally interesting...



Dresden said:


> Better yet, go to college and take years of chemistry and other science classes like the rest of us.



Then they wouldn't be so unconventionally interesting. Circumventing errors can derive novel exceptions, it takes a village. (Besides, I like saying I'm self-taught, maybe another eight years and I can fool somebody)






Serious attempt:

RTI-430 + Tamagnan


----------



## pharmakos

Nagelfar, the guys were being a bit too harsh on you, but some of the concepts they've mentioned for you to look into get covered in like week three of freshman year of a chemistry degree.  Snort some coke and read about orbitals some weekend.


----------



## Midnight Sun

clomethiazole dimer (aka bastard child between clomethiazole & sulbutiamine)


----------



## Nagelfar

pharmakos said:


> Nagelfar, the guys were being a bit too harsh on you, but some of the concepts they've mentioned for you to look into get covered in like week three of freshman year of a chemistry degree.  Snort some coke and read about orbitals some weekend.



I'm always at the public library to get online, so any prevalent/common texts to suggest worth literally "checking-out" from the library would be appreciated.

...

Anyhow, these anti-emetic serotonin subtype receptor antagonists (5-HT3) are very close to cocaine analogues:
Zatosetron:




Bemesetron:




Ricasetron:




Granisetron:





So would the following in the same class of above, _i.e._ Ondansetron:





Be modified to be a MAT reuptake inhibitor / DARI? Could someone give me an attempt who can overlap it and, perhaps cocaine, troparil or methylphenidate, in 3D and give a 2D of one they think may float that function?


----------



## Bagseed

also peroxides in a drug? no thx


----------



## MrPorter

bruh http://www.masterorganicchemistry.com/getting-started/ is what i used to get ahead in school and now im actually studying chem and still using the site


----------



## aced126

Bagseed said:


> also peroxides in a drug? no thx



There exist a few drugs with peroxide FGs in them, artemisinin being quite a common one. But you're right, peroxides are generally not a great idea unless the drug is required in extremely low dosages.


----------



## Dresden

Sorry Nagelfar, I didn't mean to be overly harsh with you like that, but a lot of your sulfur creations in particular would simply never hold together.


----------



## pharmakos

Nagelfar said:


> I'm always at the public library to get online, so any prevalent/common texts to suggest worth literally "checking-out" from the library would be appreciated.



we're talking about introductory level chemistry textbooks here.  there's so many of them out there that it is hard to say which ones any individual library would have.  some of the chemistry stuff that you aren't aware of that people have suggested you look up, like say molecular orbital theory, was covered in my high school chemistry textbook.  there's just so many possible references for this stuff out there that no one is going to be able to give you a single name to grab.  just go to the reference material section and see what ya can find.


----------



## Dresden

Might this Leuckart intermediate be active in its own right?


----------



## Dresden

This one is intended to be a shorter acting methamphetamine fairly quickly metabolized into an inactive methylamino acid.


----------



## Dresden

Perhaps a shorter acting, less potent DOM (with 8 count 'em stereoisomers as shown).


----------



## neurotic

hey Nagelfar if you're serious about learning about this shit and don't wanna have to look for information scattered around everywhere on the internet (tiresome), i'd suggest you Khan Academy's organic chemistry course. it's pretty neat. if you want to go a little bit deeper / put some more effort on it too, then you can pick up an introductory book on organic chemistry such as Janice's one. you can find a PDF of it online. considering the amount of time you spend on this subject (drugs) i'd think it'd be a great thing for you to do, very rewarding: the more chapters you read, the deeper becomes your understanding and a lot of things you see start to make more and more sense. it's just so cool. it'll give you a more solid basis for your molecular ideas.

quick unrelated question: can benzoic acid crystals look like little tiny white needles?


----------



## MrPorter

^ Benzoic acid often crystallises to be colourless needles. As does very similar compounds - even aspirin can be fine colourless needles.

Dresden, they may be active but will be very rapidly metabolised and aldehydes are typically avoided because it's so reactive. In acidic conditions it's going to go one of two ways - Best case: disintegrate into CO2 and H2O, Worst case: The carbonyl carbon will be an easy site for nucleophiles.
The first has the fragile N-C-O moiety people were discussing earlier


----------



## Dresden

The first has the very stable R-(C=O)-NH-R' amide functional group which is found all over the place, most notably in proteins and peptides.  People were discussing aliphatic N-C-O's earlier.  I thought amides were so commonly known to be stable not to need mention in the earlier discussion.


----------



## Dresden

The other molecule is remedied easily enough by this:


----------



## aced126

Dresden said:


> The other molecule is remedied easily enough by this:



Amphetamine's logP is already low enough.


----------



## Dresden

Does that stop ephedrine?


----------



## aced126

Dresden said:


> Does that stop ephedrine?



It's probably one of the reasons why ephedrine is required in higher molar concentrations than amphetamine, and why it has so much peripheral action but really not that much central activity.


----------



## DotChem

Psychedelic Indoles alkaloids: Ibogaine: 


> Ibogaine is a psychedelic.[12]  The experience of Ibogaine is broken down in two phases, the visionary  phase and the introspection phase. The visionary phase has been  described as oneirogenic, referring to the dreamlike nature of its psychedelic  effects, and lasts for 4 to 6 hours. The second phase, the  introspection phase, is responsible for the psychotherapeutic effects.  It can allow people to conquer their fears and negative emotions.  Ibogaine catalyzes an altered state of consciousness  reminiscent of dreaming while fully conscious and aware so that  memories, life experiences, and issues of trauma can be processed.[13]













Design simpler : 






would that retain MUCH of ibogaine activity (5HT2a/2c and 5HT3 agonist, mu, kappa,  sigma opioid agonist, NMDA antagonsism and DAT inhibition among others?


----------



## DotChem

or even simpler still.  






pretty easy to synthesize (may be somebody did it already??


----------



## DotChem

disclaimer: wiki 


> As of 2009, ibogaine is unregulated in Canada[56][57] and Mexico.[5]
> 
> 
> As of 2015 in the United Kingdom, ibogaine is not listed under the  Misuse of Drugs Act and so is legal to possess, however distribution is  illegal.[58][59]
> 
> 
> Ibogaine is schedule I in Sweden.[60]
> 
> 
> *Ibogaine is classified as a Schedule I-controlled substance in the United States**,**[*61]  and is not approved there for addiction treatment (or any other  therapeutic use) because of its hallucinogenic, neurotoxic, and  cardiovascular side effects, as well as the scarcity of safety and  efficacy data in human subjects.[62]
> 
> 
> Ibogaine is illegal in Norway (as are all tryptamine derivatives).[63]
> 
> 
> Ibogaine is unregulated in Germany, but for medical use it can be regulated by the pharmacy rules (AMG).
> 
> 
> Ibogaine was gazetted in New Zealand in 2009 as a non-approved prescription medicine.[64]
> 
> 
> On January 14, 2016, Ibogaine was legalized for prescription use in  São Paulo, Brazil, with this legalization to extend to the rest of the  country in a few months.[14]
> 
> 
> In most other countries it remains unregulated and unlicensed.[65][66]


----------



## Incunabula

I always wondered why there weren't any more ibogaine analogues. It's a very interesting area. I know some analogues have been developed, but they were made with a focus on the anti-addictive potential of ibogaine, and not the psychedelic.

Edit:
This one would be interesting to sample. If it was possible to synthesize, that is.


----------



## roi

> If it was possible to synthesize, that is.



Should be quite easy using phosphorus pentasulfide.


----------



## Bagseed

some people here always say that N-C-O in a molecule tends to be unstable. I cannot seem to find the reason why, will sombody enlighten me?


----------



## Incunabula

Oops, I just realised that I put an oxygen instead of nitrogen in the indole (5-MeO-DIBF style). It wasn't a mistake, just drew it a while ago, and missed that it was two ideas in one. Not that either idea was very original.



roi said:


> Should be quite easy using phosphorus pentasulfide.


Okay  cool.


----------



## Solipsis

Bagseed said:


> some people here always say that N-C-O in a molecule tends to be unstable. I cannot seem to find the reason why, will sombody enlighten me?



That REALLY depends on the context..   N-C-O can exist in pretty different ways in a molecule, it's present in a peptide bond which is way stable and makes up proteins by linking amino acids. If it's terminal, as in an R-N-C-O (R being rest, X would often be halogen), then there are a few kinds depending on whether there are double or triple bonds and where. Then they are cyanates and isocyanates.

I think iirc what made someone or some people say something like that is when you e.g. have cyclic or polycyclic molecules and there is an N-C-O present but in particular in a R-C(NR'2)(OR")-R''' pattern called a hemiaminal ether.






Like acetals, those are 'unstable' in that they exist not only in ring formation but also a ring-opened 'chain' formation. Carbohydrates (sugars) do that, too: they flop open and closed very fast and those states are in an equilibrium.

In the case of hemiaminals it's worse cause under a lot of conditions it collapses to the imine.


----------



## aced126

DotChem said:


> Psychedelic Indoles alkaloids: Ibogaine:
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> Design simpler :
> 
> 
> 
> 
> 
> 
> would that retain MUCH of ibogaine activity (5HT2a/2c and 5HT3 agonist, mu, kappa,  sigma opioid agonist, NMDA antagonsism and DAT inhibition among others?



I would say not really. The thing separating ibogaine from say 5-Meo-DMT is of course the cyclic system and unconstraining the molecule as you have done results in the cyclohexane taken much out of its original plane. I'd say this would effect binding affinities of its many targets to an appreciable degree.


----------



## aced126

roi said:


> Should be quite easy using phosphorus pentasulfide.



It would be very hard due to integrating the benzofuran system into the molecule. You would probably have to do it this way, but of course replace the indole with the benzofuran:

https://www.youtube.com/watch?v=QcHxjckH0DE


----------



## aced126

Bagseed said:


> some people here always say that N-C-O in a molecule tends to be unstable. I cannot seem to find the reason why, will sombody enlighten me?



A non-amide N-C-O is unstable for the same reason that acetals are unstable, as said above. The 2 substituents on the carbon pull electron density from it and make it susceptible to nucleophilic attack by even weak nucleophiles like water. The only way they would be stable is if they are cyclic (entropic stability) or if the carbon is sterically protected from nucleophiles.


----------



## Dresden

This one is probably shiite, based on my experience with 3-MeO-MA.


----------



## Dresden

Not even sure if this one is isolabe.


----------



## Dresden

MTXE


----------



## Pomzazed

Dresden said:


> Not even sure if this one is isolabe.



This; also, can be easily obtainable by P4S10 and the corresponding ketone
if solubility of the sulfide is a problem there is also a better (and more expensive) choice of Lawesson's Reagent
by just _---snip: no synthesis discussion  ---_

That looks very much isolatable and I predict it to have an intense "color"; (of conjugated-aromatic thioketone)



			
				Solipsis said:
			
		

> etc


That's what I try to explain when people design a molecule with that Hemiaminal or Aminal in them, thanks for re-emphasizing that.


----------



## Dresden




----------



## Dresden

I have a feeling this would make a wicked good stimulant.


----------



## Dresden

Nicotine X Methamphetamine, part deux:  The Pyridinyl Rendition.


----------



## roi

beta-hydroxy-2'-fluoro-3-methyldifuranylfentanyl.


----------



## Dresden

Ritalindole


----------



## Dresden

Possibly innovative.


----------



## roi

Reverse ester, I like it!

I think this one is definitely active as well:


----------



## Solipsis

roi said:


> Reverse ester, I like it!
> 
> I think this one is definitely active as well:



That is the (even by shulgin) suspected psilocin hydrolysis product, via (acid but better base catalyzed) oxidation and loss of 1 and 4 position H's.

It is also believed or even observed to be reduced back by vitamin C (blue-black discoloration of this compound or complexes formed betray its presence rather obviously it seems).
This and other sensitive tryptamines are widely seen crapping, in the case of 4-acetoxy esters the acetoxy is also found winding up at the 1-position, I think in the process of oxidation of the tryptamine and partial reversal of that process but with the acetoxy ending up on the other end.

Considering people have consumed moderately crapped tryptamine solutions and found pretty much no loss in activity, the above compound is either active itself or upon achieving the same equilibrium with psilocin under physiological conditions as when consuming psilocin itself there is possibly just little difference in the end result. Would be interesting to see if parenteral ROAs lack activity circumventing GI conditions.
However it may be subject to _further_ degradation, which in that case should be expected to lead to products losing activity... eventually. From pseudocrap to actual crap.


----------



## Bagseed

okay, if the problem is similar to acetal hydrolysis, maybe a ring constrained version of some sort might work? the methylenedioxy group in MDMA et cetera is an acetal as well so maybe something like this yould work. more "oxo-amphetamines": 










ps: can anybody recommend me a good freeware molecule builder. the one I use kind of sucks.


----------



## Dresden




----------



## Dresden

opsin.ch.cam.ac.uk


----------



## Dresden

Thought this might be legal in China.


----------



## Dresden

This too.


----------



## Solipsis

Pomzazed said:


> This; also, can be easily obtainable by P4S10 and the corresponding ketone
> if solubility of the sulfide is a problem there is also a better (and more expensive) choice of Lawesson's Reagent
> by just _---snip: no synthesis discussion  ---_
> 
> That looks very much isolatable and I predict it to have an intense "color"; (of conjugated-aromatic thioketone)
> 
> 
> That's what I try to explain when people design a molecule with that Hemiaminal or Aminal in them, thanks for re-emphasizing that.



Hemiaminals would be a pretty bad plan since they are not so stable, but aminals like acetals should be kinda stable though. They'd be sensitive to acids, but when eaten I guess some of the aminal/acetal will hydrolyse to "hemi's" BUT of course this is different from starting out with a hemi drug, cause there is an intramolecular equilibrium reaction.
Worse though is that CYP P450 enzymes metabolize methylenedioxies to catechols which fortunately get O-methylated by transferases otherwise it would be Neurotoxicity eh City. I think your drug then better be quite active so that the metabolism can be afforded. I believe only a fraction of the already tiny standard doses of LSD make it to the body and it still rules, so it goes to show it can all be fair game. But it just seems like a bad plan to start out with aminals and acetals if you are just designing drugs and have other options, stacking the odds against you. *That's* the point imo. MDMA was not designed intentionally with the methylenedioxy at all - in fact it was some iirc agraric industrial compound that was sort of rediscovered as a drug.

Toxicologically speaking, if you are going to design instable linkages - the more unstable it is the more you better account for the other formations of your compound - as part of degradation under certain conditions, so that's on top of metabolic problems.

@ other post: I thought ethcathinone was pretty bad

Also bagseed... tolazoline analogue?

Hey @ that 5-sub tryptamine... I wonder, is 5-AcO-DMT a thing, thought of / tried or a possibility I mean?

edit:



> DR. GESSNER: We do have some preliminary data which make us
> believe that the reason bufotenine is not found to be active is because it
> simply does not get into the brain. If you put an O-acetyl group on it, it gets
> into the brain, and then it's hydrolyzed back to bufotenine. It's quite active.



Sounds like it, from the guy who wrote 2 articles on it..


----------



## Dresden

Yeah, ethcathinone was bad,


----------



## Dresden

But not as bad as buphedrone.


----------



## aced126

Bagseed said:


> okay, if the problem is similar to acetal hydrolysis, maybe a ring constrained version of some sort might work? the methylenedioxy group in MDMA et cetera is an acetal as well so maybe something like this yould work. more "oxo-amphetamines":
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> ps: can anybody recommend me a good freeware molecule builder. the one I use kind of sucks.



The benzodioxole system is unlike normal acetals. It is much more stable. Benzodioxole is completely planar, suggesting that aromaticity is involved which contributes to its stability. It doesn't hydrolyse to catechol and formaldehyde.


----------



## Solipsis

aced126 said:


> The benzodioxole system is unlike normal acetals. It is much more stable. Benzodioxole is completely planar, suggesting that aromaticity is involved which contributes to its stability. It doesn't hydrolyse to catechol and formaldehyde.



Really..? 
Read page 258 though:
https://books.google.nl/books?id=RU...age&q=acetal stability methylenedioxy&f=false

Maybe I missed something


----------



## Bagseed

well the carbon between the two oxygenes is sp3 hybridized. so how can it be part of an aromatic system?


----------



## Solipsis

Oh, that is true for the oxygens as well... it's not 'just flat', it's nearly a tetraeder if you consider the lone pairs instead of the hydrogens of the methylene. I say nearly cause the bond angles are probably a little off. But yeah the polycyclic structure itself without its subs is planar but I'm not sure that it has to do with anything here.


----------



## aced126

Solipsis said:


> Really..?
> Read page 258 though:
> https://books.google.nl/books?id=RU...age&q=acetal stability methylenedioxy&f=false
> 
> Maybe I missed something



There was a thread I posted a while ago which discusses this in depth.

http://bluelight.org/vb/threads/773845-Storage-of-acetals-(eg-MDA)-in-water


----------



## aced126

Bagseed said:


> well the carbon between the two oxygenes is sp3 hybridized. so how can it be part of an aromatic system?



I guess it isn't formally aromatic, but there does seem to be some delocalisation of oxygen lone pairs that makes it planar. 

There's this study which at first theoretically calculates that the puckered conformation is stable: http://pubs.acs.org/doi/abs/10.1021/jp994354s?journalCode=jpcafh

Then this later study experimentally shows that that the planar conformation is a lower energy conformation than the puckered one: http://www.sciencedirect.com/science/article/pii/S0009261410003830


----------



## Solipsis

aced126 said:


> There was a thread I posted a while ago which discusses this in depth.
> 
> http://bluelight.org/vb/threads/773845-Storage-of-acetals-(eg-MDA)-in-water



Even if the aromatic ring of benzodioxoles contributes to more stability due to delocalized electrons, that doesn't actually show how well benzodioxoles hold up in an acid. MDX compounds are probably too short a time in the stomach for it to be a serious matter, and it seems from that other reference that its cytochrome enzymes anyway that metabolize the methylenedioxy if the acetal wasn't hemi'd already.

MDX compounds may hold up a bit better in plain water, but I think acetals do fine already. So not quite sure if someone is saying that benzodioxoles are as an exception incredibly stable and we shouldn't consider them in the acetal discussion but that doesn't seem to be true. Or perhaps relatively speaking it is - according to what aced said, or adder somewhere.

Either way, if you must paste potentially unstable moieties in your designed drug, at least be sensible and reinforce it with pi bonds around it.

It seems the would-be amph analogues drawn earlier could be stable 'enough' given the same advantages, again as long as it's active enough to afford loss from our acidic stomachs and bodily enzymes.


----------



## aced126

Solipsis said:


> Even if the aromatic ring of benzodioxoles contributes to more stability due to delocalized electrons, that doesn't actually show how well benzodioxoles hold up in an acid. MDX compounds are probably too short a time in the stomach for it to be a serious matter, and it seems from that other reference that its cytochrome enzymes anyway that metabolize the methylenedioxy if the acetal wasn't hemi'd already.
> 
> MDX compounds may hold up a bit better in plain water, but I think acetals do fine already. So not quite sure if someone is saying that benzodioxoles are as an exception incredibly stable and we shouldn't consider them in the acetal discussion but that doesn't seem to be true. Or perhaps relatively speaking it is - according to what aced said, or adder somewhere.
> 
> Either way, if you must paste potentially unstable moieties in your designed drug, at least be sensible and reinforce it with pi bonds around it.
> 
> It seems the would-be amph analogues drawn earlier could be stable 'enough' given the same advantages, again as long as it's active enough to afford loss from our acidic stomachs and bodily enzymes.



The extended aromaticity over the whole system means the methylene carbon is less electropositive than it normally would be in a normal acetal, and so it is less susceptible to attack by water. Furthermore, if the oxygen lone pairs are involved in aromaticity, they are less likely to get protonated by the acid and so the whole hydrolysis slows down. 

You probably would be able to hydrolyse it, but you'd need much harsher conditions than your usual acetal hydrolysis.


----------



## Dresden

Adding an amine to a CP synthetic cannabinoid.


----------



## Dresden




----------



## Dresden




----------



## Dresden




----------



## Dresden




----------



## Pomzazed

Dresden said:


>




Heh funnily i posted this one and their related family like 2-3 years ago while there wasnt much spice-stuffs in rc scene.
(Not posted here in bluelight)


----------



## roi

MA prodrug, similar to Mefenorex


----------



## Solipsis

roi said:


> MA prodrug, similar to Mefenorex



Not quite similar as a N-Cl is not the same as chloroalkyl on the N... this one ^ yields hypochlorous acid i.e. bleach, which oxidizes many biocompounds including DNA and the like. Question is perhaps if it is in appreciable quantities but it's not desirable per say..
May react with water in the air to make at least trace amount of meth which is then a legal drug detection hazard?

What about N-fluoromethylamp though? (Rhodium seems to have supported the idea)


----------



## DotChem

Known and (commercially available) compound:
Phenyl (1-piperidinocyclohexyl) ketone but no bioactivity data!

any data source on this?


----------



## Nagelfar




----------



## AlphaMethylPhenyl

Nagelfar said:


> Interesting. The cyclopropane on it. Wonder what modification'd be needed to make a dopaminergic instead of an MAOI



This isn't including biochem but oh well: What scant literature I've come across on it seems to suggest that it does have some DRA activity. There's that unsourced "fact" on wikipedia about it being 1/5 as potent as dexamp, but yeah there's no source for that...

Can someone explain to me how it's also useful for psychotic depression yet it's such a stimulating compound? Seems like one of many psychiatric inconsistencies.

Also it probably is obvious but it should be useful for ADHD too, considering MAOI-B activity in terms of direct cognition enhancement and MAOI-A activity to deal with impaired cognition as a result of depression.

It really doesn't make sense to continue the war against MAOIs.


----------



## Dresden

Neither does it make much sense to continue the war against chlorinated amphetamines such as SHIVA:


----------



## neurotic

hey Dresden where did you get that your username from? you don't look like you're German...


----------



## Dresden

I took a semester of German in college and liked it.  I also have a thing for German engineered cars.  And I'm a big fan of the trance duo, "Gabriel and Dresden."  And I read the chapter in pihkal by the same name which described the German city as being one of he most beautiful in Europe until it and its innocent civilians were brutally firebombed by the US; thus the name was meant to critique the atrocity that is modern warfare.  Finally, Dresden is the German equivalent of my real first name,  Andrew.  Both are derived from the Greek, andros, meaning man or strong.  Hope that helps.


----------



## pharmakos

you ever read _Slaughterhouse Five_, the novel by Kurt Vonnegut Jr. that uses the fire bombing of Dresden as a central event/location?

partially based on Vonnegut's real-life experience being a POW during the fire bombings.  but it gets away from being autobiographical pretty quickly when they start travelling through time and space and whatnot.  =p


----------



## Nagelfar




----------



## Dresden

pharmakos,

I bought that book once, but I never read it.


----------



## Dresden

ICE (IndolylCyclohexylEthylamine)


----------



## Dresden

ICP (IndolylCyclohexylPiperidine)

ICP also stands for inductively coupled plasma and insane clown posse.


----------



## Dresden

ICE also obviously stands for recrystallized:






Or frozen water.  Can everybody tell I'm on an indole kick?


----------



## Dresden

iso-AMT


----------



## roi

Fentanyl/Moramide hybrid thingy


----------



## Solipsis

psy daydreams


----------



## Raihiar

roi said:


> Inspired by pregabalin



I think this hasn't gotten the attention it needs.

In my experience PGA needed an awfully long time to start working (in the 2hr. ballpark). Additionally i remember that GHB-Blood-levels do rise faster when consuming GBL instead of GHB (gets absorbed better and the ring-opening takes place very fast in the body.

So is it legitimate to assume the cyclised Pregabalin would be absorbed faster than the open version?
and can i even extend that theory to cylclised Gabapentin?


----------



## Solipsis

Raihiar said:


> I think this hasn't gotten the attention it needs.
> 
> In my experience PGA needed an awfully long time to start working (in the 2hr. ballpark). Additionally i remember that GHB-Blood-levels do rise faster when consuming GBL instead of GHB (gets absorbed better and the ring-opening takes place very fast in the body.
> 
> So is it legitimate to assume the cyclised Pregabalin would be absorbed faster than the open version?
> and can i even extend that theory to cylclised Gabapentin?



Not necessarily: gabapentinoids are tricky bastards to get absorbed well, because they rely on amino acid transporters. Cyclized versions are not candidates for that I think, but OTOH you lose some polarity so it might be absorbed by more 'typical' ways.

Also I think that the correct condensed version would be the gamma lactam:






Cyclizing gabapentin would yield the beautiful spiro:











_2-azaspiro[4.5]decan-3-one_

_(4S)-4-(2-methylpropyl)pyrrolidin-2-one_

Anyway if lactams are metabolized in plasma as readily as lactones (within minutes even), the absorption is a non-issue anyway since it would be very effective pro-drugs i.e. having near parent drug properties.


----------



## Soulfake




----------



## adder

Solipsis said:


> psy daydreams



A while ago I had an idea based on 4,5-MDO-DMT. 4,5-MDO-DiPT entry in TiHKAL has a very laconic description of effects, but somehow encouraging, 4,5-MDO-DMT should be active as well with the right ROA, so why not try these & various analogues with different alkyl substituents on the amine:






According to this article 4,5-MDO-DMT is presumably quite similar in potency to 5-MeO-DMT and 4,5-MDO-DiPT is substantially more potent than 4,5-MDO-DMT, so perhaps we're also dealing with qualitative change in effects vs. regular N,N-dialkyltryptamines.


----------



## Solipsis

Cool  This whole thread started with the epic wild spotted methylenedioxy fandom..

I briefly considered the above substitutions, but 4-MeO trypt doesn't really bode well for it? But who knows, borrowing from ramelteon is possibly a big mistake since MT receptors are a completely different target, I don't actually know what the tolerance is for 6 and 7 pos substitutions for trypt when you make a structure increasingly PEA-like, and I've got big questions about the 5-HT2a pharmacophore anyway, and the different approaches of trypts and PEAs...:

In my above post I tried keeping the lysergic structure / perspective imaginable.. In LSD and tryptamines a tertiary amine is pretty much essential for major activity (I say major cause obviously there are exceptions that are not inactive), but with the PEA approach suddenly that same amine must be primary?? Making it secondary doesn't do the psy activity good at all, is suggested by the data.

Is there a way trypts are shoved into the receptor considerably deeper or more shallow compared to PEAs changing the pharmacophore SAR rules? Or would we see some interesting things when some PEA amines are made tertiary and *some* trypt amines are made primary? (! AMT) - Could be a matter of weakness to MAO then, but if so what makes 2C PEAs active?

Not sure how much of this territory I am asking about is known, but for 'hybridized' structures to be fancied, insight into the matter must be resolved?


----------



## crmt28

"Extended" arylcylcohexylamines, remind me of Ephenidine:













After seeing the 3rd molecule, it itched me to close that ring, resembles MK-801. Plus silly bonus molecule.










A few more, but also changing the position of the amine:


----------



## belligerent drunk

aced126 said:


> The extended aromaticity over the whole system means the methylene carbon is less electropositive than it normally would be in a normal acetal, and so it is less susceptible to attack by water. Furthermore, if the oxygen lone pairs are involved in aromaticity, they are less likely to get protonated by the acid and so the whole hydrolysis slows down.
> 
> You probably would be able to hydrolyse it, but you'd need much harsher conditions than your usual acetal hydrolysis.



I would say the methylene has a bigger partial positive charge in 1,3-benzodioxole, because the electron density of the C-O bond is shifted towards the aromatic ring (the same way phenolic O-H is weaker and H is more positively charged as opposed to aliphatic alcohols). However, acetal hydrolysis in acidic conditions proceeds by protonation of one of the oxygens, not by a nucleophilic attack on the carbon by water. And as you said, the oxygens are less basic because their lone pairs are delocalized into the ring, making it less susceptible to hydrolysis. If acetals were hydrolyzed by nucleophilic attack of water, then acidity would actually hinder their hydrolysis (H3O+ is a very poor nucleophile).


----------



## Solipsis

Benzylcyclohexylamines would be nice 

Good overlay with NMDA as well yeah.. 

The bottom two compounds look more like something in the direction of pipradrols or https://en.wikipedia.org/wiki/Beta-Phenylmethamphetamine or other beta-subbed stimulating drugs that really rev your blood pressure.

Gonna compare DXM with the rest ;p

Wondering about this:






_2-[2-(3-hydroxyphenyl)-1-(propan-2-ylamino)ethyl]cyclohexanone_


----------



## aced126

Wouldn't the concentration of H3O+ be negligible compared to the concentration of H2O if H2O is the solvent. But yeah, the oxygens being protonated is definitely required to make it into a reasonable leaving group.


----------



## belligerent drunk

Well yeah, of course in mild acidic conditions it would be negligible, but in principle it would decrease, albeit insignificantly.


----------



## DotChem

Wonder if this compound has any LSD-like activity? 





Sumanirole

a D2 selective agonist (D2 agonists make rats(and humans!) incredibly horny!, is that right?




> *Sumanirole* (*PNU-95,666*) is a highly selective D2 receptor full agonist, the first of its kind to be discovered.[1][2][3] It was developed for the treatment of Parkinson's disease and restless leg syndrome. While it has never been approved for medical use [4][5]  it is a highly valuable tool compound for basic research to identify  neurobiological mechanisms that are based on a dopamine D2-linked (vs.  D1, D3, D4, and D5-linked) mechanism of action. [3]


----------



## DotChem

Ketamine:







Bromadol:







merge and melt (metabolites des-phenethyl ) DAT + OP + NMDA

Ketamadol (2P-K): Buddha Haus


----------



## roi




----------



## chatsnap

Don't have a chemdraw app I can upload from but have MDMA analogues with a C-C double bond ever been considered? [h=2] [(1Z)-1-(2H-1,3-benzodioxol-5-yl)prop-1-en-2-yl](methyl)amine and  [(1E)-1-(2H-1,3-benzodioxol-5-yl)prop-1-en-2-yl](methyl)amine would be the two isomers. Would the double bond be too easily substituted?[/h]


----------



## Solipsis

@Chatsnap: this stuff happens I believe: https://en.wikipedia.org/wiki/Enamine
ketimine (lol) tautomerization then perhaps hydrolyzation in the stomach?



Is it known what this does?:






Or any non N-cyclic dialkyl ACH?


----------



## roi

@chatsnap: You can paste the IUPACs into http://opsin.ch.cam.ac.uk/.






@Solipsis: yes, low potency prodrug, see https://en.wikipedia.org/wiki/Dieticyclidine. Maybe that's similar for diarylethylamines as well, meaning lefetamine is mainly a prodrug for mephenidine? Who knows.


----------



## Dresden

That's not a stable molecule.


----------



## belligerent drunk

Why not? The double bond is conjugated with the ring.


----------



## Dresden

The double bond will naturally migrate to the adjacent N and form an imine (R-N=R').  Imines break apart when touched by H2O.  Saliva and gastric juices are wet.


----------



## Dresden

You'll end up with methylamine and 3,4-methylenedioxyphenyl-2-propanone, neither of which is gone get you high.


----------



## Dresden

We've covered this before.


----------



## belligerent drunk

Dresden said:


> The double bond will naturally migrate to the adjacent N and form an imine (R-N=R').  Imines break apart when touched by H2O.  Saliva and gastric juices are wet.



Not necessarily. As I said, the double bond is conjugated with the aromatic system, which gives the enamine tautomer stability. Analogous to how in aniline the enamine is the more stable form as opposed to the imine. However, that doesn't necessarily give it stability against water, that is true.


----------



## Solipsis

Isn't the aromatic system already stabilizing the methylenedioxy ring?

Plus finally as you say: even if the equilibrium is a bit more favorable to the enamine, doesn't it become irrelevant when the ketimine hydrolysis is a much less reversible reaction of another order of magnitude?

Even if the details are not agreed on, it seems it's agreed this is not a fruitful direction.


----------



## belligerent drunk

Solipsis said:


> Isn't the aromatic system already stabilizing the methylenedioxy ring?



That doesn't mean the double bond cannot be stabilized as well, that's not how it works. On the contrary, the bigger the conjugated system, the more stable it is generally.



Solipsis said:


> Plus finally as you say: even if the equilibrium is a bit more favorable  to the enamine, doesn't it become irrelevant when the ketimine  hydrolysis is a much less reversible reaction of another order of  magnitude?



Yes, that is what I meant by it still probably not being very stable in water. Even if the enamine is the favored form, it may still be in a significant enough equilibrium with the imine, which would in turn be hydrolyzed. However, without empirical data I cannot really say whether it would render the compound useless or not. I mean, benzos have imine moieties too, which can be prone to hydrolysis, yet they're stable enough_ in vivo_, are they not?


----------



## Solipsis

oh yeah, thought for a moment it was electron withdrawing..

@benzo

http://www.auburn.edu/~deruija/GABA_ Benzodiazepines2002.pdf

page 7

Poor solubility precludes degradation? , otherwise I cannot explain why benzo's retain activity orally if the stomach is very acidic and hydrolytic reactions render it inactive irreversibly.


----------



## perpetualdawn

Are there any psychoactive drugs that have lithium substituted in where a hydrogen or some other group would normally be? I'm imagining something like 2C-Lithium. Is this even possible?


----------



## aced126

perpetualdawn said:


> Are there any psychoactive drugs that have lithium substituted in where a hydrogen or some other group would normally be? I'm imagining something like 2C-Lithium. Is this even possible?



No, because you'll end up with an incredibly reactive molecule which will alkylate ... many things in the body.


----------



## Bagseed

yeah organometallics, and especially R-Li is not a good idea in a drug molecule


----------



## belligerent drunk

Solipsis said:


> oh yeah, thought for a moment it was electron withdrawing..
> 
> @benzo
> 
> http://www.auburn.edu/~deruija/GABA_ Benzodiazepines2002.pdf
> 
> page 7
> 
> Poor solubility precludes degradation? , otherwise I cannot explain why benzo's retain activity orally if the stomach is very acidic and hydrolytic reactions render it inactive irreversibly.



Actually, I've been thinking about it and I would probably explain benzo's stability by the fact that the imine is cyclic and actually the hydrolytic reaction is not irreversible (the molecule stays intact and the reactants don't diffuse away from each other). So, considering that intramolecular reactions typically occur very rapidly, because molecules like that change conformations very rapidly and the amino moiety has a lot more chance of "hitting" the carbonyl. As opposed to it being a reaction between two separate molecules by way of diffusion. Well, that's just my thoughts. Then again, the amine would probably be protonated quite strongly, even at blood pH, which renders it quite a useless nucleophile.

Anyway, sorry for off-topic posts.



Bagseed said:


> yeah organometallics, and especially R-Li is not a good idea in a drug molecule



Unless you like to live life on the edge ;-)


----------



## Bagseed

well maybe alkylating your DNA bases gets you high???!!


----------



## pharmakos

high on mutated chromosomes mmmm


----------



## Bagseed

yo pharmakos, with dat cisplatin in your body you should be able to give some anecdotal evidence!

(I hope you are doing well regarding the circumstances...  )


----------



## pharmakos

I'm worth slightly more on the black market!


----------



## roi

Less talk, more structures!

Aminotetralin inspired structural isomer of MDPHP.


----------



## roi




----------



## roi

Methiolone


----------



## roi

Should be similar as methadone


----------



## roi

Probably somewhere between MDA and PAL-287


----------



## Dresden

But the Gods are immediately perceptible to each other, as quickly as like is to like, and so too had M. de Charlus been to Jupien.


----------



## roi




----------



## Bagseed

^ decarboxylation in vivo is the goal I assume?


----------



## sekio

hydroxyflunitrazepam water soluble prodrug aka "super roofies"

drug companies in india take note


----------



## Bagseed

lol :D


----------



## blueberries

roi said:


> Should be similar as methadone



I have a /lot/ of these drawn up! The patterning in the open chains is beautiful. What got me even more excited was Piritramide; it's (almost) pethidine jammed onto where your pyrollidine ring is. I had a chance to try it last year actually, lovely compound.


----------



## blueberries

This is probably a rookie mistake but something got to me this morning; Shulgin missed out one of the TMAs. It's this one:






Is there any reason why he missed it out or does the a-methyl flip round to make TMA-3 or something?


----------



## blueberries

sekio said:


> hydroxyflunitrazepam water soluble prodrug aka "super roofies"
> 
> drug companies in india take note



Heh! I had a similar idea: Nitrifluorazolam






I love the water soluble touch though, you could take a page out of Rilmazafone's book there. Something like this:


----------



## blueberries

Final one, I swear. So...I started out by trying to make a lefetamine analogue but with oxymorphone attached to one of the phenyls, then I got a bit carried away and made a sort of "cube" (I can't remember the word for a six sided 3D structure, it's not even that anyway) from it's arch. I'm 99% sure it will never work but what about the possibility of creating 3D structures over morphine aside from the original arch? 







Ooh and quickly; is there any possibility of a dioxycyclobutyl (not really butyl anymore though!) ring instead of an MDO on amp? Eg:


----------



## aced126

blueberries said:


> Final one, I swear. So...I started out by trying to make a lefetamine analogue but with oxymorphone attached to one of the phenyls, then I got a bit carried away and made a sort of "cube" (I can't remember the word for a six sided 3D structure, it's not even that anyway) from it's arch. I'm 99% sure it will never work but what about the possibility of creating 3D structures over morphine aside from the original arch?
> 
> 
> 
> 
> 
> 
> 
> Ooh and quickly; is there any possibility of a dioxycyclobutyl (not really butyl anymore though!) ring instead of an MDO on amp? Eg:



Artemisinin is the only drug I know with a peroxide bridge. In your particular case, there would be too much strain as well. See how in benzocyclobutene, the square isn't really a square, it is more a trapezium, because the phenyl bonds are trying to project from an angle of 120 degrees. I guess the same issue would happen here, but only with a much more reactive moiety. https://en.wikipedia.org/wiki/Benzocyclobutene#/media/File:Benzocyclobutene-3D-balls.png


----------



## Incunabula

blueberries said:


> This is probably a rookie mistake but something got to me this morning; Shulgin missed out one of the TMAs. It's this one:
> 
> 
> 
> 
> 
> 
> Is there any reason why he missed it out or does the a-methyl flip round to make TMA-3 or something?



That _is_ TMA-3


----------



## blueberries

Yeah, I figured soon after!! There's definitely something interesting there though, I was reading the Isomescaline entry earlier. Fascinating. I wonder what could activate them both? I mean it's said that DMT is present in schizophrenic patients' urine, so perhaps it's something there; maybe sigma in spades! Then again there's probably a lot more going on than just DMT so it's anyone's guess. Also what's even more interesting is the difference in potency between MMDA and MMDA-3a. If we're following the 2,3,4 rule, shouldn't MMDA-3a be inactive instead of 4-5x the potency? The difference seems to be TAAR1 agonism, so perhaps the key to treating schizophrenia is with TAAR1 antagonists? So; https://en.wikipedia.org/wiki/EPPTB

Sorry I was kind of thinking aloud there!


----------



## Nagelfar

aced126 said:


> Artemisinin is the only drug I know with a peroxide bridge.



Resiniferatoxin too, but it's more of a, *ahem*, toxin than drug. But as per Paracelsus, it's the dose that differentiates.

The above I mentioned with a nitrogen bonding it a bit round-about:


----------



## Dresden

roi said:


> Methiolone



I've never seen a 1,3-dithiaindan group anywhere, and I've seen (and memorized) many organic chemical structures in my day.  I also remember Rhodium saying the same thing, years and years ago at The Hive.  The magic eight ball signs thus point to the impossibility of that molecule in this case, unless you can come up with a workable synthesis or extant counter example.






1,3-DITHIAINDAN (using the often very convenient replacement nomenclature that opsin also accepts)

To use replacement nomenclature, simply use oxa plus the correct locant number to insert an O in a molecule, thia for S, and aza for N.  For example, 1,3-benzodioxole aka 1,2-methylenedioxybenzene becomes 1,3-dioxaindan.






1,3-DIOXAINDAN


----------



## Dresden




----------



## Dresden

The above molecule is the amphetamine version of histamine, basically.  There's really no telling what it might do such as release large amounts of histamine possibly or act as a longer-acting histamine.  It could possibly be quite unpleasant or toxic to some unknown degree and may be devoid of psychoactivity to boot.  Sasha Shulgin dedicated a page or two to it in the back of TiHKAL IIRC and mentioned that its existence and pharmacological action were publicly unknown at the time of the publication of that book.  Who knows?  It may possess some yet as unknown patentable medical application, but that scenario seems unlikely at the this point as surely at least one multinational pharmaceutical company has investigated its action as of now, 2016, at least in house.  Furthermore, I think anyone who tries to have an underground chemist make and test it will likely fail in that endeavor.  Underground chemists tend to like to focus on such tried and true, crowd pleasing, high profit margin classics such as 






2-METHYLAMINO-1-PHENYLPROPANE






1-(1,3-BENZODIOXOLE-5-YL)-2-METHYLAMINOPROPANE

&






N,N-DIETHYL-LYSERGAMIDE

While those inclinded to botany, supply us with the equally important






DELTA-9-THC

&






PSILOCYBIN

&






DIMETHYLTRYPTAMINE

This last little gem can, of course, be made synthetically but is a lot more easily extracted from Mimosa Hostilis root bark.

I posted all these classic drugs to emphasize that this late in the drug discovery game, all the very best psychoactive drugs have most assuredly already been discovered, and we should content ourselves with bringing them back into widespread circulation, rather than continue the research chemical fiasco--which did, nevertheless, help uncover a last few diamonds in the rough such as 






MXE






MEPHEDRONE

&






alpha-PVP

These last three research chemicals are more than good enough to make it on the street drug black market IMO.


----------



## DotChem

Indozolam


----------



## Nagelfar

The best 'amylocaine/stovaine + dimethylaminopivalophenone' I think I've done yet. V. straightforward.


----------



## Dresden

Never seen a plain ol' N-S sigma aliphatic bond before like that, but hey, maybe that's just me?


----------



## Dresden

N,N-diethyl-1-pentyl-4-oxo-lysergamide

Note that the above molecule has the 1-pentyl indole and carbonyl indole-3-yl moieties necessary to conceivably function as a JWH cannabinoid.  Of course, the 4-oxo group means that this molecule would have to be synthesized from scratch, which would be difficult though not impossible without going into its gritty, verboten on bluelight synthesis details.  I have personally always noticed a visceral similarity between tje highs of LSD and cannabis.


----------



## Draven26

^^ The good stuff!


----------



## Draven26

Well.. Methamphetamine being the good stuff hahaha one of my favorite stimulants of all time! To me personally.. very clean.. you get shit done on the stuff and it makes you feel invincible! Granted it's a very disgusting drug because of all the shit it's made out of.. but damn it feels good!


----------



## Draven26

Going on 5 years of sobriety.. but the damn mind.. sometimes it still can't stop thinking about it from time to time! But I pray that I stay sober for the rest of my life.. I'm proud of my sobriety and I don't want to fuck that up!


----------



## Draven26

^^ Another one of my ole time favorites back in the day! Some good trips taken!


----------



## roi

...you don't understand this thread.


----------



## Draven26

roi said:


> ...you don't understand this thread.



Then elaborate!


----------



## Bagseed

this thread is for chemicals not existing yet conceived by the posters...


----------



## Doc Aliquot

The idiot who first synthesized fenfluramine should have been given an epidural at C-2. A.H. Robins killed god-only-knows chubby housewives with that shit. I wrote a lot of script for it.


----------



## Bagseed

shaggyfin is back! http://www.bluelight.org/vb/threads...tchen-s-Spice-Cabinet?p=13570845#post13570845 :D


----------



## DotChem

What exactly makes a compound selective dopamine reuptake/releaser or selective serotonin-dopamine reuptake/releaser _devoid_  of any norepinephrine activity? It is extremelly difficult to separate  DAT and NET activity as the two transporters have virtually identical  susbsttrate requirements. More difficult still is separating NET from  DAT activities while retaning SERT activity intact.  They are only 2  known compounds that are selective SDRI. 
RTI-83




Ki values DAT(15nM) SERT(7.1nM) and NET(28,000nM).

and
UWA-101








> Its chemical structure is very similar to that of the illegal drug MDMA, the only difference being the replacement of the α-methyl group with an α-cyclopropyl  group...



My question is: those 2 molecules look so  dissimilar it is hard to see what make them selective for DAT and SERT  as opposed to NET. Is there a common motif I can't put my finger on that  kills binding at NET transporter? second question: afaik there is no  erowid experience reports on selective SDRI those, especailly the MDMA  analog UWA-101 that is apparently now availaible in NZ/australia?  correct me if I am wrong.

Comparison of SDRIs to SNDRIs https://en.wikipedia.org/wiki/Serotonin-dopamine_reuptake_inhibitor



> Relative to serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs), which also inhibit the reuptake of norepinephrine in addition to serotonin and dopamine, SDRIs might be expected to have a reduced incidence of certain side effects, namely insomnia, appetite loss, anxiety, and heart rate and blood pressure changes.[1]..blablabla


----------



## aced126

DotChem said:


> What exactly makes a compound selective dopamine reuptake/releaser or selective serotonin-dopamine reuptake/releaser _devoid_  of any norepinephrine activity? It is extremelly difficult to separate  DAT and NET activity as the two transporters have virtually identical  susbsttrate requirements. More difficult still is separating NET from  DAT activities while retaning SERT activity intact.  They are only 2  known compounds that are selective SDRI.
> RTI-83
> 
> 
> 
> 
> Ki values DAT(15nM) SERT(7.1nM) and NET(28,000nM).
> 
> and
> UWA-101
> 
> 
> 
> 
> 
> 
> 
> 
> My question is: those 2 molecules look so  dissimilar it is hard to see what make them selective for DAT and SERT  as opposed to NET. Is there a common motif I can't put my finger on that  kills binding at NET transporter? second question: afaik there is no  erowid experience reports on selective SDRI those, especailly the MDMA  analog UWA-101 that is apparently now availaible in NZ/australia?  correct me if I am wrong.
> 
> Comparison of SDRIs to SNDRIs https://en.wikipedia.org/wiki/Serotonin-dopamine_reuptake_inhibitor



I think it's not really fair to try seek comparisons between the 2 molecules as the first is a reuptake inhibitor and the second is a releaser. I know on Wikipedia it says it's a reuptake inhibitor but I doubt this claim. Butylone has clear acute empathogenic qualities and we all know that serotonin reuptake inhibitors cannot induce this.


----------



## Nagelfar

DotChem said:


> RTI-83
> 
> 
> 
> 
> Ki values DAT(15nM) SERT(7.1nM) and NET(28,000nM).



Those aren't RTI-83s values, those are:






RTI-304s values. RTI-83s are:

(Ki)
55 nM @ DAT
28.4 nM @ SERT
4,030 nM @ NET

As for your question, it seems, if you look at the difference between DA & NE, that the ethyl or cis-propenyl (and in the amphetamine skeleton, the alpha methyl lengthened to a cyclopropane) somehow leaves the hydroxy group that alters NEs binding free to pry itself into the transporter that are otherwise blocked when it comes to DA or 5-HT; of course, that's an obvious non-explanation explanation, but such is QSAR.


----------



## DotChem

aced126 said:


> I know on Wikipedia it says it's a reuptake inhibitor but I doubt this claim...


It  seems counter-intuitive but actually IT IS a reuptake inhibitor unlike  MDMA. It reverses inward-pre-pulse synaptic current in fashion similar  to Cocaine and not AMP-like releasers such as methylone which basically  dump dopamine in synaptic cleft without reversing the current.  The SAR (at that  alfa-position) is that the more substituents you put there beyond a  methyl the more cocaine-like reuptake inhibitors you end up with. This  is true for both AMP-like and methylone-like(bk-AMPs. 

So you got  from Methylone(---->ethylone--->butylone---.pyrovalerone from  (releaser ----> reuptake inhibitor). or from AMP ----> Prolintane  which is more cocaine-like DRI and less AMP-like). Here is a thorough  review on this question by the upmost expert on the field Pr Rick  Glennon : (a gold mine to design new and improved Cocaine-like):



> “Deconstruction”  of the Abused Synthetic Cathinone Methylenedioxypyrovalerone (MDPV) and  an Examination of Effects at the Human Dopamine Transporter ACS Chem Neurosci. 2013 Dec 18; 4(12): 1524–1529.




The  data on UWA-101 reported by the references on the wiki entry refer to  Reuptake Inhibition. Granted, we dont know whether the UWA series are  also releaser as the authors didin't mention it in their abstracts but  one thing is certain: their pharmacology is dramatically different from  MDMA and very much closer to cocaine. Which bring back my question: Do  they have anything in common(structurally, electronically...etc) with  the tropanes like the RTI-83? Or may be they bind to the transporter similarly (same site and triggering same conformational change of the transporter leading to current reversal.. who knows?





Nagelfar said:


> Those aren't RTI-83s values, those are:
> 
> 
> 
> 
> 
> 
> RTI-304s values. RTI-83s are:
> 
> (Ki)
> 55 nM @ DAT
> 28.4 nM @ SERT
> 4,030 nM @ NET
> 
> As for your question, it seems, if you look at the difference between DA  & NE, that the ethyl or cis-propenyl (and in the amphetamine  skeleton, the alpha methyl lengthened to a cyclopropane) somehow leaves  the hydroxy group that alters NEs binding free to pry itself into the  transporter that are otherwise blocked when it comes to DA or 5-HT; of  course, that's an obvious non-explanation explanation, but such is  QSAR.


Thanks @nag for pointing that out. The Ki data refer to the  4propenylphenyl tropane instead of the 4ethylbenzene dervative.  It is  even more intriguing now considering the rgidity put by the propenyl.   if you consider the DAT and NET, (any) substitutenst that kill NET  activity wil also kill DAT binding but obviously this is not the case!


----------



## roi

I wish UWA-001 was available =/






The diarylethylamines on the market so far only substituted the other phenyl ring. I wonder if it's still a dissocoiative. Or a stim. Or whatever.


----------



## Incunabula

What a fascinating molecule.


----------



## adder

roi said:


> I wish UWA-001 was available =/
> 
> 
> 
> 
> 
> 
> The diarylethylamines on the market so far only substituted the other phenyl ring. I wonder if it's still a dissocoiative. Or a stim. Or whatever.



Well, if one looks into this article, one might wonder if it would be possible to derive some new psychedelic phenethylamines with alpha-aryl substituents, perhaps it would even be therapeutic. If UWA-001 has 10x increased affinity to 5-HT2A vs. MDMA, then what would N-desmethyl-UWA-001 do vs. MDA and what would 2,5-dimethoxy & mescaline derivatives of that derivative do? There's no guarantee that they would be psychedelics, but they may be. Moreover, if an alpha-phenyl group increases affinity to 5-HT2A receptors 10x & alpha-isopropyl and alpha-cyclopropyl decrease it 5x and ~2x (also let's keep it mind how the effects change from DOM to alpha-ethyl-2C-D), that means the phenyl group must bind to something, perhaps one could play with it by putting EDG or EWG groups onto the ring to get some interesting stuff.


----------



## roi




----------



## pharmakos

so looking at potential modifications of UWA-001, here's one of the first obvious ones i suppose?






can't imagine that no one has ever made it before

and yeah then like adder said, start sticking various groups on that bare phenyl ring to see what happens.


----------



## roi

2,5-dimethoxy-4-bromo would be even more obvious, given its theoretically much higher potency than 3,4,5-trimethoxy and likely easier synth (also I love 2C-B).

If that works, 4,N-dimethyl + beta-ketone. Pyrophenidone (4-methyl, N-pyrrolidine, beta-ketone) was briefly sold and got mixed reviews...I don't know I loved it. 25mg vaped -> insane euproria for 25-35 minutes.


----------



## clubcard

When I look at 5HT2a ligands, I overlay them with LSD. Note how DMT & AMT are both buried in the structure.


----------



## TheBlackPirate

clubcard said:


> When I look at 5HT2a ligands, I overlay them with LSD. Note how DMT & AMT are both buried in the structure.



5HT1A is also influential and worth thinking about. Actually LSD binds most strongly with 5HT1A. LSD is a super agonist at the 5HT1A site.


----------



## DotChem

roi said:


> If that works, 4,N-dimethyl + beta-ketone. Pyrophenidone (4-methyl, N-pyrrolidine, beta-ketone) was briefly sold and got mixed reviews...I don't know I loved it. 25mg vaped -> insane euproria for 25-35 minutes.



Any reasons as to why pyrophenidone effects last only half hour so. If  anything one would expect it to last longer than alfa-PVP(4-8hours). Since only difference is the phenyl replacing the propyl group of PVP.  More metabolically stable


----------



## roi

a-PVP definitely doesn't last 4-8 hours vaped, hah. Not sure where you're getting that from.


----------



## Midnight Sun

DotChem said:


> Any reasons as to why pyrophenidone effects last only half hour so. If  anything one would expect it to last longer than alfa-PVP(4-8hours). Since only difference is the phenyl replacing the propyl group of PVP.  More metabolically stable



With all of the pyrrolidine stimulants the main enemy is rapid lactamization of the pyrrolidine ring...

***

linking 2 images because they're huge, but:

http://imgur.com/a/bpn7l

discounting potential metabolic nasties for the moment, would it be possible to use powerfully electronegative N-substituents in an attempt to get a ligand to conform in a certain manner?  (see images, MET vs N-methyl-N-trifluoroethyltryptamine) - in this case I believe the nitrogen still has some kind of positive charge and I was _hoping_ to maybe use CF3 to make the "antlers" bend a certain way...


----------



## adder

clubcard said:


> When I look at 5HT2a ligands, I overlay them with LSD. Note how DMT & AMT are both buried in the structure.



Yes, they are, but that doesn't mean all psychedelic phenethylamines or tryptamines have to be share key structural elements with LSD. N-benzyl-2C-X's can be overlaid with LSD too in theory if the o-anisyl can substitute for the amide, but it appears they bind differently. Obviously not all 5-HT2A agonists are psychedelics though, nor-UWA-001 may not be, but it'd still be a nice find if it was a mellow therapeutic empathogen.



> 2,5-dimethoxy-4-bromo would be even more obvious, given its theoretically much higher potency than 3,4,5-trimethoxy and likely easier synth (also I love 2C-B).



Provided that the 2,5-dimethoxy pattern would work with alpha-phenyl, it might be that alpha-phenyl is the missing part for the 3,4,5-trimethoxy pattern to show its full capacity if it boosts affinity vs. alpha-methyl for 3,4-methylenedioxy. :D I'd start with the primary amine analogue of UWA-001 and see how it works out, at least it seems logical to compare nor-UWA-001 with MDA having UWA-001 already compared to MDMA in the article.



> discounting potential metabolic nasties for the moment, would it be possible to use powerfully electronegative N-substituents in an attempt to get a ligand to conform in a certain manner? (see images, MET vs N-methyl-N-trifluoroethyltryptamine) - in this case I believe the nitrogen still has some kind of positive charge and I was hoping to maybe use CF3 to make the "antlers" bend a certain way...



Having a strongly electron-withdrawing group that close to the amine you make the amine less basic (less able to donate its lone pair), thus likely to bind less strongly with its target residue.


----------



## roi

Furanylpsilocin


----------



## aced126

DotChem said:


> Any reasons as to why pyrophenidone effects last only half hour so. If  anything one would expect it to last longer than alfa-PVP(4-8hours). Since only difference is the phenyl replacing the propyl group of PVP.  More metabolically stable



Pyrophenidone is extremely lipophilic and deposits itself in fat tissues, is one explanation given previously. Lactamisation is probably another good one.


----------



## Dresden

I doubt pyrophenidone could be all that more lipophilic than alpha-pyrrolidinylvalerophenone based on the fact that there is only a single CH3's difference between the two molecules as anyone can see here below by comparing their molecular structures:






alpha-PVP






pyrophenidone

I would imagine pyrophenidone would, like alpha-PVP, still have no problem getting you high were you to ingest some within the confines of its therapeutic dosage range, but I don't know that for a fact.


----------



## Midnight Sun

Dresden said:


> I doubt pyrophenidone could be all that more lipophilic than alpha-pyrrolidinylvalerophenone based on the fact that there is only a single CH3's difference between the two molecules as anyone can see here below by comparing their molecular structures:
> 
> 
> 
> 
> 
> 
> alpha-PVP
> 
> 
> 
> 
> 
> 
> pyrophenidone
> 
> I would imagine pyrophenidone would, like alpha-PVP, still have no problem getting you high were you to ingest some within the confines of its therapeutic dosage range, but I don't know that for a fact.



That's pyrovalerone bruh

pyrophenidone is a-phenyl (so very lipophilic actually)

Kinda strange that it doesn't [apparently?] really affect half-life (if only by virtue of a long drawn out crash) -- see the long H/L beta-phenyl stims... of course those are different animals, yes, but the relation is there nontheless



> Having a strongly electron-withdrawing group that close to the amine you  make the amine less basic (less able to donate its lone pair), thus  likely to bind less strongly with its target residue.



mmm... do we know how much legwork the ethanamine does vs indolamine in terms of how tryptamines bind? 

really just morbid curiosity at this point


----------



## belligerent drunk

adder said:


> Having a strongly electron-withdrawing group that close to the amine you make the amine less basic (less able to donate its lone pair), thus likely to bind less strongly with its target residue.



But then again, the population of that less basic substance wouldn't be protonated as much. Would that help, what do you think?


----------



## adder

> But then again, the population of that less basic substance wouldn't be protonated as much. Would that help, what do you think?



The interaction of the amine with aminoacid residues with negatively charged side-chain (aspartic or glutamic acid) is based on proton transfer (the amine must be protonated first to interact with the residue), so lower basicity can't be any good, also higher lipophilicity doesn't mean more compound getting to the brain, it will be deposited to fat tissues, no advantage here. One example of a compound with a less basic amine than the parent compound and less activity is beta,beta-difluoro-p-chloroamphetamine, it's pKa is 6.8 while p-CA have a pKa of 9.3, so you can see that the amine is strongly deactivated by those two fluorine atoms. As a result beta,beta-difluoro-p-CA needed five times the dose of p-CA to reach similar levels in the brain, but they are not maintained as it's metabolized much faster (source). In the case of the tryptamine analogue we're discussing there are three fluorine atoms located on the beta position to the amine nitrogen atom, so one can expect a solid decrease in basicity here as well.


----------



## DotChem

aced126 said:


> Pyrophenidone is extremely lipophilic and  deposits itself in fat tissues, is one explanation given previously.  Lactamisation is probably another good one.



That makes sense. It is a bit too lipophilic but then again so is THC. But yeah  much of the dose will just sit in fat tissues and release slowly  overtime. Which will give it longer t1/2 but less rush. imho First-pass metabolism via Lactamization may be bigger issue.  It is hard to replace a pyrolidine though as playing around with it "kill"  DAT activity (see original paper of SAR of pyrovalerones here).





> 1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) analogs. A promising class of monoamine uptake inhibitors









MDPP (methylenedioxy pyrophenidone LogP:3.35 vs LogP of PVP 3.88.  More reasonable LogP!
But probably not a stim (if UWA-001 is any indication: it has ZERO DAT affinity) maybe a Disso similar to diphenidine..who knows?



may be the bk analog of UWA-001 (mephedrone homolog)


----------



## Nagelfar

DotChem said:


> What exactly makes a compound selective dopamine reuptake/releaser or selective serotonin-dopamine reuptake/releaser _devoid_  of any norepinephrine activity? It is extremelly difficult to separate  DAT and NET activity as the two transporters have virtually identical  susbsttrate requirements. More difficult still is separating NET from  DAT activities while retaning SERT activity intact.  They are only 2  known compounds that are selective SDRI.




As about the SDRIs and phenyltropanes, check out this paper by Kuhar et al. and you'll see that there are many better SDRIs without NET affinity than RTI-83. (_e.g._ Those are not the "only two", far from it) This paper, unlike Singh's (pg. 9), says that RTI-304 is not infact 28,000 for displacement of NET but only 2,799. (which would make it not the, by far & wide, most selective SDRI known. *However* I've noted several typographical errors, esp. in the 2D structure of the PT compounds given; _i.e._ RTI-111 and RTI-112 are both given as di-chloro with just different conjugate salts, when in-fact the latter is para-chloro, meta-methyl according to other sources. And RTI compounds don't seem to have given any shorthand specific names to variants due only to salt form alone.


----------



## roi

3'-HO-2'-HO-Ephenidine - I think it would be a bit opioid-ish.






I also have a good feeling about


----------



## abaddamn

roi said:


> Furanylpsilocin


Looks like a triptan. 



Here are a few coke variants. The first one seems a bit silly and may not even work lol.






Ethyl ester of Salycycl ecgonine. Methyl ester said to be 10x stronger than coke.





Ethyl ester of 4-fluro cocaine.


----------



## DotChem

Nagelfar said:


> As about the SDRIs and phenyltropanes, check out this paper by Kuhar et al. and you'll see that there are many better SDRIs without NET affinity than RTI-83. (_e.g._ Those are not the "only two", far from it) This paper, unlike Singh's (pg. 9), says that RTI-304 is not infact 28,000 for displacement of NET but only 2,799. (which would make it not the, by far & wide, most selective SDRI known. *However* I've noted several typographical errors, esp. in the 2D structure of the PT compounds given; _i.e._ RTI-111 and RTI-112 are both given as di-chloro with just different conjugate salts, when in-fact the latter is para-chloro, meta-methyl according to other sources. And RTI compounds don't seem to have given any shorthand specific names to variants due only to salt form alone.



@nag:right. there are lots of tropanes with some selectivity for DAT SERT and no NET. I lump them all together in saying only 2 compounds . should've said: 2 "class" of compounds: the aryl trapanes and the UWAs. Now, imho the absolute Ki values matter less than the relative values. These are the ones that gives a better idea of the binding profile of a given compound and its psychoactivity. The relative values as defined by a selectivity index (ie Ki(DAT)/Ki(SERT) or Ki(DAT/NET)....etc) is what matters most IMHO.  So a binding constant of UWA-101 of 28000nM or 4000nM is not really the point. 4000uM gives a SI(DAT/NET) of ~ 50xtimes.  Pretty huge. The interesting thing is that is very rare("all" DAT inhibitors also inhibit NET ..the opposite is not true.) The chllenge is how to get selective DAT/SERT inhibitors ie with a selectivity index as high as possible. yea, thse are not the only compounds. I shouldve said class aryltropanes and Methylenedioxymethamphetamine anlogs.

For ex cocaine is a pretty shitty reuptake inhibitor(Ki for DAT SERT and NET in uM range.. pretty high!). But it binds and inhibits the reuptake of all 3 NTs with similar potency which gives it its unique profile and the psychoactivity it has; albeit all things being equal (PK MOA...etc). The question is how do you design Selective Dopamine Serotonin Reuptake Inhibitor? Selective DRIs are relatively abundant (eg amfonelic acid or 3C-PEP piperazine) not so for SDRIs













 I am medicinal chemist drug designer by training so my interest in asking that question is really about a compound structural features that makes it a SDRI or NDRI or selective DRI for that matter!


----------



## Nagelfar

DotChem said:


> @nag:right. there are lots of tropanes with some selectivity for DAT SERT and no NET. I lump them all together in saying only 2 compounds . should've said: 2 "class" of compounds: the aryl trapanes and the UWAs.



I noticed another source giving the smaller spread for RTI-304, though it's another RTI patent: it is Singh's paper (possibly it alone?) that gives the extremely high NET/DAT ratio of 1,867× for RTI-304

Other RTI patents (on google) for instance similarly give "2,799" and not "28,000". So perhaps this was a singular error with Singh's publishing, either that, or a pervasive RTI copy-error.

Other sources lump ones like RTI-298 as SDRIs and it's NET/DAT is only 93× (and SERT affinity is ten times lower than DAT even, so part way in-between), so I suppose as you say the ~50× against NET with DAT and moderate low numbers for SERT makes one a relative SDRI.


----------



## pr0d1gy

I found a publication regarding 5-thienyl and 5-furanyl analogs of benzos. Interestingly some of these analogs are active. 5(2')-thienyls and 5(3')-furanyls both had IC50s low enough to be considered active. They were also found to have anticonvulsant effects. I'm in the process of acquiring the 5(2')-thienyl analog of diazepam. Its IC50 is reported to be about equal to bromazepam. Another cool note, in the case of these compounds alkylation of the free amine didn't seem to make a huge difference. As expected n-methyl was more potent, but less so than the case of diazepam/nordiazepam.

Any comments on the implications of these compounds?


----------



## DotChem

Nagelfar said:


> I noticed another source giving the smaller spread for RTI-304, though it's another RTI patent: it is Singh's paper (possibly it alone?) that gives the extremely high NET/DAT ratio of 1,867× for RTI-304
> 
> Other RTI patents (on google) for instance similarly give "2,799" and not "28,000". So perhaps this was a singular error with Singh's publishing, either that, or a pervasive RTI copy-error.



You're right. It might be a typo. The IC50 of RT-304 reported by Singh is too high The one reported in the patent you cited and in this paper here is the correct value. Keep in mind though Singh's paper is just a review paper with "thousands" of Ki IC50 and EC50s of hundred of compounds. So an error is bound to slip up once in while.  The most reliable is the one reported in the reference Singh cited . The correct value should be 2,800nM (2,799..) instead of 28,000nM.  Maybe you should edit the wiki entry when you have time.


----------



## MDMQ

1P-ETH-LAZ






3-HO-TCE






BOTFM-DragonFLY


----------



## Midnight Sun

Would acetylating both terminal hydroxyls on GHB help or hurt its already shit poor BA%?


----------



## psychonauticus

*New substance structures*

Hello everybody! A friend of mine, draw a few structures for possible new substances. What do you think, do they have any sense?
Thanks for any feedback.


----------



## roi

See the random structure thread in the stickied post section.


----------



## psychonauticus

Oh, thanks. I didn't see it. 
Could I please mr. moderator, to move it this http://www.bluelight.org/vb/threads/582708-I-like-to-draw-pictures-of-random-molecules thread? Thank you


----------



## roi

TNTA


----------



## Dresden

I've thought of that one before except that I let the carbon in the amine side chain count as its methyl group.


----------



## Dresden




----------



## Dresden

Note the similarity.


----------



## Dresden

See also.


----------



## Nagelfar

RTI-143 (NET/DAT selectivity ratio of 9,919, _over nine-thouuuuusand!_) @ 2-beta substitution + RTI-436 (634.6 NET/DAT ratio) @ 3-beta para-benzene position.






Furthermore, if you compare RTI-195 to RTI-199 (pg. 16, bottom two), where the only difference is a sulfur on the latter to the oxygen on the shared heterocycle at the C2 pos., it changes NET value from 1,310 to 24,320.8 (however, the substitution pattern in the heterocycle is different than in RTI-143, and since electrostatic factors contribute in the case of C2, I'm adding rather than omitting, but without making a heterocylic di-aryl (which one would think to have had an example somewhere in literature that someone studying this nigh a decade as I have would have come across but have not so figure it'd gimp the structure completely) and keeping the electrostatic sub-pattern the same have added an internal-to-cyclopentane diaziridine to the nitrogens; meaning also putting in a near chlorine sub. on the aryl like in RTI-143 also as the di-subs show little difference between the para and meta when it comes to halogens with PTs @ the C3, so I added the C3 chlorine without forgoing the 436's para-(trans)stilbene skeleton. So taking that into account:






(though looking at its least energy state, it's more of some trilactam than a diaziridine... trilactam, sounds very "Revenge Of The Nerds-ish")






Also an extreme extended length para-pos., rigid triple bond terminating in a second phenyl on the PT C3 phenyl (namesake 'phenyl' phenyl with a side-chain phenyl attached thereon) has much higher binding than expected when longer substitutions have otherwise impaired binding from there, making it be postulated that there is another remote binding domain on DAT far off from the 180 degree nominally usual ending of the inherent PT phenyl's binding range

i.e.





_third best_ = 3.7 @ DAT binding⤴





*2nd Best* = 3.09 @ DAT binding⤴





*BEST* = 1.82 @ DAT binding⤴





_fourth_ best, or "worst of the triple-phenyl-terminating" = 6.28 @ DAT binding (still good! compared to..)⤴

Whereas for example:




tamagnan is half as potent as the worst above w/ a value of 12 @ DAT⤴

and





isopropyl-para-PT is a shockingly low 597 (five-hundred-ninety-seven) @ DAT ligand affinity(!)⤴


So following this rationale, is there anybody who has access to a 3D rendering program who could tell which of the triple-phenyl-ending-para substitutions (specifically the best / second longest one third down from top) best overlays with a 2-naphthyl substituted PT (or "NT" as it were, i.e. naphthyltropane, just perhaps?) with what would be a similar, equivalent (in 3D) addition but instead on its 6, 7 or 8 position (since it's a naphthyl there's a lot more than the phenyl, of course)?

For instance:






...could someone come up with something potentially better than the above using the naphthyl idea? (since the PT naphthyl alone, without making use of the putative "extra" binding domain on DAT off along in space beyond the phenyl, has a DAT affinity of 0.51, a SERT of 0.80, and a NET of 21.1, such might be very promising if such another binding domain is being used)


----------



## Nagelfar




----------



## roi

clenbuterol inspired


----------



## DotChem




----------



## DotChem

non-neurotoxic e


----------



## Pomzazed

[MENTION=387185]DotChem[/MENTION], ^ tried that one p-I-BZP plain weak stimulant with heart-racing effect on crash 
 [MENTION=99760]Nagelfar[/MENTION], (several structures above), i still see alot of "formaldehyde" on many cociane's analogue posted up there, (methyleneimine moeity!) also some N-N-N silgle bond in a ring seems to explode into nitrogen gas.


----------



## Nagelfar

Pomzazed said:


> [MENTION=99760]Nagelfar[/MENTION], (several structures above), i still see alot of "formaldehyde" on many cociane's analogue posted up there, (methyleneimine moeity!) also some N-N-N silgle bond in a ring seems to explode into nitrogen gas.



To be 100% honest; my only two completely serious attempts were the first and last structure I posted in my first post on this page (pg. 142) of this thread.

However, looking into the remote binding cite/site and the viability of such in phenyltropanes and cocaine analogues I think:






^I call it "*Epibatinaphthygnan*" _cf._ RTI-470 for the C2 + the "3-(2-thiophene) and 3-(2-furan)" class, then for the C3 the epibati tropane, the naphthyl, and tamagnan. Then notice the overall configuration of where the cocaine esters would be and how they were mirrored in one another is again repeated in this compound, but for different reasons and apparent optimization.






^a non-phenyltropane cocaine analogue keeping same length (with steric differences) spacer as benzoyloxy class analogues but with additions to para pos. to attempt to incorporate putative "remote ligand site @ DAT" binding affinity and C2 citalopram inspired branch.






^naphthyl-phenyltropane partial-inversion of the one above @ C3






^Anyhow... these are my recent, serious, inspirations from the ten new _para_ substituted phenyltropanes that are added to the WP 'List of Phenyltropanes' along with my usual predilections to make more cocaine analogues proper besides 'phenyltropanes' but always about as many PTs as well. etc. ;-p


----------



## Pomzazed

Looks much nicer, good work Nagelfar!
I think i have drawn somewhere similar structure to the second picture, except not naphthyl but phenyl, and the two phenolic OH are OMe in my design. i havnt paid much interest in it much tho (bcos i was then into drawing alot of cannabinoids ligands)

The last one tho, can be made pure but idk how much to expect for shelflife lifetime.
(See: Polydiacetylene))


----------



## DotChem

Pomzazed said:


> @*DotChem*, ^ tried that one p-I-BZP plain weak stimulant with heart-racing effect on crash



How does it compare to MDMA though? actually the idea behind replacing the phenyl of BZP with 4-iodophenyl is to make BZP less stim and more empathogen ie.more MDMA-like by increasing serotonergic DRA activity of BZP: (notwithstanding escaping legality issues!!)

Ratios of DA:NE:SERT releasing activity of BZP is ~ 1:1:10 (ie 10x less active as SER than DA or NE)
Ratios of DA:NE:SERT of MDMA is ~ 1:1:0.1 (ie the opposite 10x more Serotonergic than dopaminergic/NE-ergic)

On the other hand, hydrophobic substituents increase the serotonergic ratio of RAs/RIs (relative to DA/NE) as in for example:
going from amphetamine to PAL-287 (Naphthylisopropylamine) changing a phenyl with more lipophilic naphthyl:











> Naphthylisopropylamine (PAL-287) is an experimental drug currently under investigation for the treatment of alcohol and stimulant addiction.[1]
> 
> Naphthylisopropylamine acts as a non-neurotoxic[2] releasing agent of serotonin, norepinephrine, and dopamine, with EC50 values of 3.4 nM, 11.1 nM, and 12.6 nM, respectively.[3] It also has affinity for the 5-HT2A, 5-HT2B, and 5-HT2C receptors (EC50 values = 466 nM, 40 nM, and 2.3 nM, respectively),[1] ...In animal studies, naphthylisopropylamine was shown to reduce cocaine self-administration, yet produced relatively weak stimulant effects when administered alone, being a (much) lesser stimulant than d-amphetamine for comparison...and blabla..


 https://en.wikipedia.org/wiki/Naphthylaminopropane

So the idea is to design piperazines MDMA substitutes. The 4-iodophenyl doesn't seem to work according to your experience. so may be  naphthylmethylpiperazine where naphthyl replace BZP phenyl like this:








 (disclaimer: piperazines are illegal in some countries including the US, UK DE AU CA ..etc


----------



## madaboom

That's pretty cool, never really was into molecules. Although I can see why drawing them may be fun.


----------



## Dresden

I don't know a whole lot about piperazines, but I do recall hearing that






1-PIPERONYL-PIPERAZINE

isn't, subjectively, very similar to MDMA at all.


----------



## Nagelfar

Pomzazed said:


> Looks much nicer, good work Nagelfar!
> I think i have drawn somewhere similar structure to the second picture, except not naphthyl but phenyl, and the two phenolic OH are OMe in my design. i havnt paid much interest in it much tho (bcos i was then into drawing alot of cannabinoids ligands)



Interesting you had methoxy and not hydroxy for the bi-phenyl when you were *more interested in cannabinoids* at the time, seeing as there are many cannabinoids closer to the structure I gave, ala: ''cannabicyclohexanol''. In fact, it wasn't my rationale for making it, but I thought about it as I uploaded the image here that mine had some cannabinoid-related structure.


----------



## DotChem

Dresden said:


> I don't know a whole lot about piperazines, but I do recall hearing that
> 
> 
> 
> 
> 
> 
> 1-PIPERONYL-PIPERAZINE
> 
> isn't, subjectively, very similar to MDMA at all.


MD-BZP(or rather its prodrug Fipexide) is an antidepressant marketed as antidepressant/wakefulness/nootropic in italy france and germany in the 80s. MD-BZP was later shown to be the "active ingredient". I guess it is more like typical SSRIs, with no stim activity. Who knows how the naphthyl analog will behave: more like MDMA or SSRIs? hard to tell. (worth the try tho of the naphthyl-BZP as MDMA substituted ..pretty straightforward to synthesize dirt cheap).






If the hypothesis that says increase lipophilicity increase serotonergic vs. DAT/NET of piperazines, then the methylenedioxy anallog won't be more similar to MDMA as expected but a shitty stim (BZP is only 1/10 AMPH!). 

It is even less lipophilic (logP=1.00) than the parent BZP(logP=1.38 . The naphthyl-Piperazine seems way much better (logP = 2.37). Worth the try!

https://en.wikipedia.org/wiki/Fipexide


----------



## Pomzazed

[MENTION=387185]DotChem[/MENTION]
Phenyl/benzylpiperazine has different SAR to PEA-class of compound,
you cannot just apply the functional group and expecting results in the same way.

I supposed Benzylpiperazines follow more closely to cocaine-type SAR, try looking at piperazine ring as part of the 6-membered ring in that. 




Where Phenylpiperazines are unselective agonist at 5HT receptor, altering electron density on that aromatic ring u get differing ratio between subtypes, but they are still so very unselective.

   [MENTION=99760]Nagelfar[/MENTION]
I dismissed it as being CB receptor ligand as soon as i saw that, it size and shape/direction (where each groups should point to) cant seem to fit in the pocket. I also care somewhat less about the group, as CBr seems to tolerate fn grp changes quite alot as long as u have correct requirements and spacing between em. (eg, two hydrophobic patch 1-3 atoms split apart, better if one has pi bond, and a long alkyl tail (which can also bulge or puckered at the end also))

One that i drew was like having biphenyl replacing your phenyl-naphthyl and having varying amount/positions of -OMe and -OCH2O- on em. The idea was from salicylyl replacing the benzoyl.


----------



## Nagelfar

Pomzazed said:


> One that i drew was like having biphenyl replacing your phenyl-naphthyl and having varying amount/positions of -OMe and -OCH2O- on em. The idea was from salicylyl replacing the benzoyl.



I'm really interested in the naphthyl-PT substitutions: Can't wait until I get this beyond just its abstract, I'm going to have a heyday:

Synthesis of 2β-Acyl-3β-(substituted naphthyl)-8-azabicyclo[3.2.1]octanes and Their Binding Affinities at Dopamine and Serotonin Transport Sites


----------



## adder

Perhaps someone should make some use of this infinitive number of phenyltropanes and not just synthesize more and more for whatever reason. On the other hand I'd gladly see such a big number of modified morphinans, I know there are a lot of them, but still, the possibilities are endless


----------



## Nagelfar

adder said:


> Perhaps someone should make some use of this infinitive number of phenyltropanes and not just synthesize more and more for whatever reason. On the other hand I'd gladly see such a big number of modified morphinans, I know there are a lot of them, but still, the possibilities are endless



Yeah, but, none of the extant PTs show the potential they could if you've delved into the QSAR they show for as long as I have.

For example, you have π–π stacking possibilities includ. T-shaped and parallel-displaced on the secondary benzenes on the C3 phenyl that haven't even been looked into on the primary/singular; which if is an issue of steric factors, may do better than the sandwiched kind of the same coordination complex. There's just too many good avenues that haven't been exploited yet.


----------



## Nagelfar

my 3C-PEP closed/open DAT binding phenyltropane / benztropine comparison post from other thread.

^the above inspired me to make:






Perhaps the increase to the phenylethyl by one methylene unit would give it a NET/DAT ratio closer to vanoxerine? Don't see why the naphthyl, as univerally seems to at that carbon length, wouldn't dramatically potentiate its DAT affinity; and furthermore gave the first benzene of the naphthyl the chromium coordination complex that doubled the strength of PTs in similar positioning when so chelated, and gave the 2nd benzene of the naphthyl the acetoxy that would be in the same place as ortho-acetoxy-cocaine that not only potentated the latter's affinity, but greatly enhanced its speed of onset across the BBB as well (and natural de-acetylation leaving it a phenol increases potency even more after entering the BBB, but doesn't have same speed of onset prior to de-acetylation).


----------



## DotChem

Pomzazed said:


> @*DotChem*
> Phenyl/benzylpiperazine has different SAR to PEA-class of compound,


You  talking about 3C-PEP? yeah of course it is not really a  phenylpiperazine nor a PEA. Its SAR (depending on SAR of what effect you  talking about?) may or may not be similar. But 3C-PEP potential  metabolite (3-Chlorophenyl) piperazine mCPP is a phenylpiperazine. Is that what you talking about?


Pomzazed said:


> @*DotChem*
> you cannot just apply the functional group and expecting results in the same way.


Where did I do that? .. have no idea what you talking about?




Nagelfar said:


> my 3C-PEP closed/open DAT binding phenyltropane / benztropine comparison post from other thread.
> 
> ^the above inspired me to make:
> 
> 
> 
> 
> 
> 
> Perhaps the increase to the phenylethyl by one methylene unit would give it a NET/DAT ratio closer to vanoxerine? Don't see why the naphthyl, as univerally seems to at that carbon length, wouldn't dramatically potentiate its DAT affinity; and furthermore gave the first benzene of the naphthyl the chromium coordination complex that doubled the strength of PTs in similar positioning when so chelated, and gave the 2nd benzene of the naphthyl the acetoxy that would be in the same place as ortho-acetoxy-cocaine that not only potentated the latter's affinity, but greatly enhanced its speed of onset across the BBB as well (and natural de-acetylation leaving it a phenol increases potency even more after entering the BBB, but doesn't have same speed of onset prior to de-acetylation).



@Nafelgar: increasing the phenethyl chain by one carbon completely and utterly destroy DAT activity of 3C-PEP:





Ki @ DAT = 0.04nM







Ki @ DAT >10,000nM


That is: the phenylpropyl is at least 250,000 less potent than the Phenylethyl!!

That actually points toward a DAT binding site of this class different from that of large, highly lipophilic vanexorine-like DRI piperazines. It may not behave like cocaine as stim tho, since its lacking NET/SERT activity and some of cocaine stim due to NET inhibiton. At least at lower doses, enough for dopaminergic activation, you won't see any NET stimulation.  

IMHO, 3C-PEP would propably be a pure DRI stim like amfonelic acid, without antibiotic problem associated with AFA but with much of AFA extremely reinforcing effect. For one, it'll potentially be a potent aphrodisiac and nootropic like AFA.. but who knows? It looks pretty straighforward to synthesize very very cheaply! (no synthesis talk here but just saying. It may show up on the market pretty soon (as nootropic maybe??) if vendors paying attention. Would be nice to have a review of this compound..


----------



## Nagelfar

DotChem said:


> @Nafelgar:



*Ahem* (you butchered my _nom de guerre_ ;-j) (_*Nagel*_-*far* (Gmc. "_Nagel_" = "Nail", gutteral proto-Germanic "G" rather being between a _y_ & _g_ as per the "yogh" character _i.e._ "_Naȝl_" + Gmc. '_far_' = D. "fahr" = (far-afield / travelling) = Eng. 'ferry', _e.g._ "ferried across" = traversing by (finger)-nail. Typing via internet around world, etc.)



DotChem said:


> increasing the phenethyl chain by one carbon completely and utterly destroy DAT activity of 3C-PEP:
> 
> 
> 
> 
> 
> Ki @ DAT = 0.04nM
> 
> 
> 
> 
> 
> Ki @ DAT >10,000nM
> 
> That is: the phenylpropyl is at least 250,000 less potent than the Phenylethyl!!



That IMHO only reinforces why the beta-configured benztropines do better in alpha, and the mono-aryl phenyltropanes do better in beta orientation @ C3 with _the same binding site_ and I'm willing to bet it is the same even....



DotChem said:


> That actually points toward a DAT binding site of this class different from that of large, highly lipophilic vanexorine-like DRI piperazines.



...with 3C-PEP






So I'd have to respectfully disagree along with my mention above, it's all in the di-aryl configuration fitting into the binding site and having several carbons more length at one end, if the _meta_-chlorotoluene on the 3C-PEP were altered to, say a _m_-chloropropylbenzene, my guess would be that it could rotate to fit the binding site more neatly, even with the phenylpropyl chosen in place of the phenylethyl: check out the major differences in the GBRs in this case (vanexorine analogs)

e.g.






















Whether its still not compromised, well, we may need another parent privileged scaffold to get more specific in this direction.


----------



## crmt28

This was probably already posted here, but can we make any changes to the cyclohexane ring in arylcyclohexylamines without losing activity?

I know changing the ring size (cylcopentyl, cycloheptyl) makes it totally inactive, but what about substitutions?

A few examples:













Silly bonus molecule:


----------



## adder




----------



## DotChem

Nagelfar said:


> *Ahem* (you butchered my _nom de guerre_ ;-j) (_*Nagel*_-*far* (Gmc. "_Nagel_" = "Nail", gutteral proto-Germanic "G" rather being between a _y_ & _g_ as per the "yogh" character _i.e._ "_Naȝl_" + Gmc. '_far_' = D. "fahr" = (far-afield / travelling) = Eng. 'ferry', _e.g._ "ferried across" = traversing by (finger)-nail. Typing via internet around world, etc.)..


Sorry [MENTION=99760]Nagelfar[/MENTION]! reason I got that upside down was I had the naphthyl  tropane you drew in mind when I posted that. Naph you know as in Naf?!. My  german is limited (to organic chemistry german as in how to synthesize  Naphthaline-TropanSaure Esters





Nagelfar said:


> That IMHO only reinforces why the beta-configured benztropines do better  in alpha, and the mono-aryl phenyltropanes do better in beta  orientation @ C3 with _the same binding site_ and I'm willing to bet it is the same even....
> 
> 
> 
> ...with 3C-PEP
> 
> 
> 
> 
> 
> 
> So I'd have to respectfully disagree along with my mention above, it's  all in the di-aryl configuration fitting into the binding site and  having several carbons more length at one end, if the _meta_-chlorotoluene on the 3C-PEP were altered to, say a _m_-chloropropylbenzene,  my guess would be that it could rotate to fit the binding site more  neatly, even with the phenylpropyl chosen in place of the phenylethyl:  check out the major differences in the GBRs in this case (vanexorine  analogs)



Of course, yeah you can force it to adapt to GBRs binding site by  appending extended phenyl alkyl in place of the chlorophenyl. That's not  the issue with 3C-PEP in my opinion. Question really is: does it bind  (and trigger same conformational changes and downstream physiological  effect as GBR? 



Nagelfar said:


> Whether its still not compromised, well, we may  need another parent privileged scaffold to get more specific in this  direction.



Actually the piperazine scaffold is a very common widely used  scaffold  used to design anything from vaginal cream antifungal drugs to  antihistamine cold meds. Keep i mind also the issue of alfa and beta  anomer (with the tropane and piperidines or cyclhexyl for that matter)  is not there with piperazine because of the nitrogen inversion: (google  it). So the 3-chlorophenyl is really positioned anywhere in betwenn the  axial (alfa anomer) and the equatorial (the beta anomer).  basically  half way between alfa and beta. Plus, that nitrogen is also in the same  plane as the phenyl because of resonnance conjugation . So the  conformation of 3C-PEP piperazine is rather different. Actually you'll  be surprised that the energy minimized conformation of 3C-PEP overlay  with that of methylphenidate or even PVP..


----------



## Nagelfar

DotChem said:


> Actually you'll  be surprised that the energy minimized conformation of 3C-PEP overlay  with that of methylphenidate..



Really? Do you (or does anybody for that matter whose willing?) have a 3D molecular drawing program that could overlay those two for me? I'd be very interested to see it, even to have to released and uploaded on Wikimedia commons for Wikipedia; I already have methylphenidate overlays as the litmus test for typical monoamine reuptake inhibitors. As for German; "N ohne Radikal" ;-P


----------



## Dresden

I'm sure this one was checked out long ago, but then again, I don't know that.


----------



## MrPorter

Nagelfar said:


> I'm really interested in the naphthyl-PT substitutions: Can't wait until I get this beyond just its abstract, I'm going to have a heyday:
> 
> Synthesis of 2β-Acyl-3β-(substituted naphthyl)-8-azabicyclo[3.2.1]octanes and Their Binding Affinities at Dopamine and Serotonin Transport Sites



I have full access. How's best to upload?


----------



## Nagelfar

MrPorter said:


> I have full access. How's best to upload?



I do too now. No worries, even have a hard copy at home. Didn't notice they were acyl @ 1st, and sadly, the substituents on the aryl do not seem to potentiate.


----------



## DotChem

Nagelfar said:


> Really? Do you (or does anybody for that matter  whose willing?) have a 3D molecular drawing program that could overlay  those two for me? I'd be very interested to see it, even to have to  released and uploaded on Wikimedia commons for Wikipedia; I already have  methylphenidate overlays as the litmus test for typical monoamine  reuptake inhibitors. As for German; "N ohne Radikal" ;-P



Now that I manage to have some time on my hand: [MENTION=99760]Nagelfar[/MENTION]: here is  3D model so you can see I was talking about re: 3C-PEP conformation is  actually closer to that of methylphenidate:







Blue is MPH the light green is PEA-piperazine (compound to the right)

I  use the 1-phenethylpiperazine to show you that the phenethyl of 3C-PEP  overlay with that of MPH and the piperazine overlay with the piperidine  of MPH. I use the PEA-piperazine instead of the PEA phenylpiperazine  because the basic 3- point pharmacophores of MPH is there in 3C-PEP  (more or less as there is room to fit the bigger phenylpierazine).  Actually bigger may be better than the piperidine of MPH. But anyhow, you get the  idea..( you can try it yourself with various PEA piperazines substituted  at N4: Chemaxon Inc they use to have freeware for conformational  analysis and such..I don't know if it still free.. but any decent  library should have subscription!


PS: note the  1-Phenylethylpiperazine is actually a potent MAT inhibitor with more  serotonergic though.. so most likely will be like MDMA or BZP..but who  knows? unless somebody actually try it! (will get post references later)


----------



## Nagelfar

DotChem said:


> Now that I manage to have some time on my hand: [MENTION=99760]Nagelfar[/MENTION]: here is  3D model so you can see I was talking about re: 3C-PEP conformation is  actually closer to that of methylphenidate:
> 
> 
> 
> 
> 
> 
> 
> Blue is MPH the light green is PEA-piperazine (compound to the right)
> 
> I  use the 1-phenethylpiperazine to show you that the phenethyl of 3C-PEP  overlay with that of MPH and the piperazine overlay with the piperidine  of MPH. I use the PEA-piperazine instead of the PEA phenylpiperazine  because the basic 3- point pharmacophores of MPH is there in 3C-PEP  (more or less as there is room to fit the bigger phenylpierazine).  Actually bigger may be better than the piperidine of MPH. But anyhow, you get the  idea..( you can try it yourself with various PEA piperazines substituted  at N4: Chemaxon Inc they use to have freeware for conformational  analysis and such..I don't know if it still free.. but any decent  library should have subscription!
> 
> 
> PS: note the  1-Phenylethylpiperazine is actually a potent MAT inhibitor with more  serotonergic though.. so most likely will be like MDMA or BZP..but who  knows? unless somebody actually try it! (will get post references later)



I guess the reason I found it odd, overlaying with MPH while still being a DARI of that pharmacophore, is that bulky para substituents either on the benzene or the cyclohexane on the other side (see fentanyl) like another phenyl (bi-phenyl) greatly diminish MPH activity. But barring that specific 3-chlorophenyl, if that's (as you mean) 1-(2-Phenylethyl)piperazine that is a reuptake inhibitor, what about 1-(1-Phenylethyl)piperazine? The former reminds me of cyclomethiodrone/TCAT and similar.

What I find equally baffling, though, is:






and benzyl tropanes have good activity _e.g._






but...benzyl analogues of MPH _i.e._






have >5,000 Ki inhibition @ DAT

...I suppose the angle if those two specific compounds were overlayed might be off (humor me again? can't download programs on the library computer which is my sole online access), but still I would imagine to overlay in some rotations / conformations

Could I crop your name out of that overly and make it my own original to source for addition to WP?


----------



## Dresden




----------



## Dresden




----------



## DotChem

Nagelfar said:


> Could I crop your name out of that overly and make it my own original to source for addition to WP?



Yeah @*Nagelfar* no problem go ahead edit and use it as you see fit. But keep in mind it is the mono-subsituted piperazine not 3CPEP per se. So make sure you let your readers on WP knows that..



Nagelfar said:


> ...benzyl analogues of MPH _i.e._
> 
> 
> 
> 
> 
> 
> have >5,000 Ki inhibition @ DAT


do you have original source?  SAR paper (not patents !) the original peer-review paper of MPH and analogs SAR at DAT??


----------



## Nagelfar

Thanks DC



DotChem said:


> do you have original source?  SAR paper (not patents !) the original peer-review paper of MPH and analogs SAR at DAT??



Axten, J. M.; Krim. L.; Kung, H. F.; Winkler, J. D. _J. Org. Chem._ *1998,* _63, 9628._

-is the source quoted, for 86th page here


----------



## klfiend

I saw an image of a overlay of an NMDA molecule overlaid a methoxetamine molecule and had this idea.  Cannot find the original image at this point I lack good tools to explore this further but I am very curious.


----------



## pharmakos

I wonder what just increasing the length of the alkyl chain on NMDA would do.  Would be very interesting if that alone could turn it into an antagonist.


----------



## Solipsis

It would, but it doesn't seem likely: in ACA's the optimal length is ethyl, longer than that (besides constraining in heteroring) and they simply get less potent. NMDA is an excitotoxin, if any of the SAR makes any sense a lengthy alkyl chain won't cause the aspartic acid derivative to bind without activation (i.e. antagonistic), but just have less affinity so a little less toxicity.
I realize there may be a different ruleset for antagonists, but at least for ACA's the pharmacophore and similarity to NMDA should be a match?



klfiend said:


> I saw an image of a overlay of an NMDA molecule overlaid a methoxetamine molecule and had this idea.  Cannot find the original image at this point I lack good tools to explore this further but I am very curious.



Not a bad idea, I've fantasized about different ways to mimick NMDA than the typical groups in arylcyclohexylamines, but not what you posted.
However counting from one carboxylic acid to another, you seem to have one added spacer when comparing to NMDA, so that =O oxo group you have on 3 (a la MXE) would have to be on 2-position now. In MXE and other arylcyclohexylamines part of the phenyl ring (from the 2-position to the 3-position) plays a role similar to that of the oxo.
Now that you made the phenyl ring into a cyclohexyl ring, that is not true anymore, so the electron-rich moiety will now have to stick out, but closer by than the 3 position.

Am I explaining my idea well or should I draw it? (Not long ago in this thread molecules were posted that intentionally had different spacing - more specifically of the amine position compared to the carboxylic acid like functions, and who knows if some of these would work)

Another thing is that I would not be surprised if the arylcyclohexylamines work well in part because of an aromatic site in the channel that pi-stacks with the phenyl ring, good for sticky binding and coordination. Off the top of my head, MK-801 ketamine DXM diphenidine they are all aromatic.


----------



## pharmakos

Solipsis said:


> It would, but it doesn't seem likely: in ACA's the optimal length is ethyl, longer than that (besides constraining in heteroring) and they simply get less potent. NMDA is an excitotoxin, if any of the SAR makes any sense a lengthy alkyl chain won't cause the aspartic acid derivative to bind without activation (i.e. antagonistic), but just have less affinity so a little less toxicity.
> I realize there may be a different ruleset for antagonists, but at least for ACA's the pharmacophore and similarity to NMDA should be a match?



efficacy as an agonist/antagonist isn't equivalent to binding affinity, is it?  afaik, there's a correlation but it isn't the whole story.

are ACAs fully antagonists at the NMDA receptor, or are some of them mixed agonists/antagonists?  if some are mixed, then the potential for NMDA-analogues as dissociatives seems more likely to me.  having a hard time googling the answer myself.

n-ethyl-d-aspartate exists, CAS 5555-23-7.  seems to also be called n-ethylaspartic acid.  can't find any literature on it, tho, just chem supply stuff.  only one google hit on the propyl.

sounds like a decent research project for someone in the position to do such a thing.


----------



## Solipsis

Now that I think of it, NMDA binds at the glutamate binding site while ACAs bind at an allosteric site, the PCP site - so that probably means all bets are off.. Sorry about that man 

I must say that it always confuses me that there are those different binding sites but ACA's still mimic NMDA at another site than were NMDA binds to. And sometimes dissociatives have features that make no sense from a purely NMDA-overlaying point of view, so once again SAR breaks down at some point.

Way to go making it complicated, NMDA receptor. Well played


----------



## pharmakos

i knew that too but forgot as well lol.

in googling on NMDA analogues, found a couple NMDA-antagonists that are really close to NMDA itself in structure:

here's NMDA:






here's AP5:






here's AP7:







edit -- 

wow there's actually a lot of these, here's CGP-37849:


----------



## white55

crmt28 said:


> This was probably already posted here, but can we make any changes to the cyclohexane ring in arylcyclohexylamines without losing activity?
> 
> I know changing the ring size (cylcopentyl, cycloheptyl) makes it totally inactive, but what about substitutions?
> 
> A few examples:
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> Silly bonus molecule:



I believe someone on bluelight said that you can put the keto group or a methyl group on position 4 and retain activity. 

And there is also https://en.wikipedia.org/wiki/Gacyclidine (although this is technically a thienylcyclohexylamine)


----------



## aced126

pharmakos said:


> i knew that too but forgot as well lol.
> 
> in googling on NMDA analogues, found a couple NMDA-antagonists that are really close to NMDA itself in structure:
> 
> here's NMDA:
> 
> 
> 
> 
> 
> 
> here's AP5:
> 
> 
> 
> 
> 
> 
> here's AP7:
> 
> 
> 
> 
> 
> 
> 
> edit --
> 
> wow there's actually a lot of these, here's CGP-37849:



All these analogues are only really useful for studying NMDA receptors in vitro; they are way too polar to cross BBB in vivo. 

Indeed, one has to consider which binding spot the ligand in question is binding to, as different ligands binding to different binding sites have different implications.


----------



## crmt28

klfiend said:


> I saw an image of a overlay of an NMDA molecule overlaid a methoxetamine molecule and had this idea.  Cannot find the original image at this point I lack good tools to explore this further but I am very curious.



This one? https://psychonautwiki.org/wiki/File:Dissociatives_w_-_glutamate.png

These also fit:


----------



## adder

The binding site of methoxetamine is different from glutamate's, so it doesn't make sense to compare their structures.



> I believe someone on bluelight said that you can put the keto group or a methyl group on position 4 and retain activity



4-keto group dramatically increases affinity to opioids receptors especially if there is a tertiary amine present in the molecule. However, one modification of the cyclohexane ring that boosts the activity at NMDA receptors is 2-methyl group, (-)-trans-2-Me-PCP (phenyl trans to Me) is 5x more potent than PCP in vitro and 2x more potent in vivo, so perhaps:


----------



## Dresden

adder,

Is there a website you could share with us (hopefully free) to be able to use the same molecular drawing software you used for those 2-methyl dissociatives?  I like the way they look.


----------



## adder

It's from ChemDraw 12.


----------



## Nagelfar

Yet another naphthyl-tropane.


----------



## white55

adder said:


> The binding site of methoxetamine is different from glutamate's, so it doesn't make sense to compare their structures.
> 
> 
> 
> 4-keto group dramatically increases affinity to opioids receptors especially if there is a tertiary amine present in the molecule. However, one modification of the cyclohexane ring that boosts the activity at NMDA receptors is 2-methyl group, (-)-trans-2-Me-PCP (phenyl trans to Me) is 5x more potent than PCP in vitro and 2x more potent in vivo, so perhaps:


without going in to synth details would these be to hard to make and is that why we've not seen them?
 [MENTION=147526]Dresden[/MENTION] - install marvin beans, the pics are even better
https://i.imgur.com/MOMXoC0.png


----------



## Solipsis

They have two chiral centers (diastereomers), I would want to know if the other cis-2'-methyl (or 6' in the keto version?) enantiomers of those is any good, and especially not side-effect adding.. It wouldn't be that they are hard to make, but they are annoying to make as pure isomer and I don't see the industry taking a liking to such a complication.
It would be worthwhile if the cis enantiomers are nice or at worst harmless, so that the racemate - which shouldn't be very hard at all to make - suffices. In the case of e.g. 3,4-CTMP it worked out..


----------



## adder

(-)-trans-2-Me-PCP is twice as potent as PCP and four times as potent as (+)-trans-2-Me-PCP (in vivo), so the site is sensitive to stereochemistry (though with racemic 2-Me-PCP you don't lose any potency vs. PCP). It doesn't seem hard at all to obtain the more potent enantiomer in high purity, the trans racemate is separated from the cis racemate by plain crystallization and then respective enantiomers are obtained via chiral resolution.

Here's the abstract of the original paper.



> @Dresden - install marvin beans, the pics are even better



I myself like clean and elegant structures, ChemDraw gives one of the cleanest structures I've seen, ChemDoodle looks nice and clean as well. I used to use ChemSketch as I got used to it and thought drawing in ChemDraw was uncomfortable, but then I changed my mind and now I think it's more practical than ChemSketch. As for esthetics, ChemSketch's structures compared to ChemDraw's are like typescript compared to an elegant computer font. I don't like those coloured structures from Marvin Beans either. Also, with ChemDraw it's possible to export structures directly to .gif files, not to mention a lot of useful tools and simulations if you need them.

----






Let's call this one "eclectamine" and let's hope it'll live up to its name.


----------



## roi

> I don't like those coloured structures from Marvin Beans either.



View -> Colors -> Monochrome. And of course you can export structures into a variety of formats as well.


----------



## roi

Propylhexedrine + 2C-B =


----------



## w0w0mg

Can someone PLEASE make me 2 compounds, 
one having the word "Sosadisso" and another saying "w0w0mg" in different places.
Example: So ----- Sa --- Di -Ss --O  
Example: Wo --W-----O ---Mg

If someone could do that for me, I would love you all. lol.


----------



## Incunabula

adder said:


>



I don't think the trans-2-Me-ketamine would be any good, I mean, of cause it could be, but not if you consider the fact, that going by the arylcyclohexylamines we know so far, ketamine seems to *not* follow the same SAR as the other Acha's.

It'll never work taking a substitution from a PCP analog, and then transfer it to ketamine. We'll never see a "better" version of ketamine, just legal less good ones imo. Anyway, the other ones are probably awesome though, especially the MXE one. Otherwise it's better to loose the chloro and _then_ extend the _n_-methyl to ethyl and it's probably all rock'n'roll - or even better, loose the 2-ketone as well, to get Trans-2-Me-PCE.


----------



## Solipsis

Why do you say that? Ketamine was not developed as a recreational drug, so clearly they were looking for different qualities in their target compound.

If 2-fluoro-DCK is an interesting ketamine light, then who's to say that some or one of the various different subsitutions that may perhaps surface won't be an improvement? Subjectively of course.

But you may very well be right that borrowing from PCP SAR isn't predictive. Better to just compute 3D-QSAR and such for K mimics.

I wonder about 2-nitro-deschloroketamine, but with all aromatic nitro compounds there are potential dangers namely bone marrow depression and interactions with metabolic pathways (oxidative phosphorylation)...


----------



## adder

3-methoxy aryl substitution transferred well from PCP, it's the same site they're all interacting with, right? If the site can discriminate between dextrorotatory and levorotatory trans-2-Me-PCP, then in my opinion chances are the right diastereomer might benefit from 2-methyl group unless ketamine and methoxetamine bind in some drastically different way from PCP and PCE, which of course is possible.

BTW, I don't think that you can say with 100% certainty that we will not see a "better version" of ketamine. One thing is people perceive effects of drugs differently and two people enjoying ketamine effects might find another dissociative completely different. There won't be another ketamine, but there still may be an arylcyclohexanamine that will be as good as ketamine or methoxetamine, there's a still a great number of modifications and their combinations that can be applied to the backbone, so at this point statistically speaking there is a chance (well, always will be ).


----------



## Incunabula

Solipsis said:


> Why do you say that?



It's just from thinking about the changes to ketamine's structure that we'we seen so far. And it seems to me, that ketamine has very unique effects compared to all the other available ones imo. Maybe it's just because it's duration is so short. I don't know, but I just think ketamine is so much more sharp, on edge and yes, more bizarre ( Yes, I know high dose_ everything_ is bizarre  ). IMO ketamine doesn't have all those serotonergic or stimulant or "opiod" feelings that the other ArCHA's have. I know a lot of people are probably going to disagree with me about this, but I feel ketamine is unique so far. 

So what have we tried with ketamine so far?

Remove the chloro? You get something thats more like MXE.

Change the chloro to something not halogen? you get inactive

Extend the n-ethyl? You get something that's nearly inactive, even though every other ArCHA benefits from that. 

My point is, that all the other ArCHA's seem to have more in common SAR wise, than they do with ketamine. Because if some substitution or addition is great for PCP, it's probably also great for PCE and MXE and 3-MeO-PCP etc. But it doesn't mean that it's great for ketamine, because it's effects are still quite different. And ketamine just seems to be more finicky with changes. You quickly get something inactive or something which isn't related to ket at all in it's effects.



Solipsis said:


> If 2-fluoro-DCK is an interesting ketamine light, then who's to say that some or one of the various different subsitutions that may perhaps surface won't be an improvement? Subjectively of course.



Yes, of cause I can't discount that. It just seems to me that neither fluoro nor bromo in the 2 position were improvements, from what I understand. Both were less potent, so bigger or smaller is a no go. TFM might be good, and hopefully we'll see about that at some point. 

But were to go from there? Putting subs in other places on the phenyl is 100% to make something new, something very different, that's not going to be like ketamine at all - So in that sense, those analogs are just going to be new ArCHA's, not real ketamine analogs. 

Not that there probably aren't things to try. You're just not going to get predictions about it from PCP analogs, because it just seems like a completely different world, no?




Solipsis said:


> But you may very well be right that borrowing from PCP SAR isn't predictive. Better to just compute 3D-QSAR and such for K mimics.



Yes, exactly


----------



## Incunabula

adder said:


> 3-methoxy aryl substitution transferred well from PCP, it's the same site they're all interacting with, right? If the site can discriminate between dextrorotatory and levorotatory trans-2-Me-PCP, then in my opinion chances are the right diastereomer might benefit from 2-methyl group unless ketamine and methoxetamine bind in some drastically different way from PCP and PCE, which of course is possible.



I didn't see that you posted while I was writing. I didn't mean to ignore you  

Yes, I see what you mean, and of cause you might be right. As I wrote in my post above, I think there's reason to believe that ketamine interacts quite differently with the site, than any of the other ArCHA's (except fluoroketa and bromoketa and hopefully TFM-Keta) Of cause, it's just something I _think_, I have no evidence what so ever.

3-MeO-aryl seems wortwhile for more or less all constellations of ArCHA. But what if you put it on keta? 2-Cl-2-Oxo-3-MeO-PCM? A good guess is that it would be inactive. Now drop that 2-Cl and you'd have MXM, which is supposed to be like less potent, less spectacular MXE. Not that it doesn't have it's fans, but it says something about ketamine SAR imo.



adder said:


> BTW, I don't think that you can say with 100% certainty that we will not see a "better version" of ketamine. One thing is people perceive effects of drugs differently and two people enjoying ketamine effects might find another dissociative completely different. There won't be another ketamine, but there still may be an arylcyclohexanamine that will be as good as ketamine or methoxetamine, there's a still a great number of modifications and their combinations that can be applied to the backbone, so at this point statistically speaking there is a chance (well, always will be ).



I totally agree. But I believe more in seeing a new MXE type drug in the future, than a new ketamine type drug, if you get my drift. 

Definitely very fascinating with the whole trans-Me-PCP thing though


----------



## Nagelfar

w0w0mg said:


> Can someone PLEASE make me 2 compounds,
> one having the word "Sosadisso" and another saying "w0w0mg" in different places.
> Example: So ----- Sa --- Di -Ss --O
> Example: Wo --W-----O ---Mg
> 
> If someone could do that for me, I would love you all. lol.



For an avatar or something? What, like this? -


----------



## Nagelfar

Came across some interesting substitution publishing for desmethylprodine (and thus by extention pethidine/Demerol) from the early '60s.












PEPAP reminds me of a Demerol + Fentanyl hybrid:


----------



## roi




----------



## adder

How about some pethidine amide analogues? IMO there's a big chance they would be more potent than pethidine itself (the ester/amide acting as a hydrogen bond acceptor?).


----------



## roi




----------



## Bagseed

polarity overkill, no?


----------



## roi

fite me irl


----------



## Jaw Clenching

*Extensions on the Bromo Fly compounds*

The 4- position can be substituted with the standard 2C-x and DOx stuff.
The alpha-methyl can be removed to make them more like the 2C's instead of DO's.
The amine can substitute to NBOMe or NBOH.


----------



## Jaw Clenching

*Rigid analogs of DMT*

The amine can have all the normal di-alkyl substitutions the 4-HO and 5-MeO tryptamines have.
The amine can have no substitutions, and the alpha carbon can have an alpha or ethyl substitution.


----------



## Jaw Clenching

*Pyrrole- and Isofuran- groups replace methylenedioxy*

MDA, MDMA, bk-MDA & bk-MDMA analogs.
Can have all the other substitutions those compounds have.


----------



## Bagseed

roi said:


> fite me irl


ok lol

so you don't have anything to counter my point?


----------



## roi

Bagseed said:


> ok lol
> 
> so you don't have anything to counter my point?



Read the title again, carefully.

http://www.oxforddictionaries.com/definition/english/random


----------



## Nagelfar

Now with sulfinimine (N-sulfinyl-imine) chemistry C1 analogs of cocaine/phenyltropane are possible! The C1-phenyl analog of cocaine is ten times more potent than cocaine! (seeing how the the N8 analogs gimped it, and all other 6 & 7 analogs, it comes as a bit of a surprise) now make it a phenyl tropane and make that 2beta phenyl also and we get:


----------



## Solipsis

Dude you got at least 6 other places to put a phenyl ring, get back to work ;p


----------



## Nagelfar

Solipsis said:


> Dude you got at least 6 other places to put a phenyl ring, get back to work ;p



Not and gimp affinity.

But we can always front bridge it:






Bet it has affinity, if not at DAT then at least @ SERT! ;-P


----------



## Solipsis

Ha  Excellent nagelfar, why can't the half-life be half your life indeed? Next stop, speedbuckyball.


----------



## Nagelfar

Solipsis said:


> Ha  Excellent nagelfar, why can't the half-life be half your life indeed? Next stop, speedbuckyball.



Really, the possibility now open of that C1 position with the nitrogen bridge opens up all sorts of front & back bridged possibilities, the problem is their functionality is mostly based on the nitrogen's lone pair, but adding a second nitrogen at the C1 and front bridging it possibly, having two lone pairs facing each way?


----------



## roi




----------



## aced126

Rationalisation of the acetylated glucuronide moiety?


----------



## roi

2C-B-ified leftovers from something in MarvinSketch at 4AM. Truely random (technically not at all).


----------



## Nagelfar

How would someone draw a covalent binding dopamine receptor agonist? (I know, *not a safe* idea, but lets see it FWIW. ;-p )


----------



## Solipsis

Nagelfar said:


> How would someone draw a covalent binding dopamine receptor agonist? (I know, *not a safe* idea, but lets see it FWIW. ;-p )



http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115510/

Via fig 1 ^ based on FAUC50 for dopamine you get this:






Though I fear that it might not be terribly selective in disulfide linking and is mostly interesting in in vitro receptor binding experiments... Also the part on the left is pretty unstable.

The hydrazone approach seen in oxymorphazone etc seems much more interesting but it doesn't even seem like it's well understood to what amino acid residue the covalent bond is made to supposedly make a hydrazine. How many amino acid residues can it actually react with, even if in receptor binding dynamics I guess rather exotic 'enzymatic' reactions incl redox can occur... I suppose the hydrazone can bind to amines?

If that were more clarified perhaps one could continue to design a covalent agonist with such a group that targets a specific moiety in the receptor pocket.

It does seem quite evil, but on the other hand in extreme cases wouldn't it be potentially therapeutic to very harshly 'downregulate' functional receptors of certain kinds?




This is poly acetylsulfanyl thiopsilocin:






The idea is to administer it in nanoparticulate form that decomposes in the reducing environment of tumor cells. Then hope there are enough esterases available to cleave the acetyl sulfane.. In the case of braincancer, hopefully both the healing power of a bomb of psychedelia and the properties of the thiophenol then kill the tumor. ;p
You'll have to imagine the terminal units in the above pic that were sloppily left out.


----------



## N0 W4RN1NG

^^^Fascinating posts, Nagelfar & Solipsis. Is there some possibility your psilocin derivative (or one of it's inevitable metabolites, like perhaps 4-methylthio psilocin, after hydroxylation of the ketone and then N-demethylation?) might also be a potent MAO-A inhibitor once depolymerization occurs? Otherwise, really intriguing idea.

Also, I would just like to say that I tentatively agree that very carefully administered covalently binding, subtype selective "suicide" dopamine receptor ligands would be a potentially useful tool in certain disorders, like tourettes, or drug addiction. Very tricky, as you both mentioned of course, with more possibilities to go wrong than right. Still, absolutely fascinating ideas. Love checking in on this thread from time to time.


----------



## Solipsis

Of course, it's possible, but why do you ask? Not because they remind you of 2C-T-7 type sulfuric psychedelics which have MAOI concerns? I don't think drugs like thiopsilocin or 5-MeS-DMT would be inherently worrying by the sulfur binding weirdly (strongly) to MAO or something like that, never heard about similar compounds doing that. They should be similar to their parent compounds but a bit less potent. Main reasons not to make things like plain thiopsilocin are the nastiness of such thiophenol chems just generally i.e. smell & taste, possibly some metabolic toxicity.

The polymer idea was really silly, the applications don't apply even if I borrowed some theoretical stuff based remotely on reality like the disulfide bond decomposing in a tumor... it's a funny idea but it wouldn't work (injecting nano particles in brain tumor lol) in any way at all..
so it's not really worth considering the many implications.  Just another 'random' molecule..

The other one (covalent agonist) certainly is real, but meant as a theoretical / experimental probe and not for use. Even if another dopamine (for example) covalent agonist or antagonist were made to work, I have trouble thinking of a situation where it would be helpful. The receptors would just grow back is one thing, so you wouldn't even successfully destroy 'wrong' pathways like ones regarding the reward centers for addiction. Who's to say if you'd mostly end up with a person who can't be motivated whatsoever and would have to learn to motivate himself all over again?

I saw a TED talk about neuroscientists being able to locate super specific neurons that light up for e.g. only perceiving anything to do with The Simpsons. Not even very similar things. But they did it in electrode (open skull) patients.. They didn't mention being able to actively going on the hunt for something, but it doesn't seem like a stretch if going by analysis of lots of data after asking someone to focus on that specific thing for a decent amount of time? I sort of doubt myself that a single neuron would be responsible for coding for a single thing (single point of failure), but maybe something like a cluster could be critical... So I would wonder about if you could make a person forget specifically about the drug they are addicted to by excising that region.
I know for serious cases of OCD it's possible to have deep brain stimulation surgery which works miraculously if it does but in about 50% of patients. Seems conceivable you could make something similar work for addiction, idk Tourette's perhaps..
For OCD it works by suppressing activity that basically keeps going in a loop causing a person to check over and over whether it's OK, breaking the loop and making it 'OK' instead of frantically trying to fix it by various behaviors.

I think mirtazapine works for depression by changing the activity some serotonergic receptors compared to others, so the balance basically. Doing so by mainly blocking only some of them antagonistically. So, could you achieve something similar but more immediately and selectively by killing off part of the receptors? I'd expect major brain zaps as a result and huge problems titrating a good dose for it (as receptor populations vary between individuals and you cannot really see just by looking at a person.. *maybe* by giving a person a radioligand and measuring the radiation?)..

You can file all that under 'drastic' ;p


----------



## N0 W4RN1NG

Haha, well now we're entering "Eternal Sunshine of the Spotless Mind" territory! Regarding "forgetting" a drug addiction though (if an effective technology is found) it definitely would help, but depending on the addictive substance forgotten, the patient may be in such a depressed / agitated state after cessation (receptor down regulation / monoamine depletion / GcP mediated changes  / dynorphin upregulation / etc etc [from "forced forgotten" drug addiction ]) and unaware of the cause, that they may do something drastic like harm themselves. A bit far fetched perhaps, but some thing to maybe keep in mind, even when hypothetically musing about it.

Wow, can you imagine the social implications of that though? "Don't forget, XYZ doesn't know what drugs are anymore, so make sure not to bring them up around him."

It would be like the ultimate version of "The Game". (You just lost the game!) XD Except instead of being reminded of a silly fad, every time you lose THIS game you end up relapsing. What a concept. 

Re: MAO-Inhibition,

I am no Shulgin but I know enough to differentiate tryptamine SAR from subbed PEA 

No, it reminds me not of 2C-Tx but of 5-MeO-AMT! (which of course I guess does kind of borrow from PEA qsar in it's own right...now I'm just complicating things though) Of course, there, we have the a-carbon methylated, which really does throw a wrench in the gears of metabolism. 

Of course this is all pure pontification, (I.E. as you mentioned, regardless of if it inhibits MAO-A  or is a DNA cross-linker, or damages chromosomes in ovum...have fun injecting anything intracranially, through healthy tissue)

But before I derail this thread any further I will end my post. BUT I will mention, that to your credit about potential, novel agents to end addiction, I know there is a drastic Chinese surgery being offered which, quite literally, ablates areas of the Nucleus Accumbens...results supposedly vary from "instant happy sobriety" in long term heroin addicts, but also, in many, cognitive impairment and for a few...suicide within months of surgery.

Hatte Ich here the good article found:
http://healthland.time.com/2012/12/13/controversial-surgery-for-addiction-burns-away-brains-pleasure-center/


----------



## Nagelfar

Solipsis said:


> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115510/
> 
> Via fig 1 ^ based on FAUC50 for dopamine you get this:


WP page made for "FAUC50", 'dopamine native-headed' example re-drawn and added. Thanks!


----------



## crmt28

Orphenadrine is an anti-cholinergic with additional NMDA antagonism and norepinephrine reuptake inhibition. Looks pretty interesting. It's Diphenydramine with an additional methyl group.






I wonder if removing the ethanolamine group could turn it into a pure NMDA antagonist. It would look pretty similar to Ephenidine.






Close the ring and it turns into a possible stimulant?


----------



## N0 W4RN1NG

Cool idea, I am not sure if the last one would have stimulant activity though. The molecule is now constrained in the wrong shape, I believe...I could be wrong of course.

Further modification of that last one may lead to Mu affinity though!


----------



## Nagelfar

Nagelfar said:


> WP page made for "FAUC50", 'dopamine native-headed' example re-drawn and added. Thanks!



http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297708/figure/F6/








> Generic pharmacophore for biogenic amine transporter ligands. Note that transportable substrate ligands exhibit size constraints defined by the red circle. Functional groups attached to the nitrogen, α-carbon or phenyl ring that extend beyond the “edge” of the pharmacophore will generate partial substrates, transporter blockers or be inactive.



This goes with the above, and is interesting.

I suppose a good observation to keep in mind for the substrate-terminus rule is: two methylene units above and below the dimension of the phenyl-to-amine, and three methylene units parallel in front and behind the phenyl and amine.


----------



## DotChem

Not what you may be thinking.. actually a potent opioid with kappa selectivity. It has no GABA-ergic!!

Tifluadom 


> * Tifluadom*[1] is a benzodiazepine derivative with an unusual activity profile. Unlike most benzodiazepines, tifluadom has no activity at the GABAA receptor, but instead is a selective agonist for the κ-opioid receptor.[2] In accordance, it has potent analgesic[3] and diuretic[4] effects in animals, and also has sedative effects and stimulates appetite.[5][6] While tifluadom has several effects which might have potential uses  in medicine such as analgesia and appetite stimulation, κ-opioid  agonists tend to produce undesirable effects in humans such as dysphoria and hallucinations, and so these drugs tend to only be used in scientific research. Dysphoric effects are similar to those seen when using other κ-opioid receptor agonists like pentazocine and salvinorin A.



wonder if the structure can be tweaked to a MOR selective eg the 7 or 8-OH analogue!


----------



## Pomzazed

^ So interesting about the above one, including the furan analog (instead of thiophene), Lufuradom.


----------



## Nagelfar

Dopamine agonists? (Looking at existing ones, Alentemol is interesting, selective dopamine _autoreceptor_ agonist? Didn't think you could selectively single out autoreceptors!)


----------



## Midnight Sun

DotChem said:


> Not what you may be thinking.. actually a potent opioid with kappa selectivity. It has no GABA-ergic!!
> 
> Tifluadom
> 
> 
> wonder if the structure can be tweaked to a MOR selective eg the 7 or 8-OH analogue!



well, it's not-so-vaguely reminiscent of tianeptine... which as we all probably know hits mu and delta.  maybe start there?


----------



## white55

A benzo with no gaba activity? Think I'll pass.


----------



## Nagelfar

white55 said:


> A benzo with no gaba activity? Think I'll pass.



There're many of them. Benzodiazepine is a structural name, not a functional one; though people use "GABAergic" and 'benzo' almost synonymously. The 2,3-benzos are without GABA function. GYKI-52,466 is an AMPAkine and glutamine receptor antagonist. Whereas GYKI-52895 is a dopamine reuptake inhibitor a la cocaine. Talk about different functional profiles.


----------



## white55

i'd rather have some of these

http://imgur.com/a/zUsdg


----------



## Solipsis

Something about pieces of land in vietnam.... waaaay too random, dude 

I wonder if this is interesting as RC:
https://en.wikipedia.org/wiki/Dexanabinol

Talking about another drug in disguise  :D

Yeah not the purpose of this thread but I wouldn't have a clue where to even modify it for shits and giggles.. it doesn't even have an amine function, does that even bind to the PCP site? I bet it doesn't trap shit.


----------



## aced126

The molecule might not be binding to the PCP site on NMDAr. It could be binding to the glycine or glutamate site.


----------



## Nagelfar

Solipsis said:


> Something about pieces of land in vietnam.... waaaay too random, dude
> 
> I wonder if this is interesting as RC:
> https://en.wikipedia.org/wiki/Dexanabinol
> 
> Talking about another drug in disguise  :D
> 
> Yeah not the purpose of this thread but I wouldn't have a clue where to even modify it for shits and giggles.. it doesn't even have an amine function, does that even bind to the PCP site? I bet it doesn't trap shit.



If the "unnatural" isomer both of certain cannabinoids and of morphinan opioids (both phenanthrene) can be NMDA antagonists, how come we don't see a lot of cannabinoid/opioid dual-action compounds?


----------



## roi




----------



## Solipsis

Nagelfar said:


> If the "unnatural" isomer both of certain cannabinoids and of morphinan opioids (both phenanthrene) can be NMDA antagonists, how come we don't see a lot of cannabinoid/opioid dual-action compounds?



The probable answer is mentioned 2 times  there are several binding sites on the NMDAr with apparently in some ways a similar pharmacophore but with probably quite different tolerances for modified substitution on ligands for them (or maybe less than we think, when we discover nitrogen-free PCP site antagonists).. I guess that serves the role to have two (or more) very similar endogenous neurotransmitters being able to regulate different processes on a receptor complex.
https://en.wikipedia.org/wiki/Neboglamine is positive allosteric modulator on (near?) the glycine site and I am seeing similarities with the previously mentioned dexanabinol. So it appears that opioid-like NMDA antagonists we know of bind to the PCP site and cannabinoid-like NMDA antagonists (or at least this one example) to the glycine site.
[edit: just checked and dexanabinol doesn't even bind to the glycine or glutamate site 'normally' but close, so I guess also allosterically - I think the arguments still all stand]

Trying to find a hybrid while sometimes possible, can often be frustrated by the fact that the compromise between what are actually different mechanisms is unacceptable.

Finding a good ligand for one site is hard enough, but finding one that satisfies two sites is freaking challenging like composing baroque counterpoint. Maybe first practice by secretly getting married twice and raising two families.

Also:
Dexanabinol is mentioned on the 'Cannabis cures cancer' facebook page, lmao sure take the credit


----------



## Nagelfar

Solipsis said:


> but finding one that satisfies two sites is freaking challenging like composing baroque counterpoint. Maybe first practice by secretly getting married twice and raising two families.



I love J. S. Bach, and my great grandfather was a bigamist. So I'll find it...


----------



## Nagelfar

Triple covalent; but that napthyl-5′ acetyloxy just kills me. That's the clincher. Gotta be awesome.


----------



## DotChem

oops wrong thread..


----------



## Nagelfar

Check out that crazy ring formation on this cocaine analog! I think I'm going to have a cubism fetish again for a while. ;-P


----------



## aced126

Nagelfar said:


> Check out that crazy ring formation on this cocaine analog! I think I'm going to have a cubism fetish again for a while. ;-P



Has this been made? Can you post a source if so?


----------



## N0 W4RN1NG

Holy hell...a hexacyclo ring appeared...(holds "down + B")


----------



## roi

Just read the image name lol

http://www.sciencedirect.com/science/article/pii/S0968089613006664

https://pubchem.ncbi.nlm.nih.gov/compound/71716368

Looks like the series are sigma agonists without much monoaminergic activity at all.


----------



## Nagelfar

aced126 said:


> Has this been made? Can you post a source if so?



Of course: N-substituted 8-aminopentacyclo[5.4.0.02,6.03,10.05,9]undecanes as σ receptor ligands with potential neuroprotective effects












roi said:


> Looks like the series are sigma agonists without much monoaminergic activity at all.



Look again, 14b has 1.2 ± 0.1 @ DAT(!!)


----------



## Pomzazed

Wow that methylaminocubane!

You made me like it from the structure beuaty itself lol


----------



## roi

Oh yeah, but that one seems to be the only one.

(1R,2S,3S,5S,6S,7R,8R,9S,10S)-N-[(3-fluorophenyl)methyl]-N-methylpentacyclo[5.4.0.0²,⁶.0³,¹⁰.0⁵,⁹]undecan-8-amine






That is such a vastly different compound, I don't think it would be fair to call it a cocaine analogue anymore.


----------



## Midnight Sun

dirt cheap, common precursors legal everywhere.  Question is whether or not the cinnamoyl ester can force a pure NMDA antagonist to fit into the MOR.  my guess is probably, just with nowhere near the potency that the corresponding levorphanol base pharmacophore would have, but that's probably a good thing


----------



## pr0d1gy

Let's talk about desoxy analogs. 






I've been reading into some literature that goes even further, replacing additional aryl ethers with alkyl moieties. At the end of the entry Shulgin discuss such compounds as desoxymescaline, wherein all substituents are alkyl groups. As he says these compounds are active in cats and man.

Interestingly, you can find the videos of the effects in cats at this link http://www.criticalpast.com/video/6...ecomes-inactive_2-4-6-Trimethylphenethylamine

I've recently sampled 2,4,6-trimethylphenethylamine at low dose. I won't post a trip report or anything because I don't have an HNMR yet. I can say it was certainly active and much as Shulgin described DESOXY. Also because I didn't find it very interesting or worth pursuing at higher doses.

Obviously the methyl group at the 4 position seems to be the deciding factor in making these compounds uninteresting. Any thoughts on why the 4 position is so essential in mescaline like compounds whereas alkyl substituents are active in 2,4,5-phenethylamines? Also thoughts on 2,4,6 substitutions in any form? TMA-6 is active so 2C-TMA-6 should be as well.


----------



## Nagelfar

roi said:


> That is such a vastly different compound, I don't think it would be fair to call it a cocaine analogue anymore.



Functional.


----------



## Nagelfar

One day, that ring is gonna be discovered to be optimized in some kinda way... I just know it...


----------



## DotChem




----------



## Solipsis

Is that pip on the left a functional substitution as is?


----------



## DotChem

phenyl isostere hopefully! .. if it is the less basic of the two Ns, it will not be charged at physiological pH! (pKa< 5??)


----------



## Midnight Sun

DotChem said:


>



reminds me, the other night I had some interesting diarylethylamine ideas--


----------



## adder

DotChem said:


>



If anything the N-phenethylpiperidine is the more basic one, but by a small margin anyway. Also, N-piperidinyl a biostere of phenyl? In what way?


----------



## DotChem

Midnight Sun said:


> reminds me, the other night I had some interesting diarylethylamine ideas--



That's good idea (the top one): a dissociative opioid stim! 
The (R) enantiomer may be a potent mu OP (~morphine, may be a bit less codeine?) (structure superimpose nicely on morphine!?) 
and the (S) may be NMDA antagonist (superimpose on DXM) and Stim compare to (S)-PVP. Something along this line were discussed in earlier thread.(can't remember exactly): 
morphinans with S stereoisomer at the C-N carbon=> NMDA antagonist
morphinans with R stereochemistry tend to give mu opioids
PS: very easy synthesis.  What is the rationale for using propargyl (I mean in the second, the lefetamine analog




adder said:


> If anything the N-phenethylpiperidine is the more  basic one, but by a small margin anyway. Also, N-piperidinyl a biostere  of phenyl? In what way?



Thats why I qualify it: Hopefully!..yes it is not really classical phenyl bioisostere like cyclohexyl (see METH analog Propylhexedrine  ). I figure, if the pKa of the N2 piperidinyl was low enough (< 6 ), the  piperidine ring won't be charged at physiological so it might have a  logP close to that of cyclohexyl. Therefore binds to the phenyl binding  site with similar affinity to Ph. But of course, since it is the most  basic it will be mostly protonotated at physiolocal pH so might not be  the best replacement fo Ph. but if the difference of the pKa of the 2 Ns  is not so large (eg 1 log unit) it might still work (10% will still be  uncharged). Cyclohexyl may be better for this purpose. 
The reason I  thought about a piperidine there , it is way more easier to synthesize  (straighforward synthesis by reacting piperidine with  1,2-dibromoethylbenzene! or substituted benzene)


----------



## adder

Does cyclohexyl really qualify as a bioisostere of phenyl? In propylhexedrine it probably only works because there's just enough space for it to act as neutral bulk, it drastically decreases potency and changes effects as well, is it even a functional DA releaser (I guess it's just an adrenergic agonist)? I thought a bioisostere is a functional group that can generally substitute for another group due to steric and electronic similarities and not a group that manages to pass as a substitute for something decreasing overall potency substantially.


----------



## Solipsis

Yeah I think it does depend, and all the variables must be checked. The phenyl you substituted in diphenidine serves too much of a different role than the phenyl in amphetamine, I believe. Probably for that reason yes ^ sounds agreeable adder.

Functional NMDA antagonists like the ACA's are modelled on NMDA and electronically mimic the carbonic acid functions of NMDA using aromatic groups loosely. While they are not exactly the heavily polar types that appear to often act as glutamate or glycine site ligands, they still carry the NMDA signature, pretty unmistakably. I personally doubt that you can just substitute the phenyl ring which is already a 'modification' into a bioisostere (i.e. broadly resembling) of a modification - that is 2 degrees removed. Could you just swap the cyclohexane in ACA's for another phenyl? Again, I doubt it since it may heavily undermine the tolerance for changes in the electronic configuration.
It seems to me that it would be so offensive to the NMDA pharmacophore that there is either a loss of potency or overall function to be expected from it.

I'm not sure if I'm right about this, mind you, but I think you can't always substitute with a cyclohexane or pip, I think you can't if the aromatic function is already a type of partial bioisostere itself.


----------



## Midnight Sun

DotChem said:


> What is the rationale for using propargyl (I mean in the second, the lefetamine analog



there really wasn't any aside from morbid curiosity: ephenidine was well-received (as far as diarylethylamines go) and I'd be curious to compare to the propargyl

that and I saw the basic skeleton lying in the morphinan structure, and was interested in approximating part of the big ol' bridge that goes from the amide to R13.  I'm sure it means diddly especially permitted to freely rotate... but whatevs.  lol 



> That's good idea (the top one): a dissociative opioid stim!



that's what methyl-ephenidine was trying to be and failed spectacularly.  Unfortunately the days of the diarylethylamines are probably for the most part over now that the usual buffet of arylcyclohexylamines are now back on the market... I say unfortunately because the latter compounds all pop for PCP on drug tests and I'd rather keep my job


----------



## Midnight Sun

random methaqualone isomer... metamethaqualone?  






ahh... probably yet another exercise in futility.  still think the following is the best hope for quinazolinone analogues (that can actually be made at a reasonable cost)--






someday... I will expend the $ to make you a reality...


----------



## Nagelfar

These aren't mine; they're dopaminergic compounds from a patent (US 4,994,486)

I thought the "Y" and trefoil _e.g._ 'Isle Of Man Flag' cyclohexane inner -ring system is the most interesting since the endo-etheno bridge when it can be stabilized in the ring configuration and kept inside.


----------



## Pomzazed

Isnt that an adamant-1-yl?


----------



## roi

Should be 20000x M or so.


----------



## pharmakos

Pomzazed said:


> Isnt that an adamant-1-yl?



yup.

in confirming my "yup" i realized something i never saw in the adamantyl group before... its essentially a polygon made up of 4 hexagons.  =p  or 4 overlapping cyclohexyl rings, if you will.  certainly wouldn't look like a regular polygon in reality, but yeah.


----------



## Solipsis

APINACA is an example of a drug containing the moiety, also amantadine and memantine..

if you always wanted to feel adamantyls in your body  (I don't believe you find them in nature, apart from adamantane in oil) Hehe they classify it a tricycloalkyl... the fourth one is implied ;p you can't count it without "breaking the fourth wall".

Roi, is that a secondary amine?  ^ I'm curious..


----------



## Pomzazed

@Solipsis
That roi's opioid's amine has a phenethyl attached to it, so tertiary.

@pharmacos
lol *that's the "beauty" of adamantyl*, or a diamond. If you interest in this kind of shape try googling nanodiamond (or diamondoid) structure or so,
they are like adamantyl bulked with each other side by sides; in the same way of forming diamond structure.
Yet they are still organic molecule (even with vapor pressure; sublimable slowly) and has hydrogens around in the outer.


----------



## DrugDesigner

Would the molecule I designed be Psychoactive or psychedelic at all? I started with the classic bromo-hemiFLY structure, and then added a D-methamphetamine structure to it sharing the same benzene ring, I also added the structure for DMT on the bottom sharing the same benzene ring as the other two. Basically We have three different compounds that are all psychoactive on their own, and then combining all three into one big compound with all three compounds sharing the same singular benzene ring at the center. 

I am really interested in designing psychoactive molecules especially psychedelic ones. Very interested to learn and understand pharmacology and the chemistry behind this. Is there any way I could virtually test this novel compound for possible psychoactivity on my computer? or like a program that simulates and predicts the psychoactivity or pharmacological action of a novel compound? I would love to be able to somehow test novel compounds for psychoactivity and binding affinity and such without having to do it in real life - that would be basically impossible.  I am already using a program called ToxTree to test for toxicity, but no matter what even for water it always says that every compound I enter in is extremely toxic. Are there any other GUI programs for mac that accurately test for toxicity?

TL;DR: designed this compound, wondering if it would be psychoactive/psychedelic in effects. Looking for any way to virtually test or simulate the pharmacological action of compounds on the computer or online






[/URL][/IMG]


----------



## roi

14-Phenylpropoxymetopon / N-Phenethylnormorphine hybrid. Could get rid of the 5-methyl group to increase potency and probably some other substitutions as well, but eh...


----------



## Solipsis

Pomzazed said:


> @Solipsis
> That roi's opioid's amine has a phenethyl attached to it, so tertiary.



Oh yea, thought it was on the morphinan, it wasn't clear - though that clearly would have been too unusual a place for a substitution, esp one like that, wasnt using my head.



DrugDesigner said:


> Would the molecule I designed be Psychoactive or psychedelic at all? I started with the classic bromo-hemiFLY structure, and then added a D-methamphetamine structure to it sharing the same benzene ring, I also added the structure for DMT on the bottom sharing the same benzene ring as the other two. Basically We have three different compounds that are all psychoactive on their own, and then combining all three into one big compound with all three compounds sharing the same singular benzene ring at the center.
> 
> I am really interested in designing psychoactive molecules especially psychedelic ones. Very interested to learn and understand pharmacology and the chemistry behind this. Is there any way I could virtually test this novel compound for possible psychoactivity on my computer? or like a program that simulates and predicts the psychoactivity or pharmacological action of a novel compound? I would love to be able to somehow test novel compounds for psychoactivity and binding affinity and such without having to do it in real life - that would be basically impossible.  I am already using a program called ToxTree to test for toxicity, but no matter what even for water it always says that every compound I enter in is extremely toxic. Are there any other GUI programs for mac that accurately test for toxicity?
> 
> TL;DR: designed this compound, wondering if it would be psychoactive/psychedelic in effects. Looking for any way to virtually test or simulate the pharmacological action of compounds on the computer or online
> 
> 
> 
> 
> 
> 
> [/URL][/IMG]



http://www.bluelight.org/vb/threads...-molecules?p=13546642&viewfull=1#post13546642

Your molecule combines phenethylamine and tryptamine backbones, but there are a few problems:
- you have two separate ethylamine / propanamine backbones there on the right side
- a hybrid is already problematic because the substitutions are not mutually compatible, and even less when they are not overlaid properly which is what happened here and what causes the double sidechain. If you check my link, the top two show ways there is I think a better matching overlay, hybridizing the structures.
- like I said: some things like the bromo from the PEA is probably not well tolerated on that position on the tryptamine - you are trying to put a number of features in there that really push the limits - it's best to first keep it as simple as possible. Simpler than mine as well, cause I was just playing around really. But to summarize, I'd remove that methaminopropyl group on the top right and the bromo to get a constrained 5-MeO-DMT. Regarding methylenedioxy PEAs with the MDO at a different place than the 3,4 in MDMA, they should be present as entries in PiKHAL.
- I think hybrids should be designed very carefully, often the difference (between say PEA and tryptamine) means some sort of different geometry with regard to the receptor, so if you modify the backbone so heavily, it may be moved a bit, and suddenly you get very different tolerance for groups that were previously very effective. Inconsistencies like that can cause a hybrid to try and satisfy two different models, but neither really applies anymore so it fails at both.
Occasionally hybrids to turn out to be possible, which is IMO always pretty awesome.

Also
http://www.bluelight.org/vb/threads...-molecules?p=13637699&viewfull=1#post13637699

Testing the structure requires software for computational binding studies..

https://en.wikipedia.org/wiki/Molecular_design_software
https://en.wikipedia.org/wiki/Quantitative_structure–activity_relationship

If designing more simple analogues, you can try overlaying models that calculate similarity of the physical properties, some things can be inferred from that I think.
But ideally wait for the professionals to "cheme" in


----------



## DrugDesigner

Thanks for the input @solipsis 

It seems that I am on a kick with -FLY derivatives. They interest me a lot. I was wondering if any of the following -FLY derivative would be in theory psychoactive at all. 

Thanks! 






[/URL][/IMG]


----------



## Solipsis

Bromo-Dragonfly is actually more like a trivial name for DOB-Dragonfly ("Bromo" specifies nothing about the sidechain), so the upper compound is DOB-FLY.

As your 'bromo-butterfly' is similarly a suggested trivial name for DOB-butterfly, the bottom one cannot be TFM-butterfly but must be DOTFM-butterfly because of the alpha-methyl.

I'm not certain if you can use the phrase 'fully aromatic' like that, maybe you can - but the stingray compound is not entirely planar (flat) because the methoxy part of the 'wings' will affect the angles because of the hybridization of the type of bonds oxygen makes. Call it unsaturated instead. 

2C-B-FLY is not far off in dosage and duration to the parent compound 2C-B, only it has constrained methoxies which may help selectivity of action like LSZ compared to LSD.

DOB-FLY would really be expected to be similar to DOB in dosage and duration but again with slightly different or more selective effect, as the conformation may not satisfy all receptor binding energies quite as easy as a floppy methoxy. It would be interesting to see how stimulating it feels, as apparently despite being amphetamines DOX don't really behave like amphetamines at all I think, well according to @Ebola? . More selective effect could fix the stimulation despite still technically being an amphetamine. Or for all we know it could be just different or a bit worse.

All kinds of combinations of structure like Butter-  Hemi-  etc have been proposed, but afaik they are not that easy to synthesize and are largely unexplored. It's really excellent that 2C-B-FLY is on the market, but it may already be pushing the market 'demands'. It would be great to see another niche constrained PEA, but I think it will only happen if there is a particularly excellent idea that is experimentally sampled and found to be a really special gem.


----------



## adder

If there is anything worthwhile still to find in the cathinone series, I bet it's at least one of these:


----------



## belligerent drunk

Solipsis said:


> *Functional NMDA antagonists like the ACA's are modelled on NMDA and electronically mimic the carbonic acid functions of NMDA* using aromatic groups loosely. While they are not exactly the heavily polar types that appear to often act as glutamate or glycine site ligands, they still carry the NMDA signature, pretty unmistakably. I personally doubt that you can just substitute the phenyl ring which is already a 'modification' into a bioisostere (i.e. broadly resembling) of a modification - that is 2 degrees removed. Could you just swap the cyclohexane in ACA's for another phenyl? Again, I doubt it since it may heavily undermine the tolerance for changes in the electronic configuration.
> It seems to me that it would be so offensive to the NMDA pharmacophore that there is either a loss of potency or overall function to be expected from it.



Are you sure about that? I know that it's a pretty popular thought, but seems rather bullshit to me.






NMDA's both carboxyls would be deprotonated and would have a negative charge, which is significantly different from, in this example, an aromatic methoxy- and regular keto groups. And also, what's with the rest of the aliphatic and aromatic bulk? To me, it doesn't look like an NMDA bioisostere at all.

ACAs bind to the PCP site, don't they? PCP itself doesn't have oxygens at all, so it only strengthens the point that they don't mimic NMDA's electron structure at all, even if their structures on paper may "look NMDA-like".


----------



## pharmakos

was covered a few pages back in this thread IIRC... i believe glutamate and MXE bind to different sites on the NMDA receptor, so any structural similarity is merely coincidental


----------



## Nagelfar

Pomzazed said:


> Isnt that an adamant-1-yl?



Are those actually two differing conformations of the ring that exist in physics? What would the inner formation of the ring differing be called? I know outer perimeters have names like ring, boat, chair, twist boat, etc.

Exogenous Monoamines? =


----------



## DotChem

adder said:


> Does cyclohexyl really qualify as a bioisostere of phenyl?..





Solipsis said:


> Yeah  I think it does depend, and all the variables must be checked. The  phenyl you substituted in diphenidine serves too much of a different  role than the phenyl in amphetamine, I believe. Probably for that reason  yes ^ sounds agreeable adder.
> 
> It seems to me that it would be so offensive to the NMDA pharmacophore  that there is either a loss of potency or overall function to be  expected from it....
> ....I'm not sure if I'm right about this, mind you, but I think you  can't always substitute with a cyclohexane or pip, I think you can't if  the aromatic function is already a type of partial bioisostere  itself.



IMHO The whole concept of bioisoterism should be taken with a pinch  of salt.  It all depends on what one is trying to achieve: eg
beat the law while retaining all biological properties of the drug (this is the easiest: just add a methyl!)
beat the competition as with big Pharma me-too drugs  
increase affinity and/or target selectivity, modify PK parameters...etc etc 

For  Phe-->Cyclhx replacement, binding pockets of simple Phenyl of the  drug on its target protein can accomodate a cyclohexyl in general. Why?  because main types of interactions involving simple Phenyl (logP = 1.9)  are hydrophobic in nature so yeah the cyclohexyl (log p =2.6 ) can  satisfy that. even better since it is bit more interactions.  Sometimes  pi-stacking and/or charge transfer may also contribute like when the  pocket is made-up of aromatic side chain residues of the protein.  But  in general the gain/loss in affinity is not a lot (+/- 2xKi may be 10x  at most of the parent). So depending on what one is trying to do, one  one can live with that.  With a cyclohexyl, steric consideration also  may play a role..(this is probably most crucial factor ie if the pocket  is a bit tight to fit since the cyclohexyl is not as flat as Ph.

With  AMPH and Propylhexedrine, I dont know the detail (like SAR..etc). It  was just an example that came from top of my head). With NMDA antagonist  



Solipsis said:


> Functional NMDA antagonists like the  ACA's are modelled on NMDA and electronically mimic the carbonic acid  functions



That prove the point I was trying to make: it  really depends. Nobody would have thought of a 3-Methoxyphenyl as a  replacement for the propionic side chain of NMDA!! Whoever first  discover that, I bet you, it was pure serendipity. just like 80% of the  drug discovery business.  Random screening, not that the guy woke up one  day and said I am gonna put a 3-methoxyphenyl as a bioisteric  replacement of NMDA COOH and see what happen.

That means the site  where the NMDA COOH binds is rather either promiscious or it doesnt  contribute much in term of the affinity of NMDA to its receptor. May be  it does in terms of recognition of the substrate by the receptor ie  thermodynamic vs kinetic control of the binding.. but we're getting too  far in speculations re: phenyl replacement of diphenidine.  

I  guess bottom line is If that site can accomodate a Ph it can potentially  also accomodate a cyclohexyl...but each SAR is rather unique so who  knows?

It work with a 2-pyridyl : 









> Lanicemine differs from ketamine in that it is a _low-trapping_ NMDA receptor  antagonist, showing similar rapid-acting antidepressant effects to  ketamine in clinical trials but with little or no psychotomimetic side  effects


What do they mean by "low-trapping NMDAr anatagonist? slow binding: k(on)<<k(off) ? I don't get it!!


----------



## Solipsis

I doubt that it is really coincidental about the NMDA backbone but okay. Unfortunately the PCP site is an orphan site, and yes let it be clear that we are speculating.. No NMDA is not the target ligand and no dissociatives are not exact bioisosteres of it; personally I'd expect something along the lines of the middle part being rather NMDA-like but the terminal sites having a certain electronic / aromatic interaction to change the conformation of the channel for NMDA trapping. But its just a fantasy of mine. How is it not suspicious though, that nearly all dissociatives conform to that NMDA similarity but with the terminal moieties having different properties than the carboxyls. The question would be: different how, and what is the tolerance there sterically and electronically. (It would be a huge help if someone could illustrate this with some SAR.

A side-question about this whole ordeal: would ketamine with a phenyl instead of the cyclohexane work just as well? If not, why not? The why not would be relevant to my point here.

The main thing about the pip was that it seems like it has properties unlike other moieties found right about there in other dissociatives. For all we know it could work, and yes clearly pip is a bioisostere of phenyl in a number of ways. Still, the novelty of it made me curious which is why I skeptically tried to ask about it being consistent with other NMDA antagonists. Plenty of modifications could probably be made that defy the current model we have of what NMDA antagonists look like. What I want to know is: are the reasons for expecting it to behave similarly good reasons?


----------



## belligerent drunk

If you want to replace the cyclohexyl in ketamine with a phenyl ring, then it can't have the keto moiety. PCP doesn't have it, but even if you replace the cyclohexyl with a phenyl in PCP, then the nitrogen would be much less basic (aniline derivative), and possibly not protonated enough at physiological pH. Not sure how this would affect binding and activation, or lack thereof. If there was none of these problems, then a phenyl ring _could_ substitute for a cyclohexyl - electronically they're not that much different, phenyl is a little bit more polar and polarizeable; however, sterically a phenyl is planar, whereas cyclohexyl tends to be bent (boat/chair conformations).


----------



## Solipsis

Oh yeah, that's right forgot about the keto..

1-cyclohexyl-1-ethylaminocyclohexane then?


----------



## roi

So this MDA 2-aldoxime analog recently popped up in a few pills on ecstasydata. Probably not very active, but could it be psychoactive at all?


----------



## pharmakos

is that just an artifact from bad synthesis?


----------



## Solipsis

Yeah it's an intermediate.. but I can check Shulgin's last big book to see if I see any PEA's with an extra methylene spacer.. (let alone an aldoxime, which just seems reactive))?


----------



## roi

There's some stuff like (+)-CPCA with that spacer, but it's heavily modified. The N-hydroxy group shouldn't matter much, but that doublebond? No idea.


----------



## Nagelfar

roi said:


> There's some stuff like (+)-CPCA with that spacer, but it's heavily modified. The N-hydroxy group shouldn't matter much, but that doublebond? No idea.



CPCA/nocaine is a DRI not a DRA; the carbmethoxy is just like that on cocaine & methylphenidate.


----------



## malmet

Question about planar rings and such; couldn't cyclohexadiene work as an isostere? It's a lot flatter than cyclohexane:

Amphetamine: https://i.imgur.com/wiFudTm.png
1,4-Cyclohexadiene analog: https://i.imgur.com/ipiNJDU.png
Cyclohexane analog: https://i.imgur.com/4TlqmpW.png

You have the hydrogens on the saturated carbons sticking out of plane but the rest is flat. It's not aromatic of course but I'm curious as to how it would work out.


----------



## Nagelfar

malmet said:


> Question about planar rings and such; couldn't cyclohexadiene work as an isostere? It's a lot flatter than cyclohexane:
> 
> Amphetamine: https://i.imgur.com/wiFudTm.png
> 1,4-Cyclohexadiene analog: https://i.imgur.com/ipiNJDU.png
> Cyclohexane analog: https://i.imgur.com/4TlqmpW.png
> 
> You have the hydrogens on the saturated carbons sticking out of plane but the rest is flat.



EDIT: Nevermind, I was thinking benzene, yes cyclohexadiene is closer to benzene than cyclohexane. Some of those cyclopentane isostere have a few hydrogens out of plane too, so I'd venture it a possibility depending on where and how it needs to fit.


----------



## belligerent drunk

Solipsis said:


> Yeah it's an intermediate.. but I can check Shulgin's last big book to see if I see any PEA's with an extra methylene spacer.. (let alone an aldoxime, which just seems reactive))?



It would most likely hydrolyze into the respective aldehyde and hydroxylamine. The aldehyde would probably not be very useful.


----------



## adder

Probably a totally made up thing or an error, hydroxylamine is toxic.


----------



## DotChem

malmet said:


> Question about planar rings and such; couldn't cyclohexadiene work as an isostere? It's a lot flatter than cyclohexane:
> 
> Amphetamine: https://i.imgur.com/wiFudTm.png
> 1,4-Cyclohexadiene analog: https://i.imgur.com/ipiNJDU.png
> Cyclohexane analog: https://i.imgur.com/4TlqmpW.png
> 
> You have the hydrogens on the saturated carbons sticking out of plane but the rest is flat. It's not aromatic of course but I'm curious as to how it would work out.



cyclohexadiene is unstable under normal conditions: easily oxidized by air to give the corresponding benzene (driving force = aromaticity energy gain).  This is the reason why products of such compounds always contain [Oxidation] inhibitor such as BHT.  But if one of the two sp3 carbons of the cyclohexadiene is di-substituted (say by 2 methyls), then it should be fine. But disubstitution of one of these carbons will make you loose even more in terms of planarity of the system).


----------



## DotChem

MXE: open wide


----------



## adder

> If you want to replace the cyclohexyl in ketamine with a phenyl ring, then it can't have the keto moiety.



You can't have both the amine and the aryl group either, you end up with biphenyl or a substituted aniline.


----------



## Jaw Clenching

DrugDesigner said:


> Thanks for the input @solipsis
> 
> It seems that I am on a kick with -FLY derivatives. They interest me a lot. I was wondering if any of the following -FLY derivative would be in theory psychoactive at all.
> 
> Thanks!



Did you see these ones I came up with?

http://www.bluelight.org/vb/threads...-molecules?p=13637715&viewfull=1#post13637715

http://www.bluelight.org/vb/threads...-molecules?p=13637708&viewfull=1#post13637708

http://www.bluelight.org/vb/threads...-molecules?p=13637699&viewfull=1#post13637699

Not sure if some of those are even possible to make.

I couldn't find any molecules that have a Pyrrole group attached to an Indole group - basically di-indole or something.

Here's an example to better visualize what I'm saying:


----------



## Nagelfar

malmet said:


> Question about planar rings and such; couldn't cyclohexadiene work as an isostere? It's a lot flatter than cyclohexane:
> 
> 
> 
> Spoiler: Large images
> 
> 
> 
> Amphetamine:
> 
> 
> 
> 
> 1,4-Cyclohexadiene analog:
> 
> 
> 
> 
> Cyclohexane analog:
> 
> 
> 
> 
> 
> 
> 
> You have the hydrogens on the saturated carbons sticking out of plane but the rest is flat. It's not aromatic of course but I'm curious as to how it would work out.





DotChem said:


> cyclohexadiene is unstable under normal conditions: easily oxidized by air to give the corresponding benzene (driving force = aromaticity energy gain).  This is the reason why products of such compounds always contain [Oxidation] inhibitor such as BHT.  But if one of the two sp3 carbons of the cyclohexadiene is di-substituted (say by 2 methyls), then it should be fine. But disubstitution of one of these carbons will make you loose even more in terms of planarity of the system).





Spoiler: Nothing to do with the idea, just in there and big











Check out the two position, though the cyclohexadiene idea is on the three position where the arene is.





it looked like this:




...and, ironically, made the H saturated angles connected with the hope that it would come out more planar with a single carbon linking two more internal/inward-facing methylenes:

(not thinking, that duh, the one carbon between two linkers is CH2 still; could just double-bond those two but the 2D result isn't as aesthetically pleasing for a random molecule to show off)





and upon "cleaning" it got the rectangular box of the first image. Is that thing even physically possible? Tenable?

And finally:






Some kinda naphthdiene-endo-ethendio

...if you 'clean up' the image automatically in Marvin Beans.... it transforms into 






...Gengar the Pokémon:


----------



## belligerent drunk

adder said:


> You can't have both the amine and the aryl group either, you end up with biphenyl or a substituted aniline.



Yeah I didn't consider that the carbon is already quaternary. My bad.


----------



## Bagseed

>


at least this one won't be possible in my opinion. sp2 hybrid orbitals are oriented in a planar fashion. so you cannot have these bonds from the C=C sticking downwards the way they do. energetically extremely unfavorable.

also this diazo group forming the 3-ring will be extremely reactive and might disintegrate very fast to release nitrogen gas (possibly leaving behind a carbene which is very reactive and might turn the olefine into an alkine).


----------



## Nagelfar

Bagseed said:


> at least this one won't be possible in my opinion. sp2 hybrid orbitals are oriented in a planar fashion. so you cannot have these bonds from the C=C sticking downwards the way they do. energetically extremely unfavorable.
> 
> also this diazo group forming the 3-ring will be extremely reactive and might disintegrate very fast to release nitrogen gas (possibly leaving behind a carbene which is very reactive and might turn the olefine into an alkine).



Yeah well it was rather fatuitous, as my work if oft meant to be; but what of the one above it?


----------



## Bagseed

well, to be sure one would have to model the exact bond angles of that thing... sp3 carbon is most comfortable with a nice tetrahedral (~109° bond angles) structure, I guess there will be some strain on the bonds, but I have no idea if it will be practically possible.


----------



## LaGaFàNi

Totally new here, but I've got some 700 arylcyclohexylamine molecules schemed out on pdf / jpeg (according to the possible substitutions listed on wikipedia..) If any interest at all, I'll post them w/pleasure!


----------



## Nagelfar

Back to malmet's cyclohexadiene idea; would this be stable? -


----------



## Nagelfar

Fentanyl + O-desmethyl-tramadol (the methoxys)


----------



## roi




----------



## DotChem

> A *hemiaminal* (also *carbinolamine*) is a functional group or type of chemical compound that has a hydroxyl group and an amine attached to the same carbon atom.....  Those generated from primary amines are unstable to the extent that they  have never been isolated and very rarely been observed directly. In a  2007 study a hemiaminal substructure trapped in the cavity of a host-guest complex was studied with a chemical half-life of 30 minutes....  https://en.wikipedia.org/wiki/Hemiaminal


----------



## Dresden

Solipsis mentioned the ethylamino analogue of this, and I felt it deserved to be structurally pictured.


----------



## Dresden

roi and Nagelfar, 

Could ya'll please stop posting aminals and hemiaminals.  They almost never exist.


----------



## LaGaFàNi

https://imgur.com/yR0DWfF
Just gonna leave this one here


----------



## belligerent drunk

Depending on the solvent, hemiaminals would decompose into either a carbonyl, or an imine.


----------



## Midnight Sun

Santa Claus isn't real either but that doesn't stop him from molesting little boys every Christmas






Inspired by 4-OH-MPMI after I overlaid its structure onto LSD and saw this little guy.  Doubt it'd play too nice with 5ht tho.  Probably better to remove all the phenyl subs


----------



## Nagelfar

Methylphenidate inspired.


----------



## Dresden

I have read that most ghb analogues are not active, but I still was inspired by pregabalin and ghb to draw out this one:


----------



## Dresden

The N-( 2-phenylethyl) analogue of trazodone has been found to be a super potent DRI.  This one is the haloperidol version:


----------



## DotChem

^ too close to the potent mu opioid agonist pheneridine.. or was it the idea ie OP agonist from haloperidol + trazadone?


----------



## Dresden

I'm not really sure what it would do.


----------



## Pomzazed

Idk why, this idea pops up in my head immediately when i see the picture.
I dont have evidence of it at all, it is just my own thought.

Looks much like MPP+ parkinsonism to me (MPP+ acts on dopamine system even)


----------



## adder

There is no reason why haloperidol would not undergo such dehydration and then oxidation. But does it happen?


----------



## Solipsis

Apparently so


*NSFW*: 














> [...] no confirmation of the "pyridinium hypothesis," which suggests haloperidol pyridinium metabolites to be the origin of adverse effects and decreased therapeutic effect, can be derived from this study. However, the authors emphasize that pyridinium metabolites cannot be excluded as the origin of decreased therapeutic effect in long-term treatment and of adverse effects not investigated in the present study, such as tardive dyskinesia. Finally, it is concluded that the serum concentration of the parent drug remains the main variable of interest in the therapeutic drug monitoring of haloperidol during short-term treatment.



http://www.ncbi.nlm.nih.gov/pubmed/10770460

So it's a suspect alright, even if this study does not confirm the hypothesis. Interesting hypothesis in the first place.


----------



## DotChem

Pomzazed said:


> Idk why, this idea pops up in my head immediately when i see the picture.
> I dont have evidence of it at all, it is just my own thought.
> 
> Looks much like MPP+ parkinsonism to me (MPP+ acts on dopamine system even)


You're perfectly right that's the first thought that should come to mind  looking at this molecule. But IMHO, the phenethyl pyridinum would  (could! should!?) in principle probably undergo spontaneous beta  elimination to give styrene and 4-Chlorophenylpyridine. Driving force  being that the pyridinium is a very good leaving group and the energy  gain of the resonance conjugation of the resulting styrene . Unlike with  the MPTP with a MethylPyridinium with no possibility of beta  elimination..So it shouldnt have MPTP like toxicity (in principle!!)  What could happen in the brain.. who knows?











with MPP, one gets: 













MPP(+) 

nb:I think same thing might be happening with Haloperidol (further beta eleimination leading to less harmful metabolites ! So far there is no evidence that toxic pyridinium metabolites were generated from Haloperidol (correct me if I am wrong!


----------



## Nagelfar

Hetero-Prozac? -






another cocaine analog:


----------



## sekio

Trifluorosilyl group? And what is that sulfur based heterocyclic abomination? You'd never see a RC=SH(O)-(R) group in reality, sulfur doesn't like being double bonded to carbon AND to oxygen, and even less so with a lone hydrogen atom on there too...


----------



## Nagelfar

sekio said:


> Trifluorosilyl group? And what is that sulfur based heterocyclic abomination? You'd never see a RC=SH(O)-(R) group in reality, sulfur doesn't like being double bonded to carbon AND to oxygen, and even less so with a lone hydrogen atom on there too...



The triflorosilyl inspired from the phenyltropane tri-methyl-silyl-ethynyl

Speaking about ethynyl; What about triple bonded? Just fly apart? Maybe no oxygens and good parallel triple bonds on my sulfur (would need room to grow erect, and foil my nice passive feminine (or not passive but rather unstable? then feminine like Uranus castrated, the retroactive patron mystic deity of explosions /expulsions?) pent-agon/-ane cycle






OK, no oxy-carb AC/DC two-way double bigamy cheating heteroatom-bending gender infidelity. I am just trying to get the spirocyclic (without the direct fused benzene as some existing cocaine analogs using the spirocyclic cyclopentane group fused to the tropane) and instead have the phenyl which gives it the same distance as Coca-erythroxyline-classic (though the rigidity may not be able to bend and flex to fit into the ligand site quite the same, IIRC cocaine bends unlike phenyltropanes at that juncture .

Anyhow, sek, why still bite the bait, you know when I post cocaine analogues or phenyltropanes they are attemptedly superfluous and more of a "cubist" attempt at selective retention / creative limitation as to visual 2D art within the constrains of the design of skeletal molecular chemistry. ;-p

EDIT:

*This* must have been the subconscious reason I kept putting sulfur to the spirocyclic pentane ring:






Double spiro-pentane.



Spoiler: CLEANED - how it forms its skeleton within actual space using least energy? Anyhow, spoiler indeed: L.O.L.!!


----------



## DotChem

ephenidine + DMT ..


----------



## Dresden

Alcohols are generally metabolically oxidized, not dehydrogenated.


----------



## Dresden




----------



## roi




----------



## Bagseed

Dresden said:


>


Naphcyclidine?


----------



## Dresden

That name sounds good to me.


----------



## Nagelfar

^Sigma agonist type inspired






^Cleaned it doesn't look too much different in ultimate length than RTI-298 type and their "remote binding domain"


----------



## Nagelfar

Some interesting restricted rotational analogs of methylphenidate. Since finding this paper I'm going to be harried with the urge to add these tables to my analogs list on WP, already got it printed off, they are interesting, going by the assumption that decreased conformational flexibility leads to increased binding:


----------



## niflheim

2-MeO-PBPy


----------



## aced126

Nagelfar said:


> Some interesting restricted rotational analogs of methylphenidate. Since finding this paper I'm going to be harried with the urge to add these tables to my analogs list on WP, already got it printed off, they are interesting, going by the assumption that decreased conformational flexibility leads to increased binding:



Thanks for this find


----------



## Retired Trashcan

I'm new to this thread, but not to BL. I love looking at all of you guys and gals crazy molecules and discussion.  Excellent fun for someone back in school taking chem classes.  I can't draw yet, but I'd be curious to see some phenibut/GABA drugs tweaks so to speak. Thanks and keep up the great work! :D

EDIT:  Damn that shaggyfin was a trip... lol 
            Someday I'll be educated enough to draw them, but til then, are question and comments welcome from a 'noob'?


----------



## Solipsis

I imagine so if it doesn't flood the thread, but you can always switch to PMs..  nice that you take an interest, hopefully you'll keep that up..

Here's an idea:






The above is the niacinoyl amide of some novel fantasy gabapentinoid... the idea is that as in picamilon you'd hope to get it across the BBB before hydrolyzing to the parent compounds whereas most gabapentinoids fail since they use the system L transporter. Pregabalin and 4-methylpregabalin are like mimics of the endogenous substrate for that transporter: leucine and isoleucine... if it doesn't look like those, the transporter is not interested. So would a niacinoyl facilitate this? By the way what transports phenibut across the BBB?
The original idea was to draw a niacinoyl on one of the gabapentinoids Pfizer designed (mentioned in Beliotti paper?) that were found to be quite effective in vitro but are not accepted by the amino acid transporter... however I have no access to the full paper so I don't know what actually effective analogues are - so I drew a t-Bu for the basic idea.

The one below is the methionine analogue of pregabalin but I have no clue if it has a chance in hell to use system A.

Picamilon is quite nice by the way, much less sedating than most other GABAergics or GABA itself. The above compounds are not GABAergics to of course.


----------



## Retired Trashcan

Solipsis;13713494

Here's an idea:

[IMG said:
			
		

> http://i.imgur.com/KwJdJHW.png[/IMG]
> 
> By the way what transports phenibut across the BBB?
> 
> The one below is the methionine analogue of pregabalin but I have no clue if it has a chance in hell to use system A.
> 
> Picamilon is quite nice by the way, much less sedating than most other GABAergics or GABA itself. The above compounds are not GABAergics to of course.



Thank you. I won't ask all the time. Just watching, learning, studying.  Chemistry is the most FASINATING I know of.  Phenibut crosses on the phenyl ring, pregabalin, btw (I know you know) crosses(Very Well at 90% BA Oral) on the isobutyl ring.


----------



## Solipsis

No I mean what is the transport mechanism, not what functional group makes it able to cross some way or another..   The BBB has various kinds like iirc passive diffusion or what's it called - just a sort of encapsulation of a compound that gobbles a molecule up and poops it out on the other side, and proteins designed to transport necessary chemicals into your brain like those amino acid transporter systems..
Phenibut just diffuses on account of its log P?

But you are correct about the groups substituted on GABA for those compounds.. 
Still enjoying previous pages?


----------



## aced126

Retired Trashcan said:


> Thank you. I won't ask all the time. Just watching, learning, studying.  *Chemistry is the most FASINATING I know of.*  Phenibut crosses on the phenyl ring, pregabalin, btw (I know you know) crosses(Very Well at 90% BA Oral) on the isobutyl ring.



This.


----------



## Solipsis

Yeah its really the 2C-B's knees!


----------



## Retired Trashcan

Solipsis said:


> Yeah its really the 2C-B's knees!
> Still enjoying previous pages?



I think I've made it to page 112, all the way from page one.  My mind is blown that there is all this knowledge out there to be absorbed on this page. Y'all come up with ideas, critique each others work, crack jokes. Best page on BL (Gee, sorry Lounge ) I don't want to get the thread off topic, but if I have a pertinant question or idea, I'll chime in. Oh, and I did learn a lot from S Fin the fragrance guy, lol.  I will finish Chem before I propose crazy molecules that won't do s---.  I'm learning just reading this. Awesome. Carry on. 

EDIT: I believe LAT-1 is the transporter Solipsis. Damn, I feel like I'm in class, jk.


----------



## Solipsis

Yeah makes me wish I didnt eventually flunk it all in college..

People here do propose crazy chemicals, after all it is the random molecules thread so anything will do... but I guess there is different kinds of crazy, and at some point some kinds are imo a little pointless - others are entertaining, interesting etc, or educating to the poster or just in general.. imo - Mr fin didn't get that message, but don't wait too long participating either.. but yeah some fundamentals of organic chemistry and checking out multiple compounds in a 'family' or 'category' might be a minimum..

Why do you believe its the LAT-1 (I think this refers to the system L i was previously talking about ^ )? It's fine if you don't post sources from digging around online - i do it all the time, if you instead provide a rationale :D again imo


----------



## Retired Trashcan

Solipsis said:


> Why do you believe its the LAT-1 (I think this refers to the system L i was previously talking about ^ )? It's fine if you don't post sources from digging around online - i do it all the time, if you instead provide a rationale :D again imo



I was sure when I was reading up on PBT that I saw that LAT was the transporter, but I'm a rookie in that department for sure.


----------



## sekio

Nagelfar said:


> Some interesting restricted rotational analogs of methylphenidate. Since finding this paper I'm going to be harried with the urge to add these tables to my analogs list on WP, already got it printed off, they are interesting, going by the assumption that decreased conformational flexibility leads to increased binding:



Hm, and some of these remind me of the "seco" opioids / restricted rotation pethidine anaogs.

Cmpd 12a looks particularly tasty


----------



## DotChem

H ---> NO2 increase mu ~2000x (like in https://en.wikipedia.org/wiki/Etonitazene
2H ---> 2NO2 increase mu ~ 4,000,000 times (theoretical speculation! 
Fenta is ~ 100xmorphine therefore 





about 400,000,000X more potent than morphine as a mu opioid agonist!? 

or more reasonable:





Only 200,000x morphine!..


----------



## Dresden

I've always thought this one would be a duesy.


----------



## Dresden

An ultimate drug/poison?


----------



## Dresden

And while I'm on a nitro kick...


----------



## white55

adder said:


> If there is anything worthwhile still to find in the cathinone series, I bet it's at least one of these:



i've talked to a vendor about bk-5-mapb and bk-6-mapb.... they said that the synths of the non bk compounds are problematic enough since you either have to start from relatively far off precursors or buy expensive close precursors and that the bk versions would be competing for the same rare/expensive precursors and all that for a less potent and probably less enjoyable end product so making either doesn't make much sense right now..... now if someone was swimming in excess precursors for 5 or 6 mapb then making some of the bk versions shouldn't be too problematic


----------



## Solipsis

I'm interested in what some of those will do as a number of the parent compounds can be quite serotonergic while a lot of beta-ketones can be pretty dopaminergic... I wonder, is their dopaminergic action basically similar to the dopaminergic action of the parent only without most of the serotonergic (and maybe then a little less potent)?


----------



## adder

white55 said:
			
		

> i've talked to a vendor about bk-5-mapb and bk-6-mapb.... they said that the synths of the non bk compounds are problematic enough since you either have to start from relatively far off precursors or buy expensive close precursors and that the bk versions would be competing for the same rare/expensive precursors and all that for a less potent and probably less enjoyable end product so making either doesn't make much sense right now..... now if someone was swimming in excess precursors for 5 or 6 mapb then making some of the bk versions shouldn't be too problematic



Yes, I know about that, it is indeed virtually impossible to selectively substitute the less activated ring in benzofuran, so a completely different approach from usual amphetamine routes is necessary, and efficient methods rely on transition metal catalysts at some point which is certainly problematic on a market scale for a couple of reasons, I guess you can't run away from that, so the first thing to do would be to find a cheap and efficient catalyst. Working with large quantities of mixtures of positional isomer products is another problem if you don't have large preparative columns to separate them. It is nonetheless an interesting problem to solve and those beta-keto analogues might be very interesting themselves even if much of that is caused by their rarity.  MDMA wasn't really the cheapest substance to produce from natural compounds either after all, but high demand for it prompted some synthesis advancements that were worked out by _freelance_ chemists.


----------



## DotChem

The nitro analog psilocibin looks pretty neat.. as for nitro amphetamines, here is one according to Shulgin.. DOx class.. DON entry in PIHKAL:




#70 DON 
2,5-DIMETHOXY-4-NITROAMPHETAMINE


----------



## Dresden

2CN made an appearance on the rc market a few years ago:


----------



## white55

adder said:


> Yes, I know about that, it is indeed virtually impossible to selectively substitute the less activated ring in benzofuran, so a completely different approach from usual amphetamine routes is necessary, and efficient methods rely on transition metal catalysts at some point which is certainly problematic on a market scale for a couple of reasons, I guess you can't run away from that, so the first thing to do would be to find a cheap and efficient catalyst. Working with large quantities of mixtures of positional isomer products is another problem if you don't have large preparative columns to separate them. It is nonetheless an interesting problem to solve and those beta-keto analogues might be very interesting themselves even if much of that is caused by their rarity.  MDMA wasn't really the cheapest substance to produce from natural compounds either after all, but high demand for it prompted some synthesis advancements that were worked out by _freelance_ chemists.


Well, from what they told me they are first going to work on making 5 and potentially 6 mapb, since they believe that those two compounds make more sense to make, but if they ever end up with a huge surplus of the required precursors/lab time/demand they might make some of the bk versions.


----------



## Dresden

Maybe I had an idiosyncratic effect, but I really thought that 100mg of






5-MAPB sucked.


----------



## white55

Weird. In what way did it suck?


----------



## white55

a few 2-fma analogs


----------



## neurotic

white55 said:


> Weird. In what way did it suck?



I'd imagine in the same way e.g. MDAI tends to suck i.e. plenty of serotonin, but not even nearly enough catecholamines - which tends to suck. People usually try to combine 5-MAPB with a proper stimulant for the experience to be 'complete'.

And oh I so wanna try the β-keto benzofurans, I think they might be right at the sweet spot, for the reasons Solipsis mentioned. I'd be glad if you could convince the vendor you talk to of going for it


----------



## Dresden

Idk it didn't really stimulate me like I hoped it would.  It actually made me kind of delirious, I think.  I remember calling my dad, who was at home (where I was too), in the middle of the night and asking him where he was in a confused state.  I didn't feel particularly high from it.


----------



## aced126




----------



## DotChem

^ target?


----------



## pharmakos

Cyclized DMT, probably literature out there about it already


----------



## aced126

DotChem said:


> ^ target?



Various subtypes of serotonin receptors


----------



## Dresden

aced126 said:


>


That's a triptoline.  According to wikipedia, triptolines have "profound pharmacological effects."


----------



## Dresden

Such as MAOI action and SNRI/SSRI action.


----------



## Solipsis

GHB anhydride, just because its possible,

also I don't think SSRI effect is quite the same as general monoamine reuptake inhibition (the 'selective' part), and wonder if MAOI + multiple monoamine reuptake inhibition produces an intrinsic toxic interaction a la 5-MeO-aMT, basically as if you combine the wrong two drugs but packed up all in one molecule.


----------



## Pomzazed

GHB anhydride will react with itself giving the GHB-GHB ester dimer


----------



## aced126

Pomzazed said:


> GHB anhydride will react with itself giving the GHB-GHB ester dimer



Or if the solution is dilute, it will intramolecularly react with itself to give one molecule of GBL and one molecule of GHB.


----------



## DotChem

Spiroxetamine


----------



## Solipsis

Oh yeah, that's too bad - thought it would be nasty but at least survives... any way to make poly-GHB or something of the sort though? :D Oh yeah obviously, just a polyester - makes polybutyrate basically - a biodegradable plastic that does use 1,4-BDO in its synthesis... fun plastics - speaking of fun plastics and BDO:



> Bindeez (also marketed as Aqua Dots,[1] Beados,[2] and Pixos[3]) are a children's toy. It was subject to a multi-national product recall after it was found that the Wangqi Product Factory in Shenzhen, China had used a cheap chemical that was a pharmacologically active sedative prodrug instead of the safer specified one in some shipped toys, resulting in the illness and hospitalization of some children who ingested the beads



spiroxetamine is a cool name, and reminds me remotely of DXM with one of the rings unhinged... but no that ^ stuff is pretty shuffled compared to that. I wonder what lies in between though... will try to draw something later..
Would it still be called a spiro compound if the N-alkyl chain loops back to the cyclohexane ring instead of the phenyl ring? I guess you'd have to check out the 7 possible compounds you can make by attaching that alkyl chain to see what kind of constraining improves potency. Hooking it up to some of the right places might also prevent metabolism, although most dissociatives suffer from too long duration rather than too short.

Could a carbonyl be placed on one of the rings of DXM that would be the equivalent position of where K / MXE have it, and be expected to have decent effects on activity?


----------



## Nagelfar

Various restricted-rotation methylphenidate analogs

These aren't mine, these actually have been tested for affinity, as per above link (my WP inclusion of the following):


----------



## Pomzazed

Solipsis said:


> any way to make poly-GHB or something of the sort though? :D Oh yeah obviously, just a polyester - makes polybutyrate basically - a biodegradable plastic that does use 1,4-BDO in its synthesis...



That's very easy:
- Just perform a ring-opening polymerization (ROP) using either _(snip!), (snip!)_ or _(snip!)_ (Me-heh) on GBL it will give poly(4-hydroxybutyrate) already. (4-PHB)
- For that 1,4-BD is is used for synthesis of PBS (Polybutylene Succinate)

Our stomach cannot effectively hydrolyze them; though


----------



## DotChem

Solipsis said:


> Could a carbonyl be placed on one of the rings of DXM that would be the equivalent position of where K / MXE have it, and be expected to have decent effects on activity?


There are morphinans with a keto attached like ketocyclazocine






Most are Kappa selective agonists dysphoric the levo-rotatory group. But am not sure if ketocyclazocine congener of DXM ie with the "right" stereochemistry (ie dextro) are known...: 
levarphanol ---> ketocylazocine (and similar morphinans)
dextromethorphan--->ketomethorphan? Oxo-methorphan??


----------



## Solipsis

To answer my own question (I think) though: I didn't have an easy time trying to figure it out, but I think it's not possible because the 9-position of DXM which seems to correspond best with where some of the ACAs have their carbonyl, is a tertiary carbon because of the phenanthrene structure.

Thats interesting though! ^


----------



## Nagelfar

Further restrict rotation, wonder if efficacious as a stim.?

The rationale was this:






But it doesn't seem to do much in all cases unless there is a 4 position addition, or the di-chloro is added which is a bit of a cheat.


----------



## adder

The thing with decreasing flexibility is that if a restricted molecule is able to bind in an active conformation, the activity increases, but if it can't, the activity will drop. That's why they tested different compounds in that research on methylphenidate analogues trying to put the carbonyl into different fixed spaces. By restricting molecule conformationally you basically make it less capable of unbinding via rotation around certain bonds, I guess.


----------



## roi

AB-FUBIAGRA


----------



## Solipsis

Incredible.... will that make your dick stoned or your mind hard?


----------



## adder

DotChem said:


> There are morphinans with a keto attached like ketocyclazocine
> 
> 
> 
> 
> 
> 
> Most are Kappa selective agonists dysphoric the levo-rotatory group. But am not sure if ketocyclazocine congener of DXM ie with the "right" stereochemistry (ie dextro) are known...:
> levarphanol ---> ketocylazocine (and similar morphinans)
> dextromethorphan--->ketomethorphan? Oxo-methorphan??



10-ketodextromethorphan was tried in some research and it didn't turn out to be interesting for sure, if I remember well, it was even weaker than DXM itself as a NMDA antagonist or whatever. But anyway, the keto moiety decreases basicity of the amine, the same thing must be happening in ketamine as well, though its potency is likely decreased by o-chloro as well, yet the qualitative gain is more than potency drop. For toxicity it's probably bad though.


----------



## Nagelfar

This is based on further rigidifying the quinolizidine MPH RRAs in a way that shouldn't hinder/hamper binding. I really like the look of it.

The two functionalities are facing in differing places because of the limit of bonds, when they should be _R_, I tweaked it a bit:






Started with caffeine and butalbital, ended up with this:






Well 'la-tee-dah' it's planar (aryl is, anyway) should work like m-amp:






What happens if you pull those labile oxygens off of the 3 & 6 positions of morphine? (I extended the six because I couldn't see that doing anything but lengthening half life) =


----------



## EP-11

^ Im guessing this one is inactive




^ inspired by ibuprofen




^inspired by naproxen




^ idk about his one




^ inspired from the guy who was obsessed about damascone 




I couldn't even remember when I drew this one but it looks interesting.

btw im new to this place and I have been lurking this thread for a couple months and finally decided to share.


----------



## DotChem

adder said:


> 10-ketodextromethorphan was tried in some research  and it didn't turn out to be interesting for sure, if I remember well,  it was even weaker than DXM itself as a NMDA antagonist or whatever. But  anyway, the keto moiety decreases basicity of the amine, the same thing  must be happening in ketamine as well, though its potency is likely  decreased by o-chloro as well, yet the qualitative gain is more than  potency drop. For toxicity it's probably bad though.



I see..One would expect them to behave similarly to ketamine or  MXE.  But I think your're right: the alfa-keto group would decrease the  pKa of the amine hugely(2 log units??. That's probably the reason why  they suck? Note that in ketamine and PCP congener MXE, the pKa is still  way higher than physiological pH (7.4).  For ketamine it is about 8.5  which means much of molecule will be charged in the body anyway. So I  guess in the case of K and MXE, it wont really affect binding. I am not  sure what the pKa of the keto analog of DXM would be.??   

NB:In  the case of amphetamines and cathinones though, I always thought the  drop of the pKa of the amine by the keto group has something to do with  their pharmacological profile: ie from DRI (Amphetamine-like) ------>  DRA (cocaine like cathinones). Cathinones pKa is much lower than that  of the corresponping AMPH. At the very least, it would affect their  pharmacokinetic like absorption and brain distribution.


----------



## adder

I don't mean the effect of pKa with respect to the ratio of charged and uncharged form in the blood. The molecules clearly get to the brain in their freebase form as a charged amine can't pass the blood-brain barrier) and the amine gets protonated at the target site interacting with an aminoacid residue with a positively charged side-chain, so the drop in basicity here could mean lower affinity at the NMDA receptor site DXM/DXO interacts with, but if it's a meaningful drop I have no idea. I imagine the carbonyl group itself is electronically and/or sterically unfavoured there for the binding, I doubt such a small change in an otherwise lipophilic molecule could affect the amount that gets to the brain much. I tried overlaying DXM with ketamine and dizocilpine some time ago and if there is any position in DXM that might correlate with the carbonyl carbon of ketamine, it is not C10, but rather C14 which is a tertiary carbon atom (I'm using the morphinan numbering here, so it's the carbon atom that bears an extra hydroxy group in oxymorphone vs. hydromorphone). However, the site that DXO binds to may not be the same site that ketamine binds to, I remember reading an article on how DXO effects were blocked by some specific ligand that didn't block ketamine or some other arylcyclohexanamine effects (or the other way around, I'd have to find it again), the conclusion was that the site for DXO is a different one. If it is so, then comparing DXO structure with ketamine and planning structural changes based on SAR of arylcyclohexanamines makes little sense anyway.


----------



## Soulfake

"7-Spiroindanyloxymorphone" - sounds and looks pretty nice, I hope a few original morphinanes will come to the rc market.

https://en.wikipedia.org/wiki/7-Spiroindanyloxymorphone






Here some things that could have nice opioid action:


----------



## roi




----------



## Bagseed

I dunno, I wish that when someone posts a molecule which is not totally obvious, they'd write what they think about it or why they chose a certain structure.


----------



## EP-11

Bagseed said:


> I dunno, I wish that when someone posts a molecule which is not totally obvious, they'd write what they think about it or why they chose a certain structure.


I'll try


----------



## EP-11

stimulant? based off of Vitamin B6




I read somewhere that beta-phenyl made the phenylethylamine more active, would this be true in this case?


----------



## aced126

Yes, that is desoxypipradol and it is a potent stimulant with an extremely long elimination half life.


----------



## EP-11

^inspired from Diphenhydramine, 




^I'm guessing this would have a long duration




^ would this be too bulky? Im guessing yes


----------



## EP-11

Would this be active, I was thinking and this popped into my head and It really is making me curious


----------



## aced126

Maybe. It'll also have a short elimination half life.


----------



## Bagseed

maybe turn that ester into an amide? as far as I know, amides get metabolized more slowly (please correct me if I'm mistaken)


----------



## roi

canceryl


----------



## aced126

Bagseed said:


> maybe turn that ester into an amide? as far as I know, amides get metabolized more slowly (please correct me if I'm mistaken)



Yep



roi said:


> canceryl



lmfao


----------



## EP-11

Bagseed said:


> maybe turn that ester into an amide? as far as I know, amides get metabolized more slowly (please correct me if I'm mistaken)







I call it N-2-M-1-PPB


----------



## EP-11

^Still curious about this one, Could I get some insight


----------



## roi

About as active as MDPEA I guess.


----------



## Dresden

This is methamphetamine with the phenyl swapped out for a carbomethoxy.


----------



## DotChem

Ascaridol an antibiotic and soup seasosing from a Latin America tree..


----------



## DotChem

Ketophenidate..








Spirophenidate..


----------



## EP-11




----------



## Dresden




----------



## blueberries

Racemorphanol / 4-MAR prodrug; guaranteed to blow minds, sphincters and society as we currently know it!

Took me while to work out how the metabolism for this works but I'm fairly sure I'm on the money here. The 4-MAR would be left with that stray amine, the Racemorphan would be left with an acetyl bond, eventually breaking off, leaving just the extra carbon on it's amine.


----------



## blueberries

Dresden said:


>



Tried this recently. It was alright, nothing to write home about though. Couldn't get to a hole after around 750mg but the K feeling was definitely there.


----------



## polymath

Has anyone ever made 2-(indol-3-yl)ethyl-nortropane, a bicyclic tryptamine derivative?


----------



## Dresden

I've thought of this.






You want the nitrogen to be a primary amine.  The ethyl spacing is taken up by the tropane ring.


----------



## Dresden

I mean tertiary, not primary.


----------



## polymath

^ But in that molecule there's three carbons between the indole and the nitrogen, not two like in DMT or other tryptamines.


----------



## Dresden

Yeah, but it's crumpled up.


----------



## Dresden

To illustrate, compare diphenhydramine with benztropine.  Both drugs can be used to lessen extrapyramidal side effects of antipsychotic drugs and are themselves anticholinergics.






DIPHENHYDRAMINE






BENZTROPINE


----------



## Limpet_Chicken

Ascaridole is notable, for not only being one of the only known natural organoperoxides, the other source being the Boldo plant. But for being, as with other organoperoxides, explosive. Not counting the likes of biological trioxidane generation as a reactive and short lived intermediate.


----------



## EP-11




----------



## Pomzazed

Re: above molecules

Those are hughly probable to be active, but may have very high tendency to cause headache (no high tho, just altered perception)

I have tried (+)- isomer and (-)- isomer of 2-amino-2-phenylethane before, its like the above structure without substitutons on that phenyl and replace that ethyl chain with methyl.
A lot of headache from like 20mg


----------



## pr0d1gy

Pomzazed said:


> Re: above molecules
> 
> Those are hughly probable to be active, but may have very high tendency to cause headache (no high tho, just altered perception)
> 
> I have tried (+)- isomer and (-)- isomer of 2-amino-2-phenylethane before, its like the above structure without substitutons on that phenyl and replace that ethyl chain with methyl.
> A lot of headache from like 20mg



Any hypothesis on the properties of these compounds with the carbon chain shortened by one, ie: the 2-amino-2-phenylmethanes


----------



## EP-11

^lol


----------



## Solipsis

pr0d1gy said:


> Any hypothesis on the properties of these compounds with the carbon chain shortened by one, ie: the 2-amino-2-phenylmethanes



That's not a thing, what you are describing is benzylamine... I don't believe compounds like that are 'neurotransmitter-like', that distance from the phenyl ring to the amine is probably quite critical.

Also, 2-amino-2-phenylethane is incorrect nomenclature in the first place  You would say that something is in a 2-position when starting count referring to another group that has 'priority' in counting and naming the parts of a molecule (moieties). If both the amine and the phenyl ring attach to the same carbon, that is where you start counting if there are no other groups involved, so both are on the 1-position making it "1-amino-1-phenylethane" or 1-aminophenylethane since your 'reference' point is always on the 1-position if you only have 2 options like in an ethane.
But that is not really the usual approach approach either, actually the 'order' of naming is 1-phenylethylamine (hey we know that name!), or alpha-phenethylamine as opposed to the beta-phenethylamines we have all come to know and love ;P


----------



## EP-11




----------



## EP-11

N-[2-(1H-indol-3-yl)ethyl]cuban-1-amine


----------



## DotChem

fentanyll and carba-analogs bound to the μ opioid receptor in the activated state.. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2848705/


----------



## Dresden




----------



## EP-11

Dresden said:


>


looks interesting


----------



## EP-11




----------



## Limpet_Chicken

Alpha-methylbenzylamine is an MAO(a)I IIRC. Pretty sure its been described as alkylating some other CNS constituent, although I can't remember what now.


----------



## DotChem

Methamfotamine..


----------



## EP-11




----------



## EP-11




----------



## EP-11

roi said:


> About as active as MDPEA I guess.


check this out https://en.wikipedia.org/wiki/Lophophine , any chance that it could cause hallucinations?





 <--- this is the chemical for reference


----------



## Solipsis

That methoxy on the bottom left is out of place for it to be an analogue of lophophine, it would have to be on the bottom carbon of the right-side ring. On what position of a naphthyl you put substitutions can matter quite a bit for its toxicity in the human body, although I don't recall a methoxy being one of the more worrisome - but that position is tricky for some other substitutions.

Because the methoxy is out of place instead of lophophine-like it^ is like MDPEA with a methoxy sticking out of the methylenedioxy bridge (well in that vicinity) - and that is a position known to be very sensitive for benzodioxole style empathogens - messing with it usually makes it inactive.

So not a good chance for any activity, no - first better to consistently choose what drug yours will be an analogue of by having something sort of bioisosteric group - like MDMA vs. PAL-287 and then avoid the issues the parent drugs are known to have.

Also worth mentioning that PAL-287 but it seems also the analogue of that with a methoxy on the same position your suggested compound has it, are found to be MAO-A inhibitors quite a bit more potent than amphetamine. But that's the alpha-methyl version which yours doesn't have - which makes it more sensitive to MAO degradation (and I bet less inhibiting of MAO), and the activity would have to compensate for that - MDPEA needs very high doses or MAOI / is hardly active at all and lophophine is also not potent but is at least a direct MMDA analogue, being basically MMDPEA.
Finally - I'm getting bad flashes of PMA but that's not actually related.


----------



## Jonneh




----------



## Dresden




----------



## Dresden




----------



## Dresden




----------



## Dresden




----------



## Dresden




----------



## Pomzazed

1. Cannabimimetic bisindole; shoud satisfy the requirement for binding, one side is pentyl going to hydrophobic tail pocket, 
another tail is propyl, similar length to 4-ethyl, or 4-methoxy in naphthalene case which enhance activity. 
2. Carbazole-like structure instead of morphinan, with correct stereoisomer pointing the amine, which phenethyl attached for more activity. It also looks similar to tricyclic TCA, antimuscarinics and antihistamines.
3. Just for fun of more 3-D structure construction, May be inactive or toxic via metal residue.
4. Another molecule based on cyclized pyridoxine (vit B6) making it cathinone-like. just fun to imagine but I supposed this is also inactive due to polarity of phosphate ester.

P.S. Compound 1 is active _in vivo_; anecdotally


----------



## SKL

I think I'd like this:


----------



## Jonneh

Was 4-AcO/HO-PiPT never made when PiPT was around?


----------



## Jonneh

Dresden said:


> I've thought of this.
> 
> 
> 
> 
> 
> 
> You want the nitrogen to be a primary amine.  The ethyl spacing is taken up by the tropane ring.




I like this. I wonder how much of the tropane ring will be perceived as primary amine bulk (in which case it might behave like a DET-EPT/aeruginascin hybrid) versus the analogue of alpha-carbon substitution (alpha,N-DMT, anyone?). This will also apply to my 4-HO-MiPT azetidine analogue from the last page - is that 4-methyl part of the isopropyl analogue or rather an alpha-substitution equivalent?:


----------



## SKL

Jonneh said:


> SKL said:
> 
> 
> 
> I think I'd like this:
> 
> 
> 
> 
> 
> 
> 
> 
> Was 4-AcO/HO-PiPT never made when PiPT was around?
Click to expand...


I think not. But would welcome correction. As I said elsewhere, I'd expect it to be less potent but at a relevant dose at least as psychedelic and perhaps longer lasting than 4-AcO/HO-MiPT; but that's complete conjecture.

Google reveals one Bluelight post mentioning 5-MeO-EiPT circulating ca. 2013 and at least one reddit user claiming to have tried 5-MeO-PiPT but that's about the closest thing I could find … not very close … I liked 5-MeO-MiPT a bunch but the longer ones seemed less interesting, something about this structure though seems promising to me …


----------



## Jonneh

I'm sure you're right about the availability - I can't find a single reference to it. It's got a lot dangling off it, but I'm sure there's _something _midway between DPT and DiPT.


----------



## Solipsis

I think it's already a bit of a bother to make an asymmetrical trypt, but apparently 4-HO-DPT is a pain to make as well IIRC... so 4-AcO-PiPT or something like that is probably a lot of work.

Yeah I like the azetidine too! Thought of something like that a while back, but rather a more straightforward version (4-hydroxy optional):






The methyl antlers are also optional of course, depending on whether you want to make an analogue of DMT, MET or DET ... but if you were to analyze or assay different isomers it is probably interesting to add both methyls and see which one is specifically active. Possibly it is less strict than with LSZ... apparently on tryptamines much more freedom is allowed than on lysergamides.

What is a slight concern though, is that you would move in the direction of say this one:






which bears close resemblance to Pyr-T which Shulgin found to be a horrible substance. Possibly due to its metabolism? IDK

I would also be quite curious about freaky analogues like these (haha the one on the right looks funny - and a real bitch to get opsin to draw wedges since there aren't actually chiral centers):


*NSFW*:


----------



## aced126

Solipsis said:


> I think it's already a bit of a bother to make an asymmetrical trypt, but apparently 4-HO-DPT is a pain to make as well IIRC... so 4-AcO-PiPT or something like that is probably a lot of work.
> 
> Yeah I like the azetidine too! Thought of something like that a while back, but rather a more straightforward version (4-hydroxy optional):
> 
> 
> 
> 
> 
> 
> *The methyl antlers are also optional of course, depending on whether you want to make an analogue of DMT, MET or DET ... but if you were to analyze or assay different isomers it is probably interesting to add both methyls and see which one is specifically active. Possibly it is less strict than with LSZ... apparently on tryptamines much more freedom is allowed than on lysergamides.*
> 
> What is a slight concern though, is that you would move in the direction of say this one:
> 
> 
> 
> 
> 
> 
> which bears close resemblance to Pyr-T which Shulgin found to be a horrible substance. Possibly due to its metabolism? IDK
> 
> I would also be quite curious about freaky analogues like these (haha the one on the right looks funny - and a real bitch to get opsin to draw wedges since there aren't actually chiral centers):
> 
> 
> *NSFW*:



The methyl groups in the first compound do not bind in the same hydrophobic pockets as the methyl groups in LSZ. Instead, the methyl groups here bind in the same place as the methyl group on the aliphatic nitrogen in LSD. In LSD/LSZ, the alkyl groups which have a significant effect on potency are the ones connected to the non-basic amide nitrogen, which binds in a different (and weaker) way than the charged aliphatic nitrogen.


----------



## Solipsis

I know: I said apparently on tryptamines much more freedom is allowed than on lysergamides.

Maybe with 2,4-dimethylazetidine you won't see huge differences between isomers but I bet that at some point if the alkyl chains get longer the conformation becomes a problem and there would be countless ways to constrain the antlers together using bridges / rings which would still tell us something about whether DPT analogues work better when the antlers are tied together or spread apart, or bent. So comparing spatial conformations would still be interesting a la LSZ even if there is much less of a _small_ particularly shaped pocket?

Again: the metabolism might be a concern, or another reason why Pyr-T was so bad...


----------



## Jonneh

Solipsis said:


> Yeah I like the azetidine too! Thought of something like that a while back, but rather a more straightforward version (4-hydroxy optional):
> 
> 
> 
> 
> 
> 
> 
> What is a slight concern though, is that you would move in the direction of say this one:
> 
> 
> 
> 
> 
> 
> which bears close resemblance to Pyr-T which Shulgin found to be a horrible substance. Possibly due to its metabolism? IDK



Yeah, I had Pyr-T in mind when deciding where to put the azetidine (there needed to be one somewhere, obviously!). I reasoned that not having inflexible bulk hanging off the very end might help avoid going in the Pyr-T direction. Come to think of it, all the di-somethings beyond DMT have something physically iffy going on, or else are freaky in another respect (tremors with DET, strange vestibular effects of DiPT and audio trickery with DiPT and DPT). Fusing the antlers to form Pyr-T doesn't go well, which is what made me scared of going where you went with the azetidine (fused isopropyls).

As you say, though, it could be a (fairly specific) metabolic issue and thus might not apply to the azetidine. And mine might turn out to be too stubby. Oh, and fortune favours the brave.


----------



## DotChem

^ those indoles with a bulky cyclic tertiary amine more likeky will have strong anticholinergic like this  





Tolterodine  a central muscarinic anticholinergic causing VERY interesting hallucinations populated with zombies getting up from graves and attacking you Nasty stuff.. google: "detrol nightmares" So go easy on lipophilicity with the indoles and it should be fine..


----------



## aced126

Solipsis said:


> I know: I said apparently on tryptamines much more freedom is allowed than on lysergamides.
> 
> Maybe with 2,4-dimethylazetidine you won't see huge differences between isomers but I bet that at some point if the alkyl chains get longer the conformation becomes a problem and there would be countless ways to constrain the antlers together using bridges / rings which would still tell us something about whether DPT analogues work better when the antlers are tied together or spread apart, or bent. So comparing spatial conformations would still be interesting a la LSZ even if there is much less of a _small_ particularly shaped pocket?
> 
> Again: the metabolism might be a concern, or another reason why Pyr-T was so bad...



Oh yes, I see what you mean. I just thought you might be confusing the amidergic nitrogen with the aliphatic nitrogen of LSD...never mind.


----------



## Solipsis

@ anticholinergics... actually I thought the mention of DiPT having effects on hearing but also suggested on the vestibular organ quite interesting and this might cause certain similar ones and perhaps Pyr-T to be dizzying and icky. But Pip-T isn't even active and I don't really understand the reasoning behind comparison with tolterodine which has diisopropyl already. Yet even if DiPT can make some people wobbly I gotta say I found it rather pleasant on the body, however I didn't take my dosages very high.

The Pyr-T concerns are to be taken seriously I'd say, but at the same time I got this feeling that dimethylazetidine isn't actually that similar to pyrrolidine. Compared to LSD, LSZ appears to behave rather similarly and not like say LSM. For something that should look a bit like DET, it seems to me that Pyr-T and dimethylazetidine-T are rather opposite conformations.
For me dimethylpyrrolidine is like a much bigger question mark but I'm on the pessimistic side with that one. So better aziridine then or dimethylaziridine? D:  with the amide in lysergamides apparently aziridines are quite unstable but afaik it matters a whole lot that it is not a type of amide in the tryptamine version and could be stable. *Perhaps* it's better though if the 4-HO version isn't made to absolutely minimize it reacting with itself but I can't really prove it.



The previously suggested azetidine by Jonneh is clever, especially the idea to try and avoid Pyr-T similarity... but I fear that it's a problem that it constrains the amine function to be straight from the indole with hardly any flexibility...
Fortunately it seems looking at LSD that it might actually be optimal? Maybe the distance isn't though, or maybe it is - even better than LSD in that regard.. :D


----------



## Jonneh

I had a look at a couple of binding models for LSD and a tryptamine to the 5-HT2a receptor. Who knows what receptor might be mediating the nasty, weird or interesting effects we're discussing, but it's a start.

LSD ................................................................................ a tryptamine ................................................................









It's clear from the model that what one might expect to be analagous positions (the 6-position nitrogen in LSD and the amine nitrogen in tryptamines, for example) are actually not. The whole indole has flipped, for starters.

Anyway, Pyr-T might not be psychedelic because the fat ring doesn't fit inside the space defined by the Asn343 residue, a least not in a way that also allows parts of it to hydrogen bond to the Asp155, and nestle in with Phe340 and Ile152. The diethyl of LSD is off to the side, not doing much, so I'm not sure the azetidine in LSZ is analagous to things hanging of the amine group in tryptamines.

Curiously, the tryptamine ligand they use (for its rigidity and therefore reduced uncertainty), 3-(N-methylpyrrolidin-2-ylmethyl)-5-methoxyindole, has a five-membered (pyrrolidine) ring at the amine, although positioned in such a way that the whole chain is shorter than in the case of Pyr-T.








I think your azetidine analogue should fit, although one of the methyls is probably redundant. It doesn't look like the amine nitrogen in tryptamines is doing much functional legwork as far as binding is concerned, so as long as something is hanging off it in the vicinity of that aspartate residue, small variations in distance from the indole should be tolerated.

It's only one receptor, but it's a test they really ought to pass.


----------



## aced126

Where did you obtain those models from?


----------



## Solipsis

That tryptamine looks off... speaking for the more typical ones like DMT, it seems unlikely that the molecule is flipped compared to LSD (just look at the indole nucleus) - and this one was previously posted on BL showing 5-MeO-DMT to bind relatively similar to how you have LSD modelled there, and has the same pi-stacking and the 5-MeO interacts with SER239 making it not flipped but basically oriented the same way:


----------



## Jonneh

aced126 said:


> Where did you obtain those models from?



They're from a Nichols paper from 2002. 



Solipsis said:


> That tryptamine looks off... speaking for the more typical ones like DMT, it seems unlikely that the molecule is flipped compared to LSD (just look at the indole nucleus) - and this one was previously posted on BL showing 5-MeO-DMT to bind relatively similar to how you have LSD modelled there, and has the same pi-stacking and the 5-MeO interacts with SER239 making it not flipped but basically oriented the same way



That's funny, because the binding of serotonin modelled in a separate study pretty much agreed with the Nichols model above, and the Nichols group only used an exotic tryptamine because of its rigidity - as far as I can see they expected it to reflect the binding of other tryptamines. Well, it's perfectly possible that different tryptamines could bind in different ways, although I would expect 5-MeOs to form their own cluster of higher inter-relatedness in terms of biding conformation. Perhaps they don't always, and that explains why some 5-MeOs don't show the 'typical' 5-MeO dodginess (5-MeO-DALT/MiPT vs 5-MeO-DMT/AMT, for example).

In the case that our new tryptamines bind like 5-MeO-DMT, the azetidine would be the congener of something hanging off the 6-position nitrogen in LSD (cf. MALT and AL-LAD). The azetidine in LSZ is still very much its own thing, I think (and perhaps resistant to change by dint of its interactions with other receptors, or perhaps it is interacting with Gln216 and/or Val235).

Well, back to old-fashioned Linnaean heuristics then. Fine by me!


----------



## Solipsis

I guess the other model was quite amateuristic, this:
http://scholarsresearchlibrary.com/JCMMD-vol5-iss1/JCMMD-2015-5-1-45-57.pdf
(page 55)

is consistent with Nichols, showing DMT so it wasn't a fluke..

You think something like Pyr-T obscures the amine from critical interaction with the asparagine residue? Because that may mean none of these constrained bridges are a good idea and that the tryptamine substitutions would need to 'spread their legs' for the money shot to put it bluntly? Might also explain why dipropargyls which mingle and stick to each other are no good?

Very confusing though, I already thought that tryptamines, lysergides, 2C's, mesc, NBOMe's at least were a bit skooched up compared to each other making SAR different but that it would be as bad as major flips and jumps really fucks with understanding of SAR! Trying to hybridize SAR relations would be all the more problematic.


----------



## Jonneh

Solipsis said:


> You think something like Pyr-T obscures the amine from critical interaction with the asparagine residue? Because that may mean none of these constrained bridges are a good idea and that the tryptamine substitutions would need to 'spread their legs' for the money shot to put it bluntly? Might also explain why dipropargyls which mingle and stick to each other are no good?



That would be one possibility, and another would be that (even in the absence of direct interaction) the asparginine defines a space which the pyrroline is too big for (given its inflexibility), thereby preventing whatever is hanging off the amine from interacting with other residues, like Asp155. Both guesses are weighted heavily by our lack of active examples - a strong prior indeed. There might still be room for an aziridine or even azetidine - even though they might need to bend over to be with the Asp, to continue your lolworthy analogy. I think the leg-spreadability matters more than bottom-heaviness (cf. 4-HO-DSBT, which is pretty potent for all its bulk).



Solipsis said:


> Very confusing though, I already thought that tryptamines, lysergides, 2C's, mesc, NBOMe's at least were a bit skooched up compared to each other making SAR different but that it would be as bad as major flips and jumps really fucks with understanding of SAR! Trying to hybridize SAR relations would be all the more problematic.



Looking at those Chilean models for the binding of DMT, I notice they get wildly different results when assuming rigid versus flexible residues. The flexible assumption puts them more in line with those of the other studies. In any case, it does mess things up a bit. LSD being a phenethylamine/tryptamine hybrid may speak more to the parsimony of plant and fungal biochemistry than to the relation of phenethylamine to tryptamine SARs. Makes for a bit of a jarring disconnect in our levels of description, going from the atomic to the behavioural. I guess it at least gives rise to a couple of predictions, like that a 4-sub-5-MeO tryptamine should be active, mimicking LSD better than 4- or 5-sub tryptamines alone.


----------



## DotChem

Ketamphetamine


----------



## white55

4-ho/aco (and 4-po ones are even harder) tryptamines are harder to make than 5-meo or unsubstituted (naked?) ones so that the 4-ho/aco version wasn't made wouldn't be a huge surprise. 5-meo-dalt is/was around for a long time but 4-aco-dalt was only made in small amounts despite being better (not that being better than 5-meo-dalt is a huge achievement since 5-meo-dalt is trash) .....


----------



## SKL

IME acetoxy esters and asymmetrical tryptamines are almost always better but obviously harder to make for what is already a boutique market at best. Too bad. 4-AcO-MiPT was a beaut but barely circulated.


----------



## Dresden

Was it much different from 4-OH-MIPT?  I quite enjoyed a heroic dose of that.


----------



## SKL

I am not quite sure that I did both enough times to give anything approaching and "objective" answer, but as far as I can speak to it the acetoxy was in fact better; smoother in body, slightly less tension both in the muscles around the upper body, the sternocleoniomastoid and trapezius in particular which is where this sort of tension from psychedelics tends to strike me, mentally a bit _less _jumpy yet _more _hallucinogenic in a superficial sense, about equally mentally and intellectualy. This is more or less the same as the differences between 4-AcO- and -HO-DMT and may of course have been placebo-influenced and colored by my considerably larger experiences with those  (including synthetic psilocin.)  I do think the ester makes a worthwhile difference … 

Speaking of has anyone ever tried pure/synthetic 4-PO-DMT or any 4-PO-T's? I've certainly never seen or tasted them or known then to circulate though I'm sure someone has made them.


----------



## white55

Other than in clinical studies? Should be extremely unlikely as it was not that long ago that the only know synthesis was very dangerous (as in goes boom quite easily). A safer one was then developed by one of the chemists working for Nichols but it's probably still much more expensive for rc vendors.....  the fact that the leading theory was that the active compound was the 4-ho version and that any esters get removed and are inactive probably didn't help.


----------



## Dresden

This is indolylic fentanyl.


----------



## DotChem

^ Fentadol? Indotanyl?


----------



## Dresden

Doltanyl


----------



## EP-11




----------



## aced126

Quite a silly creation which I'm not gonna bother naming. I had an idea that this adamantane-guanidine fragment could function as a sort of "fat and bulky amine". Unfortunately this molecule seems to be very unstable.


----------



## DotChem

Benzovalerone .. aka Pyrozepam ..


----------



## Dresden

DotChem said:


> Benzovalerone .. aka Pyrozepam ..



Interesting.


----------



## white55

DotChem said:


> Benzovalerone .. aka Pyrozepam ..



How do you think that ring would you think this would change the effects? Imo if you are looking for a good benzo this isn't going to be good, and I'd guess that it's also not a stim...... although I'm much more certain about the good benzo  part, you need at least some of the following for that - nitro group on r7, fluorine on r2', r1 methyl or a triazolo ring on top (good benzo for me means strong hypnotic).


----------



## DotChem

Dresden said:


> Interesting.



Nice.. or:






Methioxetamine

Like  with amphetamines : 4-MTA or aleph  (dramatic change to SRA with a  4-MeO/4-MeS from MDMA) Would similar thing happens with Methoxetamine??.  am not familiar with the SAR of these



white55 said:


> How do you think that ring would you think this  would change the effects? Imo if you are looking for a good benzo this  isn't going to be good, and I'd guess that it's also not a stim......  although I'm much more certain about the good benzo  part, you need at  least some of the following for that - nitro group on r7, fluorine on  r2', r1 methyl or a triazolo ring on top (good benzo for me means strong  hypnotic).


Frankly I have no idea what it will do. It might probably making it more or less potent. But I  have come to realize that when it comes to psychoactives, small change  can have huge impact and huge change little difference. So may make a  good benzo maybe not..or a good stim or not... Just drawing molecules...but who knows..(putting a triazolo might not be bad idea but  then again you ended up with triazolam isn't it?)


----------



## sekio




----------



## MagickalKat777

sekio said:


>



That... Makes me horny. Might need to be IM or IV though?

@DotChem - have you really not learned yet that they are too smart for your shenanigans trying to get info here? Seriously, at least make it legit. That chem is grasping at straws. Figure out something other than oxygen and you might be on to something but I know who you are and you were on the right track with a certain "lam"


----------



## Solipsis

MagickalKat777 said:


> a certain "lam"



triazyolo


----------



## Dresden




----------



## DotChem

MagickalKat777 said:


> That...  Figure out something other than oxygen and you might be on to something but I know who you are and you were on the right track with a certain "lam"


 I'll go with an amidine ?






Xanaxidine ..


----------



## DotChem

Methylenedioxy IndanoValerone MDIV ..


----------



## thedukeofraoul

You can use a program on Win32 called SMiLES for building and constructing molecules.


----------



## roi

diphenidine/desoxypipradrol inspired


----------



## niflheim

roi said:


> diphenidine/desoxypipradrol inspired



I like the way you think. My first (and this so far only) random molecule was the 2-methoxyphenyl-pyrrolidine analogue of your  piperidine. (Not suggesting anything other than similar trains of thought reaching similar destinations, I just thought it was interesting seeing something similar. I'd just just been looking at this 1981 patent: US 4279918 (Nuclearly-substituted)benzylpyrrolidines, which is why pyrollidine was on my mind.)


----------



## Dresden

That could be considered a nicotine analogue of sorts.


----------



## roi




----------



## DotChem

Blue Dragon ...





deepest blue color under UV light


----------



## klfiend

desoxypipradrol/amphetamine inspired


----------



## Solipsis

^ The amine in that piperidine ring up top serves the same role as that amphetamine N on the right - so instead of overlapping desoxypipradrol / amph it is more like a siamese twin. 

You can make a cross-over drug based on desoxypipradrol and amphetamine, two actually - they already exist:

2-Benzylpiperidine
Beta-phenylmethamphetamine (and the non-methylated version you can also imagine)

But the chemical you suggest may actually have some activity as sort of weaker version of beta-phenylamphetamine. For that either the main phenyl ring or the beta phenyl ring would have to be at least remotely bioisosteric with the piperidine ring, so 2 chances for it to work. Something like cyclohexyl works (a la propylhexidrine), thiophene works (a la methiopropamine), piperidine is not quite as good I think... but maybe it works.




To offset all these new agonists:






     .  
	

	
	
		
		

		
		
	


	




wonder if that works.


----------



## aced126

Solipsis said:


> ^ The amine in that piperidine ring up top serves the same role as that amphetamine N on the right - so instead of overlapping desoxypipradrol / amph it is more like a siamese twin.
> 
> You can make a cross-over drug based on desoxypipradrol and amphetamine, two actually - they already exist:
> 
> 2-Benzylpiperidine
> Beta-phenylmethamphetamine (and the non-methylated version you can also imagine)
> 
> But the chemical you suggest may actually have some activity as sort of weaker version of beta-phenylamphetamine. For that either the main phenyl ring or the beta phenyl ring would have to be at least remotely bioisosteric with the piperidine ring, so 2 chances for it to work. Something like cyclohexyl works (a la propylhexidrine), thiophene works (a la methiopropamine), piperidine is not quite as good I think... but maybe it works.
> 
> 
> 
> 
> To offset all these new agonists:
> 
> 
> 
> 
> 
> 
> .
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> wonder if that works.



Well desoxypipradol wouldn't be binding to the substrate position at DAT (it is a reuptake inhibitor).


----------



## Dresden

Not trying to source or anything, but do you know if beta-phenylmethamphetamine aka 2-methylamino-1,1-diphenylpropane has ever made an appearance on the research chemical scene?






BETA-PHENYLMETHAMPHETAMINE


----------



## roi

100mg+, lasts 1-2 hours, mild high. 2-Diphenylmethylpyrrolidine is already much less potent than desoxypipradrol; the opened ring is even worse.


----------



## sekio

I wonder about compounds like this:





They are easily accessible from proline (used as chiral ligands) and presumably have pipradrol - type fx. Sometimes the OH group is either absent or protected/modified (e.g. methoxy, ethoxy)


----------



## DotChem

.. does the site www.chemicalize.org for quick chemical data been jacked? by MoneyGrabbin commercial shit holes..type chemicalize.org and you get redirect to chemicalize.com charging zillions for tax payers public money funded programs.. hack'em


----------



## Pomzazed

^
It is still in ChemAxon as owner(original), but they seems to manipulatethe site somehow, now i cannot view the site on my ipad anymore(yor browser is not supported, please use desktop version etc etc).

Too bad i visit and utilize the site alot on my ipad


----------



## niflheim

Does this seem like a bad idea?


----------



## DotChem

Pomzazed said:


> ^
> 
> Too bad i visit and utilize the site alot on my ipad


 yeah.. too bad! I do use it often too.  I guess have to turn to other sources


----------



## DotChem




----------



## Dresden

PCDE


----------



## Bagseed

DotChem said:


>


ring constrained ketamine... does anyone have information on what the best conformation of ketamine would be to fit into the binding site at NMDAr? this constrained version could go either way imho


----------



## DotChem

Bagseed said:


> ..this constrained version could go either way imho


Yes, hit or miss! But I think it has reasonable chance binding similarly  to ketamine. In that case may be 10x more potent than ket because of  ring constrained. + it will be legit since it is not an  arylcyclohexylamine but an indanyl! The PCP site on NMDA is not  particularly demanding: eg (+)DXM ie dextromethorphan and its enantiomer  (-)DXM levorphanol both bind NMDAr with similar affinity..It doesn't  happen often especially with brain receptors, ions channels..etc.  Usually only one enantiomer will bind. 



Bagseed said:


> ... does anyone have information on what the best conformation of ketamine would be to fit into the binding site at NMDAr?


The standard NMDAr antagonist, the most potent by far (ca 800x more potent than ketamine) is dizocilpine MK-801 MK-ultra. Very constrained molecule with not many conformations possible: pretty much a single conformation (2 for the racemic!). 









Does arylcyclohexylamines like ketamine, MXE..etc bind at the same site as MK? in that case, overlaying the aryl of arylcyclohexylamines with one of the phenyl of MK and of course the amino groups of the 2.  That means adding a phenyl to the cyclohexyl of ketamine MXE..etc(I mean to get something like a tetraline) will give more potent NMDAr than ketamine mxe..etc...and legit! at least in the UK since they won't be arylcyclohexyl but aryltetralinylamines..so technically not cyclohexylamines aryl but who knows?   

PS: now MK-ultra is way too potent imho (risks of irreversible permanent pyschosis + Olney's lesions.. but who knows?


----------



## DotChem

actually a spiroisoindolylcyclohexane





more precisely: 7'-chloro-2',3'-dihydrospiro[cyclohexane-1,1'-isoindole]-2-one


----------



## Raihiar

i didn't go through the whole thread (again), so excuse me if this has already been posted:
since propylhexedrine seems to be at least active, and i was a fan of 4-fa, i just have to ask ^^




i know this "hybrid" or "mixtures" of chemical structures is a bit misleading, you don't get the best of two worlds most of the time..
but it might be active, possibly not very enjoyable, but well... this thread has its name for a reason


----------



## aced126

Raihiar said:


> i didn't go through the whole thread (again), so excuse me if this has already been posted:
> since propylhexedrine seems to be at least active, and i was a fan of 4-fa, i just have to ask ^^
> 
> 
> 
> 
> i know this "hybrid" or "mixtures" of chemical structures is a bit misleading, you don't get the best of two worlds most of the time..
> but it might be active, possibly not very enjoyable, but well... this thread has its name for a reason



AFAIK the aromatic ring in ampethamine pi stacks with an electron rich tyrosine residue (Tyr 182? Correct me if I'm wrong) in the S1 pocket of DAT which helps stabilise its pose. Losing aromaticity means this interaction is lost, and it will reduce the potency of this drug. Not to mention it'll probably have less affinity for other relevant intracellular proteins like TAAR1 and VMAT. Propylhexedrine is significantly less active than methamphetamine.


----------



## Nexus_Tripper

Dresden said:


> PCDE



Those are  junk. Any arycyclohexamin with two things on nitrogen are inert. they are metabolized and one group gets cut of the N, soo if you take enough they can have effects.


----------



## Raihiar

aced126 said:


> AFAIK the aromatic ring in ampethamine pi stacks with an electron rich tyrosine residue (Tyr 182? Correct me if I'm wrong) in the S1 pocket of DAT which helps stabilise its pose. Losing aromaticity means this interaction is lost, and it will reduce the potency of this drug. Not to mention it'll probably have less affinity for other relevant intracellular proteins like TAAR1 and VMAT. Propylhexedrine is significantly less active than methamphetamine.



yeah, i know about the huge potency drop, and the same goes for meth vs 4fma, so the already not very potent and side-effect ridden (no 1st hand experience, don't intend to have 1st hand experience) propylhexedrine is probably going to be garbage in the best case and laden withserious side effects - neurotoxicity as with the higher halo-amphetamines, something a la PMA / PMMA or whatever in a worse scenario.. best leave this uncharted land be and sail on :>


----------



## Bagseed

something I drew while on a bus ride recently, no idea if it makes sense, but it looked nice 

edit: I am also wondering if a alpha-beta-unsaturated carbonyl is an easy target for metabolism. I made that carbonyl in order to have an sp2 carbon in there to ensure that the ring remained planar.


----------



## DotChem

^ the 4-((2-dimethylamino)ethyl)quinolone work "well" as substitute for DMT: I made similar indoles isosteres back in the days!!Tryptophan analogs with the quinolone replacing the indole  ).  It might work but lsd doesnt tolerate substitution at 2 position of the indole like with the 2-bromoLSD??) .. but who knows. NB: The one terrible thing about these types of quinolones, they're just terribly insoluble and I mean really pain in the ass to get them into any reasonable solvent.. unless you use boiling DMSO or DMF or .. cold conc sulfuric acid


----------



## DotChem




----------



## DotChem

diazepamidate ( or etomidazepam )..


----------



## Nagelfar

DAT: 52 ± 12.8





 DAT: 12.1 ± 3





 DAT: 12.2 ± 0.9





 DAT: 6.4 ± 0.27

Check this out with regard to the QSAR of phenyltropanes: the top two, 2-_para_-Thiophene & 3-_para_-Thiophene have 52 ± 12.8 and 12.1 ± 3 for DAT respectively (_i.e._ 2-thio has tighter binding for the DAT)

But with the Nor/nitrogen-demethylated of the same compounds, it's the opposite: nor-2-thio is 12.2 ± 0.9 @ DAT and nor-3-thio is twice as potent with 6.4 ± 0.27 @ DAT.... (_i.e._ the 3-thio is the tighter one)

This shows that the methylation of the nitrogen dramatically changes the position of the benzene substitutions in cocaine like molecules that affects monoamine subtype affinity in drastic ways.

Furthermore, one methylene unit length difference at the nitrogen end seems to correspond to one methylene unit length alteration at the benzene substitution end; see how the middle two compounds have basically the same affinity? But the angles have to be deeper (or shallower, or shall we just say 'more optimized'?), because it has increased affinity as it changes both, whereas just adding another unit again on the same side can completely gimp it.


----------



## Bagseed

DotChem said:


> ^ the 4-((2-dimethylamino)ethyl)quinolone work "well" as substitute for DMT: I made similar indoles isosteres back in the days!!Tryptophan analogs with the quinolone replacing the indole  ).  It might work but lsd doesnt tolerate substitution at 2 position of the indole like with the 2-bromoLSD??) .. but who knows. NB: The one terrible thing about these types of quinolones, they're just terribly insoluble and I mean really pain in the ass to get them into any reasonable solvent.. unless you use boiling DMSO or DMF or .. cold conc sulfuric acid


interesting, thanks for your comment! maybe it is too bulky, but my feeling says that putting bromine on the 2-position of a Lysergamide will be more bulky than this quinolone thing. bromine is huge! would be interesting to see, if DMT would be active with a 2-bromo-substitution.

well we'll never know unless someone synthesizes that thing and tries it. where are the shulgins of today?


----------



## Solipsis

DotChem said:


> ^ the 4-((2-dimethylamino)ethyl)quinolone work "well" as substitute for DMT: I made similar indoles isosteres back in the days!!Tryptophan analogs with the quinolone replacing the indole  ).  It might work but lsd doesnt tolerate substitution at 2 position of the indole like with the 2-bromoLSD??) .. but who knows. NB: The one terrible thing about these types of quinolones, they're just terribly insoluble and I mean really pain in the ass to get them into any reasonable solvent.. unless you use boiling DMSO or DMF or .. cold conc sulfuric acid



If the problem is localized polarity, do you have any idea whether an emulsifier would work or a surfactant like HPBCD (HBC)?

Better to start off with 4-(dimethylamino)ethylquinoline anyway? Make that 1,2-dihydro-yadayadayada.

The effect of a 2-substitution of some tryptamines is known, primarily 2,N,N-TMT (Me-DMT) and I think also the 5-MeO analogue which I might actually have somewhere... they are active but quite different, like DiPT is "different" but apparently even differenter ;p.
It's definitely possible that 2-Me vs 2-Br is not comparable anyway, but I think regarding LSD many substitutions were tried and a lot on the indole nucleus were just not tolerated, don't know if 2-alkyls were among them but wouldn't be all that surprised if BOL made the cut.
LSD fits so snug that intolerance for substitutions doesn't necessarily translate that well to tryptamines or bioisosteres of trypts?


----------



## DotChem

Solipsis said:


> If the problem is localized polarity, do you have any idea whether an emulsifier would work or a surfactant like HPBCD (HBC)?
> Better to start off with 4-(dimethylamino)ethylquinoline anyway? Make that 1,2-dihydro-yadayadayada.


yes an emulsfier might work... 1,2-dihydro? then you end up with an sp3 at C4 which will skew the conformation from that of DMT. or do you mean synthetically (ie start from the 1,2-dihydroquinoline and .. hmmmmm nothing. Actually they pretty easy access I mean the 4-quinolone one just needs serious lab setting... 


Solipsis said:


> ..LSD fits so snug that intolerance for  substitutions doesn't necessarily translate that well to tryptamines or  bioisosteres of trypts?


Exactly that's the reason for its the extreme potency!. It fits just as   perfectly as it gets. 



Bagseed said:


> maybe it is too bulky, but my feeling says that  putting bromine on the 2-position of a Lysergamide will be more bulky  than this quinolone thing...


imo the bulk is less of an issue  than the critical hydrogen bond LSD indole NH makes with the receptor.  The quinolone analog may or may not  be able to make similar interaction.   iirc the indole NH makes a critical H-bond that orientate the rest of the molecule just about right: any disruption with  that HB will kill dramatically activity because lsd is fairly  rigid:  either you have the critical NH bond then you get highly potent molecule  or you don't then  you kill the activity for the same reason (rigidity of lsd and the  like).  substitution of the 2-position of lsd  indole may make it hard to get an optimum NH-receptor H-bond. The quionolone would have a O at that position (It may actually work better because the quinolone exits in 2 forms NHCO <---->N=C-OH. So the OH may well replace the indole NH, you know what I mean?. 
With DMT you may have room to accommodate changes on the indole 2 position (and elsewhere)  since it can adjust to bind receptor without too much energy penalty.  
But definitely a very interesting suggestion: indole ---> quinolone isosteres (they may even be legit


----------



## DotChem




----------



## DotChem




----------



## Dresden

Like 2ce but with more symmetry.


----------



## SKL

doesn't that one already have a name?

edit-no,not that I can tell, I was thinking about BEATRICE but that doesn't have the other amine

f pharmacologically makes me think of some weird shit like diethylprion although simpler and more elegant; kinda interesting IMO but not sure what would happen to the elegant symmetry once getting into our system?


----------



## niflheim

DOB citraconamide


----------



## DNH

I need help with......I'm on 80mg methadone and just started a stack of nootropics (smart drug) ... However, I haven't got much from them. At less nothing that I've noticed or felt. (((I'm not looking for a high,))) Can anyone tell why this might be? Will the receptor blocker in the methadone block the nootropics from doing their job? Or haven't I found the right combination of nootropics. Please reply if you have any knowledge or thoughts on this thank you..


----------



## Dresden




----------



## Dresden




----------



## pharmakos

i bet those both exist somewhere already

the one with the napthyl probably has a JWH-designated number


----------



## DotChem

U4Rick


----------



## roi

needs more N-bombs






or BROMO-DRAGON-U


----------



## Incunabula

DNH said:


> I need help with......I'm on 80mg methadone and just started a stack of nootropics (smart drug) ... However, I haven't got much from them. At less nothing that I've noticed or felt. (((I'm not looking for a high,))) Can anyone tell why this might be? Will the receptor blocker in the methadone block the nootropics from doing their job? Or haven't I found the right combination of nootropics. Please reply if you have any knowledge or thoughts on this thank you..



This is kind of the wrong thread. To get some proper responses, either post in the big and dandy nootropics thread  in the psychedelic drugs forum, or start a new thread here in NPD (it'll get moved if it's not advanced enough) *Important*, be sure to list which nootropics you are taking, because theres litteraly hundreds of different known ones, all with different mechanisms of action.

Chances are though, that you are expecting to much of them. Not everyone gets noticeable effects from nootropics.


----------



## Limpet_Chicken

Niflheim, making the aminoalkane chain into an amide abolishes psychedelic activity.


----------



## Solipsis

DNH, Methadone is an NMDA antagonist besides being an opioid (NMDA and opioid systems are closely connected by the way). Nootropics and NMDA antagonists are found to counteract each other, that may very well be it. But yeah it's difficult to say how much that contributes because like Inc said there are many nootropics and not only do they act in various ways, definitely not all of them are that pronounced.

But please, take it to the nootropics thread if you want to continue - post in appropriate threads, use the search engine if you can't find threads cause admittedly nootropics are not easy to categorize in the forum. Thnx very much.

@Roi:






M1-U-4-lorn
Haha wow oops had not seen Dotchems nearly identical structure


----------



## klfiend

2-(2-Chlorophenyl)-2-(methylamino)cyclohexane

longer lasting, more potent analog of ketamine?


----------



## Incunabula

klfiend said:


> longer lasting, more potent analog of ketamine?


Yah, maybe. I'd hit it for sure


----------



## DotChem

U4-MX


----------



## Solipsis

How to make a longer lasting U4 analogue though?

3,4-Dichloro-N-[(1R,2R)-2-methyl-2-(N-pyrrolidinyl)-4-fluorocyclohexyl]-N-methylbenzamide ?


----------



## DotChem

^ the fluorine on the cyclohexyl ring? metabolic blockade to increase T1/2? Is P450 hydroxylation of the ring main first pass metabolism? I would expect hydrolysis of the tertiary amide to be responsible for shorter half-life. yes?


----------



## Solipsis

Yeah maybe it is futile


----------



## Dresden

DOC-MPH


----------



## Dresden

The shotgun approach.


----------



## Limpet_Chicken

Shotgun?

And what is this 'u4' I keep reading.


----------



## Solipsis

U-47700







*NSFW*: 




U-47700 is an opioid analgesic drug developed by a team at Upjohn in the 1970s[1] that acts as a selective agonist of the µ-opioid receptor with a Kd value of 5.3 nM compared to 910 nM for the κ-opioid receptor[2][3] and has around 7.5 x the potency of morphine in animal models.

U-47700 is a structural isomer of the earlier opioid AH-7921 and the result of a great deal of work elucidating the quantitative structure–activity relationship of the scaffold. Upjohn looked for the key moieties which gave the greatest activity[8] and posted over a dozen patents on related compounds, each optimizing one moiety[9][10][11][12][13][14][15][16] until they discovered that U-47700 was the most active.[17]

U-47700 became the lead compound of selective kappa-opioid receptor ligands such as U-50488, U-51754 (containing a single methylene spacer difference) and U-69,593, which share very similar structures.[18][2] Although not used medically, the selective kappa ligands are used in research.

U-47700 has never been studied on humans, but would be expected to produce effects similar to those of other potent opioid agonists, including strong analgesia, sedation, euphoria, constipation, itching and respiratory depression which could be harmful or fatal. Tolerance and dependence would be expected to develop.[28]

Combined consumption of U-47700 and fentanyl caused one fatality in Belgium. 17 opioid overdoses and several deaths in the USA had initially been associated with U-47700 in April 2016,[31] as of September 2016 at least 15 fatalities were confirmed.
*
Legal status*

Following its sale as a designer drug, U-47700 was made illegal in Sweden on 26 January 2016.

U-47700 was emergency scheduled in Ohio on 3 May 2016 by executive order of Governor John Kasich.

The United States Drug Enforcement Administration (DEA) proposed a temporary placement of U-47700 into Schedule I of the Controlled Substances Act on 7 September 2016




It apparently feels oxycodone-like to some people, so I take it it is a little more uplifting and stimulating than say morphine... the feeling is popular but it has a short-lived effect and has done terrible things for people like addictions worse than heroin.

I like opioids, or I should say liked because I don't allow myself to indulge anymore in general, but even if I did this one scared me too much - I've heard real horror stories from a BL-er I was sorta close to / heard from and of.

You should probably think twice before getting involved with U-47700.

I've tried AH-7921 though a while back and though it was very peculiar and while it may be effective as an analgesic, it's not a strong drug if you just using it for quelling shitty feelings like a junkie of sorts.


----------



## Limpet_Chicken

Had been meaning to give, I THINK it was that one, some similar looking open chain dichlorophenyl-based thing like that at any rate.

Like oxycodone? meaning meh and no rush to speak of then or am I missing something there. HOW short acting is this drug?


----------



## niflheim

Limpet_Chicken - That's not really a problem - in acid conditions the citraconic acid moiety should undergo a rapid acid-catalysed hydrolysis forming citraconic acid anhydride and DOB. See Karaman, R et al. "Design, synthesis, and in vitrokinetics study of atenolol prodrugs for the use in aqueous formulations." ScientificWorldJournal, 2014.


----------



## Solipsis

https://psychonautwiki.org/wiki/U-47700 read your heart out.. maybe it was the AH-7921 that I mentioned you are thinking of, it's indeed very close to this one: the N-desmethyl analogue.

I have not taken U-47700 so I can't pitch it to you nor do the opposite beyond the warning I gave earlier... enough people like it, but then again plenty of people like oxycodone while you don't apparently... and not diamorphine a whole lot either I think so maybe this one isn't really for you anyway.

Do tell me about the ergot if you please, that should be damn interesting. The boletes I talked about earlier were mostly Edulis (ceps), Badius and L. Scabrum...


----------



## DotChem

imho U4x pretty much like highly potent Tramadol: mu Opioid + SNDRI and  possibly releaser as well. Not surprising that it is extremely addictive..  basically speed-ball: massive Dopamine release + mu activation. But the  3,4-dichlorophenyl pattern generally gives more SERT selectivity (kind  of like 3,4 dichloropheny MPH analog).  Though I don't think anybody has  tested that but the structure looks too close to that of Tramadol and  other SNDRIs not to have dopaminergic/serotonergic.. but who knows? 

Now..even more potent opioid:




 (at least as good as fenta. 10x more than U-477 or 100x morphine at  least!! since adding phenolic OH (like with tramadol M1) jack up mu  Opioiod affinity dramatically> 1000x in the case of tramadol.

OH substitution also increase Dopaminergic as well (relative to H) and decrease serotonergic and tend to give DNRI  DNRAs selectively. SERT transporter doesnt like hydrophilic groups  (cautiously generalizing what is known about SAR of OP and SNDRI/R.. but who knows?

Now to get less Opioid and more cocaine-like (or may be more MDMA-like?? more serotonergic??  





PS: the original U4x patent doesn't cover much SAR .. would be nice to see some more U4x on the RC market!


----------



## Solipsis

What do you base the notion that U-47700 is an SNDRI on? Many opioids like oxycodone appear to have some serotonergic action (it's definitely not only tramadol that can get involved in serotonin syndrome etc) but it's another thing to compare to tramadol which is a rather significant SRI and also dangerous to mess with. If U-47700 was like that and tolerance to the opioidergic effects would be affected a lot leading to increased doses, you'd expect issues (people have been known to take a lot of it once they get going, also I've known a person to abuse it who also took a lot of other things like stimulants and I never heard of any serotonergic crisis); issues because the SRI effect wouldn't necessarily see the same tolerance development?
It's worth noting that the manner in which oxycodone influences serotonin levels or has interactions with other drugs is very poorly understood.

The phenol does seem like a good idea though, has it been tested?


----------



## niflheim

Trifuranscaline


----------



## Dresden

I kind of like that.  It made me think of this, which I'm not sure will exist.


----------



## Solipsis

Trifluoromescaline-3,5-dragonfly






_(8-(Trifluoromethoxy)furo[2,3-f] [3]benzofuran-4-yl)ethan-2-amine_

I don't know what's ambiguous about this formula?, polycyclic nomenclature is NOT my forte






The 2,3-methylenedioxy seems more analogous to MDMA but I don't know that the rings are stable... at least the 3,4 connected backbone has been made.






Strikeaposamine? Surely if you make a molecule that dabs it means it gets you very high?


----------



## SKL

a lot of oxygen in last few posts … stable?

the 2,3-MDIO looks kinda sexy if it will stay put


----------



## Solipsis

I think so for most but not sure.. kinda foresee problems with Dresdens entry, and don't know if the thiophene counterpart was made but that is why I chose the other methylenedioxy thiophene orientation. I don't know about the significance of the sulfur position in methiopropamine.

Damn, inspired by MDAI and above ideas I wanted to make something freaky, and figured out the nomenclature by myself, no copy pasta. 






_4,5-methylenedioxy-2-thiabicyclo[1.2.5]dec-3,5(1)-dien-8-ylamine_

I can make the linkage to the amine 2-carbon for you instead of 3-carbon if you like.. but I like this one because it looks like a lab mouse growing sulfur on its back.. ;p
Unfortunately now that I see it I think maybe it's too constrained?

Also: the ambiguity in opsin was just that I didn't explicitly say that the ethanamine connects at position 1 although it is implicit from the fact that the formula says the amine is on the 2-position... a normal chemist correctly infers that this only happens because it refers to something that must be happening at the other one where the counting started.


----------



## Dresden




----------



## Solipsis

Not bad and in theme :D .. question about it: if thiophene is bioisosteric to benzene does that make that benzothiophene like naphthalene and the above molecule probably PAL-287 like?
And if sulfur is in the same group as oxygen, then why isn't furan similarly bioisosteric?
I think benzofuran analogues of indoles may suffer from the problem that the 1-position nitrogen proton is missing for essential bonding interactions rather than something else, wonder if a sulfurane would solve that but those are pretty exotic..


----------



## Nagelfar

SNDRI(?)


----------



## adder

Solipsis said:


> Not bad and in theme :D .. question about it: if thiophene is bioisosteric to benzene does that make that benzothiophene like naphthalene and the above molecule probably PAL-287 like?
> And if sulfur is in the same group as oxygen, then why isn't furan similarly bioisosteric?
> I think benzofuran analogues of indoles may suffer from the problem that the 1-position nitrogen proton is missing for essential bonding interactions rather than something else, wonder if a sulfurane would solve that but those are pretty exotic..



I guess it largely depends on the molecule and its target whether 2-furanyl substitutes for a phenyl or an ortho-substituted phenyl. In case of amphetamine and MPA I suppose the 2-furanyl analogue may have a too small aromatic ring along with inappropriate electronics. After all furan is less aromatic than thiophene which is directly related to charge delocalization, obviously sulfur is better at it.


----------



## DotChem

Solipsis said:


> What do you base the notion that U-47700 is an SNDRI on? ......



This series of compounds from this danish patent (the structure at the bottom, cf the wiki to link up). They are extremely potent SNDRI but with more NDRI selectivety (Ki-SERT = 0.37uM; Ki-DA = 0.021uM and Ki-NE = 0.0097uM) about 12,000 more potent than cocaine as NDRIs.  Compare the structure to that of U4x 







Now that i have time to go through that patent again, actually the di-Chloro substitution pattern doesn't skew selectivety towards SERT as with cocaine and MPH analogs where 3,4d-Cl2phenyl or naphthyl increase SERT dramatically. That's why I thought it may be more serotonergic. But obvioulsy not. So nothing to worry about serotonergic toxicity. Assuming binding similar in both cases, it will be rather selective NDRI and not SNDRI (at least by a factor of10x !) 

Notice the inverted amide and the positively charged dimethylamino on the cyclohexyl replaced by a piperidine. For transporters it doens't really matter a lot whether or not a N+ is present (it only reduce activity by 100x at most, which is still huge going say from 0.025uM to 2uM still 150x times higher than cocaine!! .. The structural, steric shape of the molecule is most critical .. but who knows until tested? 


The Tramadol-like NDRI (if any as I assumed) may explain why the U4x are potentially extremely addictive : extremely potent NDRI + mu Opioid agonist= speed-ball without serotonergic. Which paradoxically will make them safer since deadly opiates-induced respiratory depression is balanced out by stim NE activity (correct me if I am wrong.



Solipsis said:


> The phenol does seem like a good idea though, has it been tested?


 or better yet the methoxy that can potentially get metabolized into a phenol .. I dont think they been tested: the original patent focus more on kappa selective rather that mu so they didnt really bother wasitng time on U4x!!


----------



## DotChem

correction : Ethyl instead of methyl :


----------



## Solipsis

I am pretty skeptical about all that so some peer review would be sweet but it's impressive if it's true.






Much nicer idea than O-PCM??






_5-methyl-1,2,2a,3,4,5,6,7-octahydroazecino[4,5,6-cd]indole_


----------



## Dresden




----------



## Dresden




----------



## Bagseed

what do you expect from the 3-brom? is it isobiosteric (is that the right terminology?) to a methoxy? (bromine size)


----------



## Dresden

Sometimes


----------



## Solipsis

Sekio said it's supposed to be equipotent or stronger, he also said deschloro K would not be that desirable (arguable, I don't like it but others do), that fluoro would be similar to deschloro which I find absolutely not true in any way and that N-ethyl-norK might be a good place to start, but due to some fluke it's apparently not good at all. I wonder if PCM would be a rought fucking beast of a drug, I think probably and that it would linger for even longer than O-PCM (deschloro-K) would also be horrible. But I don't think PCE was not disliked?

Rhodium is supposed to have made and assayed bromo-K but I can't find particulars. If it would be great, I don't get why it's not an RC hype. If it's indeed like 2-MeO ket then nooo thank you, that was one of the worst ones of all. Just dirty and rough feeling, not that unlike deschloro-K.
If they would make fluoro-K cheap enough to just be able to dose higher it could be good as a party-style dissociative rather than for real holing, but it's unexplainably expensive.

So I think that sekio is right in saying that the 2-halo is probably important for the drunken anaesthetic magical effects (well IMO almost completely true, but deschloro-K also totally immobilizes me but I don't find it magical - tolerance issues perhaps). And it must be remembered that SAR is different than from the PCPs.


----------



## Limpet_Chicken

Would A pyranylisopropylamine (simple) be able to bind transporters/TAAR1 as a monoamine releaser or reuptake inhibitor?

Or perhaps a substituted pyranylisopropylamine in the vein of the 2Cx type or DOx type agents?


I've often wondered about fluoro/bromo/iodo/nitro/cyanoketamines myself. Assuming no release, of -CN and there shouldn't be from an aromatic nitrile, correct? owing to both its bioisosteric similarity to halides, and the carbon chain extension of an alkyl, then it might be interesting to ascertain what it does if anything, as a kind of hybrid between methylamino and halo.


----------



## sekio

Pyrans aren't aromatic, are they? So I'd expect 1-(2H-pyran-2-yl)propan-2-amine to be sort of like propylhexidrine/DMAA - a crappy stim, and the aromatized 2-(2-aminopropyl)pyrylium would be too charged to cross BBB.


----------



## Incunabula

I remember reading way back, that bromo-ketamine wasn't supposed to be very good, or at least a lot less potent than regular ketamine - Unfortunately I can't remember were I read it.


----------



## Coolwhip

Why haven't we seen other phenmetrazine analogs, seems like the RC market goes crazy with substitutions for every other substance. Why not 2-(3-chlorophenyl)-3-methylmorpholine, 2-(3-Fluorophenyl)-morpholine, or 6-methyl-2-phenylmorpholine, or any of the other dozens of substitutions that seem to make sense? Sure, 3-FPM isn't exactly methamphetamine, but lots of people are looking for functional stims, or something like 3-FPM but a little more recreational, and the market is filled with a lot worse stims.

I don't know anything about synthesis, or phenmetrazine SAR, but surely there are plenty of analogs with potential given phenmetrazines "legendary" reputation. And honestly I really like 3-FPM, I can't dose too high, but its the first stim I've been able to take in years at all without a benzo...the kindling effect has really fucked up since smoking meth all through my teen years and speedballing through my 20's(even then I couldn't do coke without plenty of heroin on hand)...I normally can't touch stims at all without a benzo nearby, not even slightly recreational doses of dexamp or focalin.


----------



## Solipsis

Coolwhip said:


> Why haven't we seen other phenmetrazine analogs, seems like the RC market goes crazy with substitutions for every other substance. Why not 2-(3-chlorophenyl)-3-methylmorpholine, 2-(3-Fluorophenyl)-morpholine, or 6-methyl-2-phenylmorpholine, or any of the other dozens of substitutions that seem to make sense? Sure, 3-FPM isn't exactly methamphetamine, but lots of people are looking for functional stims, or something like 3-FPM but a little more recreational, and the market is filled with a lot worse stims.
> 
> I don't know anything about synthesis, or phenmetrazine SAR, but surely there are plenty of analogs with potential given phenmetrazines "legendary" reputation. And honestly I really like 3-FPM, I can't dose too high, but its the first stim I've been able to take in years at all without a benzo...the kindling effect has really fucked up since smoking meth all through my teen years and speedballing through my 20's(even then I couldn't do coke without plenty of heroin on hand)...I normally can't touch stims at all without a benzo nearby, not even slightly recreational doses of dexamp or focalin.



I'm looking at nine now, not including possibility of the sole active isomer of some. Seem like quite a few exist. Are they all really unique enough to be marketed? My experience with stims, that excludes phenmetrazines though, says no and more than half are shit anyway.



fastandbulbous said:


> My teeny-weenie contribution regarding anorectic activity (which generally corresponds to stimulant properties except for large/unusual reuptake inhibitors) of phenmetrazine derivatives (in rats anyway)
> 
> *2-phenyl-3-methylmorpholine (phenmetrazine)*
> 
> good anorectic agent, good cns stimulant. (app more euphoric then amphetamine by injection)
> 
> *2-phenyl-3,4-dimethylmorpholine (phendimetrazine)*
> 
> reasonable anorectic. Partially metabolized to phenmetrazine
> 
> *2-phenyl-3,5-dimethylmorpholine*
> 
> rather poor anorectic. Possibly steric hinderence at active site of phenmetrazine about heterocyclic nitrogen atom
> 
> *2-phenyl-3,6-dimethylmorpholine*
> 
> good anorectic. not much less active than parent molecule (phenmetrazine)
> 
> *2-phenyl-3-methylmorpholin-6-one*
> 
> Reasonable anorectic. Short half life compared with phenmetrazine





mad_scientist said:


> For what its worth the SAR data for phenmetrazine in the patent literature suggests that the only really promising substitution on the phenyl ring is 3-fluoro, pretty much every other derivative they tried was substantially less active than phenmetrazine itself (though they didn't try 3,4-methylenedioxy iirc), but 3-fluorophenmetrazine retains similar monoamine release ratios to phenmetrazine with slightly higher potency. The 3-chloro derivative appears to be a selective serotonin releaser, but these have so far generally failed to live up to expectations as novel empathogens...



By the way, when they say 'anorectic' effects, are they excessive even by stimulant standards for things like 3-FPM or just on par with amphetamine?
I wonder anyway how levo amph can be so physical while dex is very centrally acting. I get anorexia from dexamph only on high doses.


----------



## Coolwhip

Just on par ime if not less, I've also had PDM in high doses and although its sold as a diet pill it never kept me from eating, phentermine is a more powerful anorectic from what my mother-in-law says(she has been prescribed both as diet pills). 

I wonder if there would be a way to keep the SRA activity of the 3-chloro substitution while retaining stimulant affects with a substitution on the morpholine(or lack of one, maybe remove the methyl, what does removing the methyl to do the parent compound?) in order to obtain a triple releaser. I wonder how else the affects of 2-phenyl-3-methylmorpholin-6-one differ, and what the effect of a 3-fluoro/chloro substitution would do there. Or possibly going with a benzene ring, or a methyl-ester ala methylphenidate.

But from what you've told me it seems phenmetrazine is about as good as it gets(besides maybe making it more lipophilic, but I guess trying to turn phenmetrazine into cocaine would destroy everything I like about it), and 3-FPM is close enough, and there is no obvious way to increase sero affinity without losing DA/NE.

Thank you for the answer, that was very informing.


----------



## Solipsis

Coolwhip said:


> Just on par ime if not less, I've also had PDM in high doses and although its sold as a diet pill it never kept me from eating, phentermine is a more powerful anorectic from what my mother-in-law says(she has been prescribed both as diet pills).
> 
> I wonder if there would be a way to keep the SRA activity of the 3-chloro substitution while retaining stimulant affects with a substitution on the morpholine(or lack of one, maybe remove the methyl, what does removing the methyl to do the parent compound?) in order to obtain a triple releaser. I wonder how else the affects of 2-phenyl-3-methylmorpholin-6-one differ, and what the effect of a 3-fluoro/chloro substitution would do there. Or possibly going with a benzene ring, or a methyl-ester ala methylphenidate.
> 
> But from what you've told me it seems phenmetrazine is about as good as it gets(besides maybe making it more lipophilic, but I guess trying to turn phenmetrazine into cocaine would destroy everything I like about it), and 3-FPM is close enough, and there is no obvious way to increase sero affinity without losing DA/NE.
> 
> Thank you for the answer, that was very informing.



Ah nice to know it's not necessarily _that_ anorectic.. 

A methylphenidate analogue exists and is called methylmorphenate (not to be confused with any morphinate), which seems like a poor name technically speaking since the phenyl ring isn't morpholinized.
I don't know if it's interesting, check the BL thread..

Assuming that something like MDPV is a "good" drug and not evil like in my opinion, are piperidine or morpholine analogues worthwhile?

Anything known about any phenethylpiperidines apart from fent precursor?


----------



## Coolwhip

I did stumble across this earlier, isophenmetrazine

http://www.bluelight.org/vb/threads...erivative-(2S-5S)-5-methyl-2-phenylmorpholine

Looked kind of interesting, I wonder what a 3-flouro/chloro substitution would do there.


----------



## DotChem

last longer?..  closer to pipradol? naahhh may be not!


----------



## Solipsis

DotChem said:


> last longer?..  closer to pipradol? naahhh may be not!



http://www.bluelight.org/vb/threads...-molecules?p=13444634&viewfull=1#post13444634

maybe you had info then?

At least no hydrolysis to ritalinic acid... so should last longer if it acts at all..


----------



## niflheim

5-(2-chlorophenyl)-6-methoxy-octahydroindolizine

Also this:





3a-(1-benzofuran-6-yl)-5,6-dimethyl-4H,5H,7H,7aH-furo[2,3-c]pyridine


----------



## Solipsis

Care to elaborate?


----------



## klfiend

benzofuran analog of AMT


----------



## niflheim

I'll assume that was at me. If not, I'll elaborate anyway.

The first one is intended as a ketamine analogue (here's some others that might make the thinking behind it a bit clearer):





The second one amused me because it could have activity as an opioid, empathogen, reuptake inhibitor or dissociative. It likely doesn't, but I was in a whimsical mood. This might make where I was coming from with it a bit clearer:


----------



## Solipsis

Ah thanks for that, wow there would be something pretty damn weird about a dissociative empathogen..


----------



## niflheim

Solipsis said:


> Ah thanks for that, wow there would be something pretty damn weird about a dissociative empathogen..



You'd want to hug everyone, but you'd never feel them hugging you back.

ObRandomMolecule:





Kethidxmine


----------



## DotChem

Solipsis said:


> http://www.bluelight.org/vb/threads...-molecules?p=13444634&viewfull=1#post13444634
> 
> maybe you had info then?
> 
> At least no hydrolysis to ritalinic acid... so should last longer if it acts at all..


yes it does at least in mice.. This and similar acyl types MPHs are slow-onset, long-lasting and a bit more DA selective than MPH (https://www.ncbi.nlm.nih.gov/pubmed/17228864) That makes sense: they're more lipophilic! Not sure of their potential as RCs though but they'll make nice nootropics and/or hornytropics (ie sex libido shooting to the roof..no pun intended!). They'll probably behave more like Amfonelic acid, pure DRI . no re$ource$ to synthesize the keto-MPH presently but may be worthwhile for nootropic market. keep posted


----------



## perpetualdawn

I was just looking at 3-Flourophenmetrazine, and wondering about a variant putting the magic 3,4 bit from MDA and MDMA on it instead of the 3-F. I guess the molecule I'm thinking of might be called 3,4-Methylenedioxyphenmetrazine

Don't have the time to draw that right now.. but anyone heard of such a thing?

edit: there's a picture of it from Wikipedia:






and even a footnote for it referencing synthesis for some related chemical. Maybe it covers 3,4-methylenedioxyphenmetrazine too? Woop! (not that I'll ever have the skillz, just good to know others have looked at this, and maybe it will see the light of day on the RC markets some day)

Świst M, Wilamowski J, Zuba D, Kochana J, Parczewski A. Determination of synthesis route of 1-(3,4-methylenedioxyphenyl)-2-propanone (MDP-2-P) based on impurity profiles of MDMA. Forensic Science International 10 May 2005, 149(2–3): 181–192. doi: 10.1016/j.forsciint.2004.06.016

edit2: I guess the short from for this would be MDPM, following the pattern of MDA and 3-FPM.


----------



## Coolwhip

http://www.bluelight.org/vb/threads/716648-Methylenedioxyphendimetrazine-(MDPDM-RMDMA)

And if you look a few posts above Solipsis sheds a little light on phenmetrazine analogues, I posted a link about isophenmetrazine which had appreciable affinity for the serotonin transporter without losing all N/D activity, and the 3-chloro substitution seems to make it selective for serotonin, I was thinking if you could increase the N/D activity of isophenmetrazine you might be getting somewhere. Most this talk goes above my head though...

I wish I could find a high dose trip report for isophenmetrazine, I found it odd that people were describing it as equipotent to 3-FPM despite 1/2 the potency for NET and 1/7 the potency for DAT.


----------



## EP-11




----------



## perpetualdawn

Thanks coolwhip! Neat that there was a discussion along these lines already happening here. It's interesting when that kind of thing happens, shows how were all tapped into the same zeitgeist.

I wonder if MDPM would skirt the laws in the same way that 3-fpm does in a lot of places. 

It would def be interesting to see more exploration of the phenmetrazine family, esp. following the pihkal patterns - subs on the 4 position like the DOX series.


----------



## EP-11




----------



## Nagelfar

EP-11 said:


>



Is that the flux capacitor put into a dopamine transporter instead of a DeLorean?


----------



## EP-11

Possible disassociative empathogen and stimulant?


----------



## Solipsis

I think these may range from being so slow and long acting as to be ineffective for their purpose, to monstrous..
















piperonylpiperidines, what do you call that.. piped piper?

Pipradrol SAR probably has fuck all to do with MDMA SAR, so this all depends very heavily on what piperonylpiperidine does itself and if it behaves anything like either of them..


----------



## Nagelfar

coke C1-phenyl sub + singh PT 43e (conjoined w/ latter) + 83a/84a (C2 N/A) RTI-55 but non-benzene, just planar aromatic structure.



DotChem said:


> last longer?..  closer to pipradol? naahhh may be not!



Missed that^, most certainly doable AFAIK my DRI QSAR


----------



## Solipsis

will tautomerize upon demethylation but no matter:






3-phenyl-3-(piperidin-2-yl)-1-propen-2-oxymethane

or






(2,3-dihydrofuran-5-yl)phenylpiperidin-2-ylmethane


----------



## Limpet_Chicken

hybrids betwixt' desoxypipradrol and  the phenidates?

That last one looks like the bastard sprog of doeoxypipradrol, MDMA, methiopropamine and methylphenidadte.


----------



## Solipsis

Something like that, didn't really have hybridization in mind but just analogues of such DARIs by finding some bioisostere or something that can fulfill the electronic role of ritalinic acids carboxyl. Doesn't seem to me like it absolutely must be a carbonyl there looking at pipradroles. The five membered ring is merely meant to prevent too quick a loss of the O-methyl... basically here I was looking for something not as short acting as MPH but not as long as DPMP. Even the non-desoxy version of that seems way too lipophilic to me and not particularly metabolizable.

The enol ethers would be messed up in the stomach though? That wouldn't be good..


----------



## EP-11

Would this Have DRI effects










^ Also some fluorenol analogues


----------



## Pomzazed

That fluonocaine looks good


----------



## Nagelfar

EP-11 said:


> Would this Have DRI effects



Looks like tropatepine, the benztropine: a "tricyclo benzoyloxy dibenzene cocaine analogue" of similar build was found in a patent by yours truly.


----------



## Nagelfar

^anyhow, I am believing the above would have anti-chlorinergic effects, like tematropium & tropatepine, possibly, but the cyclopentane is smaller so perhaps not.






2-Thiophene with the length para addition that is between RTI-430 & RTI-298 (para of benzene equals: –C≡C-CH2Ph) which has the distal extra binding site for dopaminergic affinity.

e.g. between this:




52 ± 12.8 DAT


And this:





1.82 ± 0.42 DAT


----------



## EP-11

Nagelfar said:


> ^anyhow, I am believing the above would have anti-chlorinergic effects, like tematropium & tropatepine, possibly, but the cyclopentane is smaller so perhaps not.


Thanks for the insight


----------



## DotChem

Solipsis said:


> ..something not as short acting as MPH but not as long as DPMP. Even the non-desoxy version of that seems way too lipophilic to me and not particularly metabolizable...The enol ethers would be messed up in the stomach though? That wouldn't be good..



Would amides bioisosteres work? like this and similar NHEt NMe2...etc etc





Increased half-life relative to MPH but not too much like pipradol types?  Amides are more metabolically stable than esters. eg you go from anesthesic Procaine (T1/2 ~ 84 seconds in plasma) to procainamide (T1/2 ~ 3h). Plus they may have faster onset because less lipophilic .. and/or increased binding affinity to the transporter: with a little luck, the extra NH might picks up a hydrogen-bond or 2 with the receptor..  but who knows? 

PS: IMHO there is no point for bioisosteric replacement of MPH except maybe legal issues perhaps. The reason is that they'll pretty much have to be synthesized from MPH anyway so ended up more expensive with little advantage compared to MPH esters ET or iPr..etc Unless they may be easier cheaper route !


----------



## EP-11




----------



## Nagelfar

highest potency 'restricted rotational analog' of methylphenidate, with elements (aryl-planar ring unit, deoxygenated restricted-carbmethoxy) made to mimic fentanyl.

Another "Ritalin/Fentanyl" hybrid:

i.e.




+


----------



## Nagelfar

^Asymmetrical non-planar arene area caused increased binding in the eta-6 coordinated chelated phenyltropanes: using the bulk of those sigmaergics recently elucidated as the arene unit (one was highly dopaminergic, I used that one as a base, though it wasn't the boxed cyclopentane that did it, I reckon) in cocaine, this looks awesomely poignant even in inactive, profound even.

cf.





Various fluoxetine + amphetamine hybrid/intermediates:


----------



## Dresden

You can't have aminals and hemiaminals.  It's really simple.  If the structure has an N-C-O, then it's probably not going to exist.

There really aren't many exceptions, either.


----------



## DotChem

U-4X


----------



## Nagelfar

Dresden said:


> You can't have aminals and hemiaminals.  It's really simple.  If the structure has an N-C-O, then it's probably not going to exist.
> 
> There really aren't many exceptions, either.



I always draw 'em without thinking 'bout it when throwing together "hybrids", gotta watch that tendency better.

More cyclopentane-cage-arene-substituted phenyltropanes:










These are attested to hemiaminals that work.


----------



## sekio

^ sup dawg, we added a ring system to your ring system 'cause i herd you like ring systems


----------



## Nagelfar

sekio said:


> ^ sup dawg, we added a ring system to your ring system 'cause i herd you like ring systems



sekio gets it. ;-j


----------



## Nagelfar

^Diclofensine + Quinolizidine MPH analog structure


----------



## Dresden

This is inspired by a cocaine analogue that Nagelfar brought up.  If it's anything like PMA, then that's no good, but who knows?


----------



## EP-11

Mesocarb analogues


----------



## Nagelfar

Dresden said:


> This is inspired by a cocaine analogue that Nagelfar brought up.  If it's anything like PMA, then that's no good, but who knows?



"Like" subjectively, and "like" structurally, can be worlds apart, thank goodness. But yes those thiophene DRIs should be looked at in more detail.


----------



## Nagelfar

^OK:





DAT ligand (Mazindol) displacement: 0.14 ± 0.07
DA uptake displacement: 0.31 ± 0.09

+





DAT ligand (RTI-55) displacement: 0.03 ± 0.01

compare (note all naphthyls are 2-naphthyl, 1-napthyl is across the board higher-numbers/lower-affinity):




DAT ligand (RTI-55) displacement: 0.115 ± 0.021





DAT ligand (RTI-55) displacement: 0.28 ± 0.11





DAT ligand (beta-CFT) displacement: 0.51 ± 0.03
DAT ligand (cocaine) displacement: 3.32 ± 0.08
DA uptake displacement: 3.53 ± 0.09



sekio said:


> sup dawg, we added a ring system to your ring system 'cause i herd you like ring systems



Now that I think about it, that inspired this:






Spirocyclic Trishomocubane Tropane, or Polyspirocyclopentacagecaine


----------



## Dresden

Super dopamine reuptake inhibitor


----------



## Nagelfar

Dresden said:


> Super dopamine reuptake inhibitor



Just a para-thiophene MPH. Remember, benzyl cocaine/phenyltropane works but benzyl ritalin doesn't, so it might not stick in the same.

EDIT:

example:






Binding: 885 ± 18 IC50
Uptake: 1020 ± 52 IC50






Binding: >5000 K_i_

(of course Ki vs. IC50, and different displacement, ligands across different data sets shouldn't be too indicative, but generally in the same class I've found they balance if comparing just two and not three for which of the two are better)


----------



## EP-11

What would this be like


----------



## Dresden

No one knows what that would be like without making and trying it.


----------



## Nagelfar

EP-11 said:


> What would this be like



Looks like it would be a dopamine agonist like Pramipexole or a serotonin agonist, or maybe just inactive. But those are my best guesses


----------



## DotChem




----------



## Dresden

Not stable in aqeous media


----------



## DotChem

why not?


----------



## Dresden

It'll migrate over to the nitrogen, form an imine, and be hydrolyzed to a ketone by water.


----------



## Nagelfar

Dresden said:


> It'll migrate over to the nitrogen, form an imine, and be hydrolyzed to a ketone by water.



Give me a stability lesson with this; which nitrogens are possible with it still being stable:


----------



## Solipsis

Nagelfar said:


> Give me a stability lesson with this; which nitrogens are possible with it still being stable:



http://blogs.sciencemag.org/pipelin...wont_work_with_azidoazide_azides_more_or_less

IMO get rid of that 4th nitrogen in a row, the one connected to the azide. I don't think an azide can be connected to it, would want to start splitting off N2 instead of binding that way. It would go diazonium compound + say NaN3 --> organic azide + N2.

Not so sure about that other nitrogen in the ring either, those 3 in a row... don't know what that would do, I wonder if that N=N will want to be a triple bond if it gets a chance.


----------



## DotChem

Dresden said:


> It'll migrate over to the nitrogen, form an imine, and be hydrolyzed to a ketone by water.


I am not sure if I get what you saying but I have the impression you may  be talking enamines which are indeed not stable in water and will get  hydrolyzed quickly to the corresponding ketone and amines.  In enamines, the N is connected directly to the sp2 carbon to give vinyl amines which are not stable. But these are allyl amines(not vinyl).. they should be fine. Unless there  is something specific about these particular compounds! 
Actually, some of these have been published:





https://pubchem.ncbi.nlm.nih.gov/compound/11008589#section=Top
Interesting  thing: they are no releasers but pure Reuptake inhbitor. Unlike other  stims they do not get transporter to storage vesicles.  I think profile  should be much closer to coke than anything... but who knows?


> Title:  Characterization of a series of 3-amino-2-phenylpropene derivatives as  novel bovine chromaffin vesicular monoamine transporter inhibitors.
> 
> Abstract:  A series of 3-amino-2-phenylpropene (APP) derivatives have been  synthesized and characterized as novel competitive inhibitors, with K(i)  values in the microM range, for the bovine chromaffin granule membrane  monoamine transporter(s) (bVMAT). Although, these inhibitors are  structurally similar to the bVMAT substrate tyramine, *none of them were measurably transported into the granule*.  Structure-activity studies have revealed that, while the 3'- or 4'-OH  groups on the aromatic ring enhance the inhibition potency, Me or OMe  groups in these positions reduce the inhibition potency. Halogen  substitution on the 4'-position of the aromatic ring causes gradual  increase of the inhibition potency parallel to the electron donor  ability of the halogen. Substituents on the NH(2) as well as on the  3-position of the alkyl chain reduce the inhibition potency. Comparative  structure-activity analyses of APP derivatives with tyramine and the  neurotoxin 1-methyl-4-phenylpyridinium suggest that the flexibility of  the side chain and the relative orientation of the NH(2) group may be  critical for the efficient transport of the substrate through the bVMAT.  Comparable bVMAT affinities of these inhibitors to that of DA and other  pharmacologically active amines suggest that they are suitable for the  structure-activity and mechanistic studies of monoamine transporters and  may also be useful in modeling the mechanism of action of  amphetamine-related derivatives.  https://pubchem.ncbi.nlm.nih.gov/bioassay/216244#section=Top


----------



## Dresden

The double bond is definitely going to switch back and forth to the enamine position and from there  to a lesser extent to the imine, but if you've seen published reports of such compounds, then I must be wrong.

As far as the thing Nagelfar drew, I have never seen four nitrogens in a row, heard of a name for it, or can think of a synthesis that would accomplish it.  That tells me it's probably not going to exist.


----------



## Bagseed

the carbon connected directly to the amine is sp3. the double bond cannot go there.


----------



## Nagelfar

Singh's phenyltropane "41b" (16 ± 2 @ DAT) +  para-pos.-subst. –C≡C-CH2Ph (1.82 ± 0.42 @ DAT) + 84p/(CH2)4Pht (2.38 ± 0.22 @ DAT) + C1 phenyl (32.3 ± 5.7 @ DAT _cf._ 326 ± 106 of parent compound)


----------



## nau5ea

has anyone already thought of this one? https://imgur.com/gallery/81Ggg


----------



## EP-11




----------



## Pomzazed

Bagseed said:


> the carbon connected directly to the amine is sp3. the double bond cannot go there.



double bond can migrate there in acidic condition, styrene-type structure is very easy to get protonated,
after protonation and de-protonation, db has 2 site to go, one to original, other to the enamine.


----------



## Nagelfar

nau5ea said:


> has anyone already thought of this one? https://imgur.com/gallery/81Ggg








^This? Looks like a benzyl-gimped quasi/cyclopentanified phenmentrazine with a methylene-dioxy on it. Probably a far from optimum configuration for anything but again, who knows.


----------



## niflheim

If it were a pyrollidine rather than a pyrroline, this would be a 2-benzylpyrrolidine, which are covered in this 1981 patent: US 4279918 2-(Nuclearly-substituted)benzylpyrrolidines. The methylenedioxy isn't mentioned specifically, but in general the compounds in the patent have a variety of stimulant, analgesic and hypotensive effects, so it's probably active.


----------



## Bagseed

Pomzazed said:


> double bond can migrate there in acidic condition, styrene-type structure is very easy to get protonated,
> after protonation and de-protonation, db has 2 site to go, one to original, other to the enamine.


I am not sure that I follow... you mean that the benzylic carbon will be protonated I guess? but how will that turn the sp3 carbon at the 2-position if the butane chain into sp2. can you clarify the mechanism?


----------



## MDPV_Psychosis

EP-11 said:


>



That looks like a dead frog laying on the ground with its penis sticking up in the air.

Sorry for the interruption.


----------



## Limpet_Chicken

Frogs have cloacae, not penises.

And that phenyltropane monstrosity thingy, bet thats a buggering twatting shitbox to synthesize haha. And that terminal pthalimide would likely come off in the stomach if orally taken, pthalimidopropiophenones can be used as cathinone prodrugs this way for cathinone (this was an israeli popular drug iirc, pthalimidopropiophenone) and SOMEONE has ambitions of seeing it done with psychedelic cathinones to stabilize them.

The benzyamine would possibly be an MAO(a)I, alpha-methylbenzylamine is.

You don't want to be tasting that azido thingy either. Azido functionality can make for irreversible (covalent binding) ligands. No thanks.


----------



## Limpet_Chicken

Heh if it were pramipexole-like that wouldn't be a bad thing. Pramipexole is lovely stuff, and damn does it ever take a sledgehammer to the male refractory  period! plus you can watch porn with dogs mounting and shagging girls doggy style, missionary style any style a dog will to do a girl, believe me, see it and you'll watch it for hours on pramipexole. And get off repeatedly every minute or two.

Plus its pretty much nice, added as an adjunct to morphine, or dipropionylmorphine or both mixed together, even nicer with a wee dash o'clonidine added to it before banging the mixture. Wouldn't mind trying pramipexole/clonidine/morphine sulfate/dipropionylmorphine/dibenzoylmorphine with cyclizine though too. Haven't done that yet though because whilst I've a lot OF it, I have only cyclizine hydrochloride, of which the solubility can suck the ballsack of the same dogs that I yanked off for about 8 hours straight that time I accidentally came (see what I did there) upon that video of the blonde girl of about 17yo wearing the dog collar with the golden retriever. Plus a whole bunch of ugly ones who if they did appear in porn I would not be interested in even ON pramipexole, like pitbulls, mastiffs, bulldogs or those tiny yappy little shithead anklebiters that posh twats like to take for 'walkies' in their prada cunting well handbags, the vapid islamonecropaedophile theresa-may-worshippers.

Just need to get round to basing the cyclizine and forming a soluble salt.

Anyone know how the phosphate or citrate salt do? or the ascorbate? I KNOW the lactate is, but rather not buy something I'll rarely ever use otherwise (the lactic anhydride/lactyl chloride)


----------



## Nagelfar

Limpet_Chicken said:


> plus you can watch porn with dogs mounting and shagging girls doggy style, missionary style any style a dog will to do a girl, believe me, see it and you'll watch it for hours on pramipexole. And get off repeatedly every minute or two.



I find it rather striking how some most otherwise very intellectual / articulate e.g. well spoken individuals, can be at times seemingly unable to convey the earnest confessions of their own utter abject debauchery (regarding extra-curricular hobbies pivotal to hedonistic, vulgarly epicurean, endeavors)

I mean, the language immediately reflects the proportion to which the candid broaching of the subject might be stereotyped to libelous adverse ad hominem refinement of your character. Even in admittance of such thing in a frank way, can't we approach this too, like scientific minds that are quite literal about what it is they are engaging in? Bestial trans-species coitus for auto-erogenous attempts at higher plateau of subjective crossing of the taboo, etc.?


----------



## DotChem

Bagseed said:


> Pomzazed said:
> 
> 
> 
> double bond can migrate there in acidic   condition, styrene-type structure is very easy to get protonated,
> after protonation and de-protonation, db has 2 site to go, one to original, other to the enamine.
> 
> 
> 
> I am not sure that I follow... you mean that the  benzylic carbon will be protonated I guess? but how will that turn the  sp3 carbon at the 2-position if the butane chain into sp2. can you  clarify the mechanism?
Click to expand...



@Pomazazed: is that what you mean? 






You're absolutely right but only in strongly acidic media. Could it happen in stomach acids? ... who knows?  I see that happening very easily with the corresponding ketone though (keto-enol tautomerisation) which will result in hydrolysis of the corresponding enamine.  Now that you mention it, it may be the reason why cathinones like mephedrone methylone...etc are rather unstable in aqueous media; probably get hydrolyzed via similar enamines formation to give the corresponding glyoxal and amine. (couldn't catch time to draw same things with cathinones but you get the point! .. 
the styryl seems to be more stable than the cathinones at least in buffer.. but who knows unless synthesized and tested..


----------



## Limpet_Chicken

Was speaking theoretically and had to type in a hurry, in between nod-wake-nod-wake


Plus I was munted.


----------



## Pomzazed

Yes, that is absolutely what i meant; but on my second thought; the amine might make this styrene much more acid resistant.
N would get protonated real first; and getting doubly protonated cation is not so much likely.

This may still happen in conc. HCl i suppose, (12M)
Acid stomach is pH 1-2; and 1M HCl pH=1; so its 12x to 120x more dilute than conc HCl; idk if this still happens.


----------



## Limpet_Chicken

How, may I ask, can I libelously ad-hom MYSELF?

One can only libel another, you cannot, as I understand it slander myself. but yeah, put me in a room with a horny spesh chick (preferably classic autism rather than asperger's, but either will do and BE done, I've known a Rett's girl who's a friend and cared about deeply too who is one of THE most shockingly, amazingly, stunning and eath-shatteringly GORGEOUS, sparky, fiery, and so damn smart. Not to mention she's got a snark on her that is positively a massive fucking turn on to see being used to ensnark the vile curebie filth such as the likes of autisn squeaks), a dog she's willing to take it up the arse from whilst I cervix-fuck her senseless, give me enough opioid not to be in withdrawal, my antiseizure med (chlormethiazole, gabapenturd is sort of doing the same thing but I hate it and am trying to get off it), some clonidine for me to keep from a nasty rebound, just a low dose as it can be counterproductive to the erotic then toss is a box of pramipexole pills, and for the girl at least, some ondansetron plus buscopan if she's new to glepark, of course I'd not dose the dog, because I HATE abuses of animal welfare. And you can betcha  that if the girl is willing for videotaping, and of course there would need be a mask to cover my eyes and identifying features so that I'd not actually get prosecuted for the kink or for being the naughty autie clandestine this, that and t'other by way of non-autie/aspie/Rett's&canidae specimen transspecies hedonistic shits'n'giggles, the kind of thing that I often post in ADD about that of course the filth probably like about as much as they'd like my tagteaming a Kanner's girl with a dog. Now I don't like the cheap mechanically processed 'meat' product, but that'd bring a new entire sense of meaning to 'could go for a hotdog'


----------



## Limpet_Chicken

As for primary amine cathinones being unstable, they dimerize.


----------



## roi




----------



## EP-11




----------



## EP-11

Based off of FUBINACA (or one of those)








Nootropics


----------



## Dresden




----------



## DotChem

Stims..


----------



## Solipsis

Dresden said:


>








Cyclohexyl doesn't really work well for psychedelics though cause of not being planar?


----------



## adder

IMO there is very little similarity between cyclohexyl and phenyl aside from similar size and shape, but other than that both sterically and electronically they are different, so if the interaction via an aromatic ring in a given compound is crucial for it to bind at all, then there is no way cyclohexyl could substitute for phenyl. The case of propylhexedrine is rather a rarity among simple compounds bearing basically one or two functional groups through which they can bind via dipolar interactions, and it is much less potent than its phenyl counterpart, methamphetamine. As for secondary or tertiary interactions that impact binding, I imagine that the size, shape and environment of the site/pocket that can tolerate cycloalkyl as well as aromatic rings is likely crucial, if such a group is just a filler that is required only not to disturb the binding, then as long as it fits in/can locate itself, it could be either aliphatic or aromatic.

In case of psychedelic phenethylamines cyclohexyl doesn't work because the stacking interaction must be crucial likely as well as the right orientation of the methoxy groups on the ring.


----------



## Bagseed

most importantly, as adder said, no pi-stacking is possible with a cyhex, as opposed to benzene, so if that interaction is needed for activity, it's already bad. furthermore, benzene is perfectly planar, while cyclohexyl isn't, and can also exist in more than one conformation, which makes things more complicated.


----------



## Dresden

It is a stimulant, not a psychedelic.  Are you familiar with propylhexedrine?






PROPYLHEXEDRINE


----------



## Solipsis

Dresden said:


> It is a stimulant, not a psychedelic.  Are you familiar with propylhexedrine?
> 
> 
> 
> 
> 
> 
> PROPYLHEXEDRINE



I know, the comment wondering about psychedelics was unrelated to propylhexedrine..

Also reminds me of DMAA which is an even more abstracted aliphatic analogue, but also has effects that aren't really that typical or similar anymore, in any case I hated it.
But yeah propylhexedrine sounds alright actually, never tried it, no idea if it can be found easily in the netherlands.


----------



## EP-11




----------



## Incunabula

Frankensteins tryptamines  

Reminds me, how I'd love to try Shulgins 3,4 and 4,5-MDO tryptamines.

Edit: Just occured to me, what about changing the 4-hydroxy to 4-sulfanyl in dimethyltryptamines? It's so obvious, someone must have done it already.


----------



## Solipsis

Incunabula said:


> Edit: Just occured to me, what about changing the 4-hydroxy to 4-sulfanyl in dimethyltryptamines? It's so obvious, someone must have done it already.



http://www.bluelight.org/vb/threads/286591-4-thio-DMT-aka-quot-Thiopsilocin-quot


----------



## Incunabula

Thanks, interesting.


----------



## DotChem

Spiroxetamine..





 12x more potent than ketamine (IC50 0.065uM v 0.86uM.. https://pubchem.ncbi.nlm.nih.gov/assay/bioactivity.html?cid=44370217  Add a methoxy somewhere?or a Halo? look pretty easy straightforward synthesis https://pubchem.ncbi.nlm.nih.gov/compound/44370217#section=Top


----------



## sekio

probably has a pcp type pharmacology, high logP etc... so long trips & high potency


----------



## Solipsis

It's the oxalate?
Inhibition of TCP binding to NMDA is not conclusive is it? I agree it is probably active and potency but binding is not the only factor, there's also Mg trapping?

What about first starting with that replacement of the carbonyl with aromatic function in K?:






2-(Chlorophenyl)-2-(methylamino)tetralin


----------



## DotChem

^^ definitely closer to pcp than anything in terms of both pharmacology and pharmacokinetic may be with more stim effects than dissociatives..

^ yes the oxalate salt was used, but no special reasons for that really: It just crystallized easily from alcohol giving nicer crystalline solid than the hydrochloride. else there's no difference w/the hcl afaik

The 2-amino-2-aryl tetraline? it is probably quite potent but much like pcp though than K. the keto at the alfa of K, MXE..etc makes the pKa of the amine lower (ie less basic) which changes its distribution and/or binding mode at nmdar.  But its looks neat ..
now wait a minute: I think the 2-amino-2-aryltetraline may also bind to opioids not sure how potently: at least one of the steroisomers! superimpose the structure with that of morphine or ethorphine: it overlays not too bad.. 
How about 2-amino-2-aryl-1-tetralone? I mean still retain the keto of K..MXE..?


----------



## sekio




----------



## Bagseed

is that supposed to be an opioid?


----------



## sekio

probably, maybe with pethidine type stimulant effects too


----------



## sekio




----------



## DotChem

^ Nice! I like the last one but 3 chiral centers + cis/trans = lots of stereoisomers?)


----------



## Solipsis

That's true but at least there won't be too few quaternary carbons ;p


----------



## Raihiar

DotChem said:


> ^ Nice! I like the last one but 3 chiral centers + cis/trans = lots of stereoisomers?)


sorry, not really advanced but.. i don't immediately see the cis/trans isomerism - is it on the "piperidine" subunit where the two chiral centers are next to each other? i guess i can see it now, i was just conditioned to only see it on C=C bonds %)


----------



## sekio

there, is that better ?  squiggly lines denote chiral centers and the two on the right form a cis/trans pair


----------



## Solipsis

But don't 2 of the substitutions have to be the same for them to be zusammen or entgegen each other? In this example above, there is no symmetry in the piperidine ring and rest of the molecule as seen from the bond you say has cis/trans or E/Z. If it would have just been a cyclohexane and nothing else on the left then you'd be right.

I'd say since there is no symmetry or interchangability you have (R,S), (S,R), (R,R) and (S,S) when talking about those chiral centers on the right. I've never heard of (R,R) and (S,S) being pairs, is that a thing?
edit: oh never mind, it is a thing then, when speaking of highest priority groups being together or not.

Doesn't add extra isomers to list though right? On top of just the permutations of the 3 chiral centers?


----------



## Pomzazed

There will be RRR RRS RSR RSS SRR SRS SSR and SSS so yes there are so many stereocenters,

Also note the the N- on the rightmost side which seems to be asymmetric too (sp3) but that is no chiral center bcos N can go "umbrella-like-flip" inversion easily with low energy barrier, som3 stereocenters are right (2^3=8 isomer)


----------



## adder

Solipsis said:
			
		

> But don't 2 of the substitutions have to be the same for them to be zusammen or entgegen each other? In this example above, there is no symmetry in the piperidine ring and rest of the molecule as seen from the bond you say has cis/trans or E/Z. If it would have just been a cyclohexane and nothing else on the left then you'd be right.



I don't think it's a prerequisite for cis/trans notation, you can basically use it with respect to any two substituents on any cycloalkyl ring, so specifying to which substituents the notation refers is preferable if necessary to exclude ambiguity. If you take bromadol for instance, I suppose you could pair any two substituents at C1 and C4, and name their relationship as cis or trans, but the tendency may be to choose functional groups rather than alkyl substituents from what I've seen. It is pretty loose and not official nomenclature. As for E/Z notation, if there are more than 2 substituents along a double bond the Cahn-Ingold-Prelog system is used to establish the two substituents that determine the stereochemistry, no ambiguity is ever present with this notation.


----------



## Incunabula

sekio said:


> there, is that better ?  squiggly lines denote chiral centers and the two on the right form a cis/trans pair



Lol, I'm actually a little bit confused by this drawing. I assume the squiggly lines denote that the carbon atom og group can go either into the "paper" or towards the viewer. What confuses me is that I thought that single carbon-carbon bonds could swivel around freely in all directions. Have I misunderstood that? Is it because they can only swivel around their own axis? 

But the consequence of that, is that it would be possible to have cis/trans isomerism without a double bond? wtf, what am I missing? :D


----------



## Bagseed

the swirly lines denote chiral centres... basically, where there is a chiral centre, the molecule isn't the same if the substituent faces in the one or the other direction.

imagine methane with four different substituents: there are two ways to arrange the molecule (two mirror images), and you cannot get one of those to become the other by turning it around in any way. it's asymmetric, and hence two stereoisomers (enatiomers) exist.


----------



## Pomzazed

You forget to imagine hydrogen, C has 4 bounds and H atoms isnt present in drawing, so you cant "swivel" it to make the stereoisomer


----------



## sekio

when there are a pair of chiral centers next to each other, there is a cis/trans or erythro/threo/meso relationship 

you are correct about the swirly lines meaning the bonds can either stick out front or behind the paper. however only sp3 carbon bonds that are unconstrained can rotate - like the bond between the two carbons in ethane. if it's constrained in a ring then bond rotation would invert or pucker the ring and there can be a singificant energy barrier to that.


----------



## Ajenks420

*I wanna learn this better!!*

How do you do this?? Always wanted to know if you can make like a mdma-dxm-psilocybin(or psilocin)? Anything like that haha


----------



## Incunabula

sekio said:


> when there are a pair of chiral centers next to each other, there is a cis/trans or erythro/threo/meso relationship
> 
> you are correct about the swirly lines meaning the bonds can either stick out front or behind the paper. however only sp3 carbon bonds that are unconstrained can rotate - like the bond between the two carbons in ethane. if it's constrained in a ring then bond rotation would invert or pucker the ring and there can be a singificant energy barrier to that.



Thanks, I get it now


----------



## Solipsis

Ajenks420 said:


> How do you do this?? Always wanted to know if you can make like a mdma-dxm-psilocybin(or psilocin)? Anything like that haha



Fortunately, not really.. DXM and MDMA are very dangerous to mix so having them combined in one drug if that were possible would be a recipe for disaster.

Hybrids of existing drugs, what you seem to be talking about, well you can draw them, you can even make them. But in most cases it won't act the way you want it to. The compromise you make by modifying a molecule so heavily is that it usually doesn't work anymore like the original drug, so combining 2 or 3 drug molecule structures you end up with a molecule that is likely to fail to act as either of them let alone as a combination of all of them.

However, sometimes there is a sort of overlap where different kinds of SAR seem to come together. (SAR is the relationship between structure of a drug and what it does)

For example, bk-2C-B involves making a psychedelic into a cathinone which is usually something done with stimulants. The overlap is that both various psychedelics as well as a lot of stimulants are phenethylamines and that 2C-B is forgiving of this modification to some extent.

@chirality / cis-trans isomerism: thanks for clarifying guys!


----------



## DotChem

Raihiar said:


> sorry, not really advanced but.. i don't  immediately see the cis/trans isomerism - is it on the "piperidine"  subunit where the two chiral centers are next to each other? i guess i  can see it now, i was just conditioned to only see it on C=C bonds %)


sorry I missed that thread re cis/trans, R S isomerism of piperidine fanta related. got kick out the shelter and trying to stay warm but anyhow, you got pretty concise answers from the guys for your question. Here is a picture to summarize: 





The 2 groups COCH3 and NMePh can be cis (Z zusammen, same side) of the piperidine ring or trans (entgegen, opposite side) of the lateral plane of the ring. This is the commonly used nomenclature to describe their relationship just like with the cis-trans stereoisomerism of olefins. (@solipsis: actually, in general the E/Z or cis/trans nomenclature refers to the 2 "biggest" substituents (according to Cahn Ingold Prelog rules. But it is usually pretty loosely as it is obvious in general what one is talking about).

Since the C3 and C4 carbon are chiral you'll have, as already noted: RR, RS, SR and SS. Multiply that by 2 of course for each structure since the carbon alfa to the piperidine is also chiral. Therefore you ended up with 8 possible configurations.: RRR, RRS...etc

In term of OP activity, the reason why this is relevant is that in the case of fanta substitued at C3 by a methyl and a 2-fluoro on the Phenyl ring, only one isomer the cis 3R,4S,βS is active at about 18000X more potent than morphine; the others are pretty much "inactive". But this is not really an issue here because it is so potent it won't make a difference I mean the mixture of the 8 stereoisomers or a pure enantiomer! 1/8 of 18000 you still get 2250x more potent than morphine or about 20x more than fanta! Deadly shit!! so caution


----------



## Raihiar

Well thanks for the ton of answers!
I remembered that the same applies for different sugars (they are a mess in that regard)... I just didn't spot it right away, but i'll keep my eyes open next time


----------



## Incunabula

Ajenks420 said:


> How do you do this?? Always wanted to know if you can make like a mdma-dxm-psilocybin(or psilocin)? Anything like that haha



Like this?


----------



## Solipsis

Yeah only you'd link DXM onto the 4-position of psilocin rather than the 5 - and you could consider making it just one nitrogen where you link DXM and MDMA rather than a hydrazine.

Actually that does make me wonder about this compound somehow:






_3-[2-(Dimethylamino)ethyl]-4-methoxyindole_

Do you think it could tell us something about the probability of 4-AcO-DMT being active itself or just a pro-drug?

Or instead a better ester bioisosteric group, without having it turn into psilocin:









However I can't get opsin to properly remove the ambiguity about where fluoros are if I were to use isopropane in the nomenclature instead of cheating by using trifluoromethylethane. 2' prime locant designation doesn't work. Any help with that?


----------



## Bagseed

Solipsis said:


> Yeah only you'd link DXM onto the 4-position of psilocin rather than the 5 - and you could consider making it just one nitrogen where you link DXM and MDMA rather than a hydrazine.
> 
> Actually that does make me wonder about this compound somehow:
> 
> 
> 
> 
> 
> 
> _3-[2-(Dimethylamino)ethyl]-4-methoxyindole_


https://en.wikipedia.org/wiki/4-MeO-DMT

not very active apparantly


----------



## Dresden

Yeah, 4-MeO-DMT is in TiHKAL.  Not very active apparently.


----------



## DotChem

https://pubchem.ncbi.nlm.nih.gov/compound/70028078#section=Top





benzopradol.. or benzopradone rather! since it is not alcohol but ketone


----------



## Pomzazed

Looks like isopropylphenidate to me^


----------



## sekio

benzoylphenidate more like


----------



## Pomzazed

sekio said:


> benzoylphenidate more like



Agreed, but my rationale is the molecular "length" which is closer to isopropyl,
The ipso- position is the same place of Oxygen in mph. Where the rest aromatic bulky occupies approximately same space of isoporpyl group (apart from the flatness differences)

"Benzoyl" phenidate is one oxygen longer


----------



## Incunabula

Solipsis said:


> Yeah only you'd link DXM onto the 4-position of psilocin rather than the 5 - and you could consider making it just one nitrogen where you link DXM and MDMA rather than a hydrazine.


Thanks, yes I know. It was early and I hadn't had my coffee yet


----------



## DotChem

^^ yes It looks much closer to iPr-phenidate in terms of steric factors.  more like a bioisosteric replacement of the COOiPr with a COPh. Not a COO2Ph! But actually I was thinking more along the lines of replacing pipradol with one with a keto stuck in between the Phenyl ring and the benzylic tertiary carbon.  That way may reduce the ridiculously long half-life of pipradol (up to 3 days!!) while retaining its activity. + adding a keto (or similar COOMe like in MPH) to stims seems to shift their activity from AMPH-like to cocaine-like as in MDPV, MPH....etc .. but who knows?





https://en.wikipedia.org/wiki/Desoxypipradrol


----------



## niflheim

4-Me-PCMAR


----------



## Solipsis

beneticyclidine






isophetenidine






ketenamine






phenpentidine






mephentiquine






diphendetamine






benzyltiquine (intriguing..)


----------



## LeviathanBaphomet

Some things.















Cyclopropylphenidine





Methylenedioxy-Epheindine





Alprazinam

*Edit:* New additions


----------



## DotChem

isoketamine .. isomethoxetamine


----------



## Incunabula

Interesting  How do you reckon they'd be?


----------



## DotChem

Who knows? but here is an old BL thread I dug up http://www.bluelight.org/vb/archive/index.php/t-361085.html.. the following dimethylamino congerner is supposedly an opioid equipotent to morphine NOT a dissociative!!.. very strange!



> @fastandbulbous:
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> This much simpler molecule is supposed to be equipotent with morphine.  Given that the synthesis is so simple, I can see this stuff turning up  somewhere or other.
> 
> 
> Now that is so close to being an NMDA antagonist that I'd reckon any  analgesic effect in rats rtc would be due to it's dissociative effect.  That structure is effectively covered in a paper on PCP SAR studies I  read qute a while ago (mentions alterations in potency by a) changing  the amine group from a 1-piperidyl & 2) moving the keto group of  ketamine around the alicyclic ring .. http://www.bluelight.org/vb/archive/index.php/t-361085.html


----------



## Ire206

^^ Definitely seems as though the structures of opioids and NMDA antagonists are closely linked, DXM to Morphine and Diphenidine to Lefetamine, MT-45 etc.

Anyway, drew up a few basic molecules I had thought up, tried to get the naming the least whack as I could.





After drawing this I found a molecule extremely similar, but with a 4-methyl substitution, basically a-PVP to Pyrovalerone, called O-2556. I went with O-2555 for this as there wasnt anything with this name in the paper.
Apparently it should have reasonable action at DAT and NET...






Naphyrone / N-EthylPentedrone crossover. Expected SNDRI due to the naphthalene, as Naphyrone was the only pyrrolidine stimulant with any activity on SERT, at least in 1 detailed study of Pyrovalerone SARs






5-Amino Phenmetrazine. 4-Methyl Aminorex but with an extra carbon on the oxazoline ring, changing it to an oxazine I think.






1-Formyl-AL-LSZ. Another basic meshing of a few lysergamides.


----------



## Solipsis

Ire206 said:


> ^^ Definitely seems as though the structures of opioids and NMDA antagonists are closely linked,



Opioid receptors and NMDA receptors are also closely linked.. they colocalize on neurons in a lot of brain regions..


----------



## adder

I suppose we need moar valerones. According to one study (J Med Chem. 2006 February 23; 49(4): 1420–1432) the racemic isohexyl analogue of pyrovalerone seems to be very close in affinity to DAT and NET to the more potent (S)-enantiomer of pyrovalerone itself, IC50 values are even more promising (for DA uptake 5.9 nM vs. 16.3 nM for (S)-pyrovalerone), we could be in for even more potent a-PiHP and MDPiHP (or a-PCP and MDPC - as they are analogues of alpha-pyrrolidinylcaprophenone, but the first one might be confusing). According to another study (ACS Chem. Neurosci. 2013, 4, 1524−1529) MDDMV (dimethylamino analogue of MDPV) has ~1/5x the affinity of MDPV to DAT, so MDDEV seems a reasonable option to consider.


----------



## TrippyZebra

was reading about astatine and wondered if it would produce similar effects to 2c-I if you made 2c-At.  Would this be deadly or even possible to make considering how rare astatine is?


----------



## Solipsis

physically impossible is not economically impossible.. my guess is it should be possible but unrealistic to attempt to make a reasonable quantity, also it's not that reactive so I'm not sure if it will even bind to carbon in the 2C-I synthesis manner. I imagine you might have to use some tricks?
Was Alexander Litvenenko's drug of choice, i'm sure.


----------



## TrippyZebra

Cool thanks for the detailed answer. It sounds interesting if it could ever become a reality,*sigh* but a psychonaut can dream.:D


----------



## adder

I'm far from an expert in radiochemistry (I wonder why it has "chemistry" in its name even...), so I don't know how damaging consuming such a compound would be (or perhaps beneficial as supposedly small doses of radiation are), but why would you want to ingest a compound with an alpha-particle-emitting atom with a half-life of ~8 hours in it at all?


----------



## Solipsis

For the novelty of course.
Radiochemistry is about the chemistry of radioactive compounds or the influence the use of radiation has on chemistry... so it just doesn't really focus on the physics or the application is much about chemistry? I guess it's an overlap of the fields like physical chemistry, which isn't even nearly close enough about proper chemistry as I would like and I always hated the subject.. Radiochemistry is about a way to be able to calculate chemical reactions as is done in physical chemistry?

Say the dose is 40 mg in a 70 kg man, 0.10 mmol 2C-At with astatine-211 then you get 1.43 x 10e15 Bq radiation while in rats 8.4 x 10e8 Bq (also from At-211) at the same body mass (never seen a 70 kg rat though, apart from splinter from the Teenage Mutant Ninja Turtles - I guess that whole mutagen treated animal thing is writing on the wall...) 
... that radiation caused changes and destruction to thyroid and lymphatic tissue..

So you would get 1.7 million times that toxic dose. It's ridiculously radioactive and toxic because of that short half life, like a juiced up plutonium during it's 15 minutes of fame.

(thanks wolfram alpha)

Other isotopes are considerably less radiotoxic though so it depends, but still it seems like quite enough to be a big problem - even 10 times less radiotoxicity is still way6 too much. I could be off here.



			
				PIHKAL 2C-I said:
			
		

> Where else can one go, from 2C-I? The iodine is the fourth, and the last of the so-called halogens, at the bottom of the classical periodic table. But, thanks to the miracles that have accompanied us into the nuclear age, there is a fifth halide now known, Astatine. All of its isotopes are radioactive, however, and it seems unlikely that there will ever be an entry (other than this one) for 2,5-dimethoxy-4-astatophenethylamine. What might be speculated as to its activity? Probably similar in potency to 2C-I, requiring maybe 10 or 20 milligrams. The duration would be dicey to measure, since the isotope with the longest known half-life is half decayed in about 8 hours, and the longest lived natural isotope (for those who insist on natural rather than man-made things) is half decayed in less than a minute. Two predictions would be pretty solid. You might have quite a job accumulating your 10 milligrams of Astatine, as the most that has so far been made at one time is only about 0.05 micrograms, approximately a millionth of the amount needed. And the second prediction? You would not survive the screaming radiation that would bombard you if you could get the needed 5 or 10 milligrams of radio-astatine onto that magic 4-position, and the resulting 2C-A into your tummy!


----------



## TrippyZebra

Solipsis said:


> For the novelty of course.


Lol my thoughts exactly.

*Wow thanks for finding that didn't know Shulgin already covered it.


----------



## sekio




----------



## aced126

XR benzo - interesting


----------



## Bagseed

I like the intramolecular imine formation to create the ring. Pretty clever, will that happen in the stomach though?


----------



## Solipsis

Yes clever.. Will there be an equilibrium of the other (12-membered ring?) imine also being formed while/until lysine cleavage progresses? Or even various more possible imines? Would be an interesting dance.

I like the shape of that thiobarb orientation 

Why not this by the way:






It's actually not trypsin / pepsin that would cleave something like this but aminopeptidases red blood cells, which begs to wonder if it is after the stomach you probably wouldn't get [quite as much] imine formation due to pH, isn't that azepine ring necessary for BZD binding?
Isn't your secondary amine metabolized by cytochrome P450's anyway?


----------



## aced126

sekio said:


>



I just realised the benzo has an amine rather than amide linker. If you were hoping for PLP-dependent aminotransferases to remove the lysine, I don't think that will work because those enzymes are substate specific and used in amino acid synthesis. I'm pretty sure it'll definitely only accept primary amines if anything. Of course CYP metabolism will dealkylate the amine but at a much slower rate I reckon. Also as Solipsis mentioned, imine formation might take a while in a neutral environment, so the compound might be mostly excreted before it actually gets a chance to cyclise.


----------



## aced126

Solipsis said:


> Yes clever.. Will there be an equilibrium of the other (12-membered ring?) imine also being formed while/until lysine cleavage progresses? Or even various more possible imines? Would be an interesting dance.
> 
> I like the shape of that thiobarb orientation
> 
> Why not this by the way:
> 
> 
> 
> 
> 
> 
> It's actually not trypsin / pepsin that would cleave something like this but aminopeptidases red blood cells, which begs to wonder if it is after the stomach you probably wouldn't get [quite as much] imine formation due to pH, isn't that azepine ring necessary for BZD binding?
> Isn't your secondary amine metabolized by cytochrome P450's anyway?



Actually trypsin preferentially cleaves amide bonds where the carboxyl side of the bond is a positive Lys or Arg residue, so your compound fits. As I mentioned earlier, it would really be preferable if it gets hydrolysed in the stomach so the imine can form quickly under acid catalysis. But then that kind of defeats the whole purpose of the XR mechanism anyway.

Pretty sure the ring is necessary for binding activity.

Rings above size 7 are quite hard to make because of the entropic cost associated with their formations. There are several possible conformations that the free chain can adopt, making it less likely that the ring-forming conformation is adopted. They have no problem with enthalpy/stability though, as they have essentially no ring strain. On the contrary, for small rings it is the exact opposite - few possible conformations means ring formation is more likely, but the ring itself is highly strained making it unstable.

The ideal ring size is 5 or 6.


----------



## adder

The strain energy actually does increase upwards from cyclohexane with cycloheptane having a similar ring strain energy to cyclopentane and the maximum being around cyclodecane or so, this is due to unfavourable eclipsed and flagpole interactions between C7 and C12-4 rings, and diminishing when the increasing ring size makes such interactions matter less and less. I'm sure the ring strain does matter as well beside long distance between two ends when they do meet and the whole to-be-the-ring structure takes a conformation close to that of the ring itself, it's probably hard to see for bigger rings as they would all typically need longer reaction times for the reaction to complete, but the strain must be the factor too, otherwise you would only need to increase reaction time to make it statistically possible for all the molecules to happen to be in the right conformation to close into a ring, right? In more complex organic compounds (I mean more complex than simple alpha-halo-omega-lithioalkane to be closed into a ring) the relationship between the ring size and the yield of a cyclization reaction is not going to be a simple one due to other steric and electronic factors, and often reaction medium as well, with reaching the energy level enough to warrant ring-formation impossible without degrading other moieties. Still, there are reactions in which bigger rings are formed in good yields under fairly mild conditions, e.g. Heck reaction and many other TM-catalyzed ones.

Anyway, that's a bit carried away.



			
				Solipsis said:
			
		

> Radiochemistry is about the chemistry of radioactive compounds or the influence the use of radiation has on chemistry... so it just doesn't really focus on the physics or the application is much about chemistry? I guess it's an overlap of the fields like physical chemistry, which isn't even nearly close enough about proper chemistry as I would like and I always hated the subject.. Radiochemistry is about a way to be able to calculate chemical reactions as is done in physical chemistry?



I'm not sure if radiochemistry as a subject is that common outside of physical chemistry, but I had the pleasure of having it and it was mostly about memorizing how various counters are built and how they work with one of the most boring lab classes ever each one coming down to sitting and taking hundreds of measurements. I don't know why you would need a lab coat for that but it was mandatory. I still have an exam to take which is going to be fun for sure.


----------



## aced126

adder said:


> The strain energy actually does increase upwards from cyclohexane with cycloheptane having a similar ring strain energy to cyclopentane and the maximum being around cyclodecane or so, this is due to unfavourable eclipsed and flagpole interactions between C7 and C12-4 rings, and diminishing when the increasing ring size makes such interactions matter less and less. I'm sure the ring strain does matter as well beside long distance between two ends when they do meet and the whole to-be-the-ring structure takes a conformation close to that of the ring itself, it's probably hard to see for bigger rings as they would all typically need longer reaction times for the reaction to complete, but the strain must be the factor too, otherwise you would only need to increase reaction time to make it statistically possible for all the molecules to happen to be in the right conformation to close into a ring, right? In more complex organic compounds (I mean more complex than simple alpha-halo-omega-lithioalkane to be closed into a ring) the relationship between the ring size and the yield of a cyclization reaction is not going to be a simple one due to other steric and electronic factors, and often reaction medium as well, with reaching the energy level enough to warrant ring-formation impossible without degrading other moieties. Still, there are reactions in which bigger rings are formed in good yields under fairly mild conditions, e.g. Heck reaction and many other TM-catalyzed ones.
> 
> Anyway, that's a bit carried away.
> 
> 
> 
> I'm not sure if radiochemistry as a subject is that common outside of physical chemistry, but I had the pleasure of having it and it was mostly about memorizing how various counters are built and how they work with one of the most boring lab classes ever each one coming down to sitting and taking hundreds of measurements. I don't know why you would need a lab coat for that but it was mandatory. I still have an exam to take which is going to be fun for sure.




Surely if you increase reaction time in order to try and make a large ring forming reaction to go, the reactant will just react with other molecules instead of attacking itself?


----------



## sekio

WHoops, I may have got the lysine backwards, Soli drew the 'correct' isomer that I really meant


----------



## adder

aced126 said:


> Surely if you increase reaction time in order to try and make a large ring forming reaction to go, the reactant will just react with other molecules instead of attacking itself?



Chances increase it will, yes, that's why in order to diminish such side reactions intramolecular cyclizations are often carried out in fairly dilute solutions.


----------



## DotChem

sekio said:


> WHoops, I may have got the lysine backwards, Soli drew the 'correct' isomer that I really meant









would that be stable in solution? The amine at alfa position of the lysine will most likely attack the CO of the N(Me)CO amide to give a six membered pyrazinedione + N-Methyl-4-nitro-2-(2-fluoro)benzoyl-Aniline. The driving force beeing the 4-nitro-2-(2-fluoro)benzoyl strongly activates the amide toward nucleophilic attack and is an excellent leaving group + relative ease of intramolecular Rx to form stable 6-membered ring... but who knows?


----------



## Dresden




----------



## Solipsis

aced126 said:


> Actually trypsin preferentially cleaves amide bonds where the carboxyl side of the bond is a positive Lys or Arg residue, so your compound fits. As I mentioned earlier, it would really be preferable if it gets hydrolysed in the stomach so the imine can form quickly under acid catalysis. But then that kind of defeats the whole purpose of the XR mechanism anyway.
> 
> Pretty sure the ring is necessary for binding activity.
> 
> Rings above size 7 are quite hard to make because of the entropic cost associated with their formations. There are several possible conformations that the free chain can adopt, making it less likely that the ring-forming conformation is adopted. They have no problem with enthalpy/stability though, as they have essentially no ring strain. On the contrary, for small rings it is the exact opposite - few possible conformations means ring formation is more likely, but the ring itself is highly strained making it unstable.
> 
> The ideal ring size is 5 or 6.



The entropy vs ring strain do clear things up regarding which reactions are more favorable in this case!



adder said:


> The strain energy actually does increase upwards from cyclohexane with cycloheptane having a similar ring strain energy to cyclopentane and the maximum being around cyclodecane or so, this is due to unfavourable eclipsed and flagpole interactions between C7 and C12-4 rings, and diminishing when the increasing ring size makes such interactions matter less and less. I'm sure the ring strain does matter as well beside long distance between two ends when they do meet and the whole to-be-the-ring structure takes a conformation close to that of the ring itself, it's probably hard to see for bigger rings as they would all typically need longer reaction times for the reaction to complete, but the strain must be the factor too, otherwise you would only need to increase reaction time to make it statistically possible for all the molecules to happen to be in the right conformation to close into a ring, right? In more complex organic compounds (I mean more complex than simple alpha-halo-omega-lithioalkane to be closed into a ring) the relationship between the ring size and the yield of a cyclization reaction is not going to be a simple one due to other steric and electronic factors, and often reaction medium as well, with reaching the energy level enough to warrant ring-formation impossible without degrading other moieties. Still, there are reactions in which bigger rings are formed in good yields under fairly mild conditions, e.g. Heck reaction and many other TM-catalyzed ones.
> 
> Anyway, that's a bit carried away.



That's a lot of variables to consider.. this ring opening and all the possible side-reactions really opened up a can of worms.

(Also somewhere Gollum creamed his pants reading that ^)





aced126 said:


> Surely if you increase reaction time in order to try and make a large ring forming reaction to go, the reactant will just react with other molecules instead of attacking itself?



Speaking of which: also dimerization to form other pyrazine derivatives? Polymerization crapping your product? I don't know if I see a way for that here, are the ingredients there?

IIRC with experimenting on bk-2C-B a little bit, if purple discoloration is any indicator (I guess what you expect with such conjugated systems?) that kind of alpha amino ketone dimerization is especially base-driven but I really fuzzy on that. Should also happen spontanously under influence of oxygen..

5-MeS-DMT should be in tihkal i believe?


----------



## Dresden

No, I don't think it is.


----------



## Solipsis

https://www.erowid.org/library/books_online/tihkal/tihkal46.shtml







 (in a world where NBOMe's are ok)






Seems like a good question why 4-thiomescaline is not a popular RC..


----------



## Pomzazed

Looks stinky lol.
The cmpds themself seems odorless but those remaining synthetic reagents impurity is ouch...
Even ppm impurity seems so.. ugh   (try sniffing aromatic thiols)


----------



## Nagelfar

Pre-084 + Pethidine/Demerol:


----------



## Nagelfar

Bullvalene-styrene DARI (phenyltropane, tropane-to-bullvalene influenced)


----------



## DotChem

DRUG DESIGN:
Here is the crystal structure (the 3D) of cocaine bound to the drosophila dopamine transporter DAT"






Too much details but here is a close up view:






The 2 blue dots and 1 green dot are the 2 sodium Na+ and 1 Chloride Cl- co-transported along with the dopamine substrate. The  extra sodium used to depolorize the neurons by increasing the charge inside.  I mean it transports 2Na+ and 1 Cl-(net charge = +1). Dopamine, d-AMPH, methamphetamine, RTI-55, b-CFT   ..etc all bind to the same site similarly with some minors difference but not as tight as cocaine (check out their structures with DAT on pubmed).  I dont know about MPH and cathinones. No structures yet but I guess it should be same!
The dotted line shows the drug NHMe+ making contact with a COO- of the DAT transporter making a salt like interaction (like in ammonnium acetate). 

Notice how the phenyl ring of cocaine is sandwiched between 3 phenyl rings of the aminoacids of the DAT protein.  Since there is more rooms, that explain why a bigger group there like a nathpthyl of CFT tropanes is even better or dichlorophenyl. it fills the space and interact more tightly with the tranpsorter.  Not much room to play around with the tropane side thouh as it sits on a narrow channel made up of the protein. the ester COOMe of cocaine points toward the solvent outside the drug binding site so one can put a bunch of shit there without affecting binding.  The bridge CH2CH2 of the tropane seems useless maybe just orienting the rest of the molecule.
So if If you were to design analogs of cocaine (at least in so far as DAT inhibition is concerned) your best bet is the phenyl side of the drug. Disclaimer: all this is available public information of the pubmed NIH website here:

"4XP4: X-ray Structure of Drosophila Dopamine Transporter in Complex With Cocaine: https://www.ncbi.nlm.nih.gov/Structure/pdb/4XP4 "

They have nice 3D viewer software way much better than these static pictures here where you can view in movie-like turning zooming eliminating adding ..whatever.. pretty cool! check'em out:


----------



## DotChem

Oops I forgot: Here is the reference paper by the authors who solved the structure:
Wang KH1, Penmatsa A1, Gouaux E2. Neurotransmitter and psychostimulant recognition by the dopamine transporter. Nature. 2015 May 21;521(7552):322-7. doi: 10.1038/nature14431. Epub  2015 May 11 https://www.ncbi.nlm.nih.gov/pubmed/25970245


----------



## aced126

The bridge is important -  if you lose it, almost all potency is lost iirc.


----------



## DotChem

Not quite @aced126. This is a about twice as potent as cocaine (as DAT NET and SERT reuptake inhibitor)..! 





https://pubchem.ncbi.nlm.nih.gov/compounds/44337739#section=Top
or this even more active:





https://pubchem.ncbi.nlm.nih.gov/compounds/44337825#section=Top

But I guess it is hard to compare since a Chlorophenyl replace the benzoate ester of cocaine and a secondary amine replacing the NMe in these cases.


----------



## Dresden

Mephedrone might not have anything on this, in that case...


----------



## Dresden

Which made me think of this...






3-carbomethoxy-fentanyl


----------



## Dresden

Both of the two previous submissions are loosely related to the seductive arecoline.


----------



## Dresden

In fact, the first 






could be dubbed 3,4-dihydro-4-(4-methylphenyl)-arecoline!


----------



## Nagelfar

aced126 said:


> The bridge is important -  if you lose it, almost all potency is lost iirc.



There are even triple bridges that are more active, see the (extra)bridged-phenyltropane


----------



## aced126

DotChem said:


> Not quite @aced126. This is a about twice as potent as cocaine (as DAT NET and SERT reuptake inhibitor)..!
> 
> 
> 
> 
> 
> https://pubchem.ncbi.nlm.nih.gov/compounds/44337739#section=Top
> or this even more active:
> 
> 
> 
> 
> 
> https://pubchem.ncbi.nlm.nih.gov/compounds/44337825#section=Top
> 
> But I guess it is hard to compare since a Chlorophenyl replace the benzoate ester of cocaine and a secondary amine replacing the NMe in these cases.



This is a big finding and I'm surprised I didn't know about this. This stems a new set of DRIs - why haven't more of these been made by RC suppliers?


----------



## Nagelfar

aced126 said:


> This is a big finding and I'm surprised I didn't know about this. This stems a new set of DRIs - why haven't more of these been made by RC suppliers?



I wrote a large part upon the WP phenyltropanes list about just this and how many have been made.


----------



## adder

^ Synthetically the difference between phenyltropanes and those 4-aryl-3-carboalkoxypiperidines is huge IMO. I don't know if there are any short-acting phenyltropanes, but if we limit ourselves to the simplest 2-carboalkoxy-3-aryltropanes, they are all long-acting stimulants which most possibly makes them poor recreational drugs which combined with not necessarily cheap common substrate makes them not attractive as "RC's".

The piperidines might as well be more like SSRI/SNRI antidepressant with little recreational value, they might have been tested in small groups of volunteers and turned out not interesting.


----------



## Dresden

If they were any good, we would probably already know by now.


----------



## aced126

adder said:


> ^ Synthetically the difference between phenyltropanes and those 4-aryl-3-carboalkoxypiperidines is huge IMO. I don't know if there are any short-acting phenyltropanes, but if we limit ourselves to the simplest 2-carboalkoxy-3-aryltropanes, they are all long-acting stimulants which most possibly makes them poor recreational drugs which combined with not necessarily cheap common substrate makes them not attractive as "RC's".
> 
> The piperidines might as well be more like SSRI/SNRI antidepressant with little recreational value, they might have been tested in small groups of volunteers and turned out not interesting.



They are only long lasting because of loss of ester functionality. Bridge the piperidine with the aryl ring with an ester to reduce half life.

Compared to cocaine itself, the syntheses of these piperidines would be much, much easier. They look quite reasonable to synthesise and the data for some of them makes it look much more potent than cocaine itself.


----------



## Nagelfar

adder said:


> they are all long-acting stimulants which most possibly makes them poor recreational drugs





Dresden said:


> If they were any good, we would probably already know by now.





aced126 said:


> They are only long lasting because of loss of ester functionality. Bridge the piperidine with the aryl ring with an ester to reduce half life.



What aced said is true; there is no reason why not to believe these piperidines should be any different than Troparil, which has been colloquially reported as "disappointing"

Cocaine analogs show a lot more potential for this reason. The C1 substitutions being the newest in the interesting additions:






^3betaStyrene-OrthoAcetoxy-C1Phenyl-"Cocamentholene"


----------



## Dresden

That one looks as possibly dissociative as fuck.


----------



## sekio

it looks to have too much stuff everywhere to bind to _anything_.
huge gif alert:

*NSFW*:


----------



## Nagelfar

Dresden said:


> That one looks as possibly dissociative as fuck.





sekio said:


> it looks to have too much stuff everywhere to bind to _anything_.



Thanks for that animation sek. (From everything I know and have studied, however, it has enough room at all the proper spaces to fit nicely at DAT; the C1 group substitution was originally on a C3 benzoyloxy derivative, and the styrene alkylphenyl is the same length in angstroms, etc.)


----------



## Pomzazed

aced126 said:


> The bridge is important -  if you lose it, almost all potency is lost iirc.


Then why alkylphenidates work?


----------



## Dresden

A study found this






to be a stimulant but not a psychedelic.  No word on possible neurotoxicity.


----------



## aced126

Pomzazed said:


> Then why alkylphenidates work?


 Alkylphenidates have different connectivity to cocaine. Try to overlay to conformations of methylphenidate and cocaine. It doesn't seem to me like a good overlay. I've always wondered why alkylphenidates and cocaine have been compared structurally. They might both have the same effect at DAT, but they are structurally quite different.


----------



## Nagelfar

aced126 said:


> Try to overlay to conformations of methylphenidate and cocaine. It doesn't seem to me like a good overlay. I've always wondered why alkylphenidates and cocaine have been compared structurally. They might both have the same effect at DAT, but they are structurally quite different.







beta-CFT (the prototypical PT; the fluoro makes it closer to coke @ SERT than Troparil) with methylnaphthyldate (the naphthyl making it, similarly, closer to cocaine @ SERT than MPH)

Looks like a *perfect* *overlay* to me.
Given below singly:







which follows:







^(despite cocaine being longer at the aryl-linkage; greatening serotonin transporter affinity in contrast to CPT & MPH.)


----------



## aced126

Nagelfar said:


> beta-CFT (the prototypical PT; the fluoro makes it closer to coke @ SERT than Troparil) with methylnaphthyldate (the naphthyl making it, similarly, closer to cocaine @ SERT than MPH)
> 
> Looks like a *perfect* *overlay* to me.
> Given below singly:
> 
> 
> 
> 
> 
> 
> 
> which follows:
> 
> 
> 
> 
> 
> 
> 
> ^(despite cocaine being longer at the aryl-linkage; greatening serotonin transporter affinity in contrast to CPT & MPH.)



Binding is very intricate. 

The way you have overlayed it, the 2 aromatic systems are orthogonal to each other. The two compounds will then pi stack differently with their residues, altering affinity. Not to mention the carboxylates and amines are pointing in different directions.


----------



## Nagelfar

aced126 said:


> Binding is very intricate.
> 
> The way you have overlayed it, the 2 aromatic systems are orthogonal to each other. The two compounds will then pi stack differently with their residues, altering affinity



Yes, they freely spin in their respective mechanics, that is I presume so the two aryls can be seen as distinct in the 3-dimensional overlay between the two different compounds. It shows more intricacy doing it in three dimensions. As for pi-stacking, look at the amount of things and alterations can be given to the carbmethoxy, and even the hybrid compound DMNPC is half way between MPH and PTs/cocaine:






I didn't make that overlay, however, BTW. I am not wanting to get into a squabble over this; earnestly and in legitimate curiosity to learn, be proven wrong, etc., how would you overlay them as they "would" then? What are the intricacies to which you are referencing that make my overlay given over to tentative plausibility?



aced126 said:


> Not to mention the carboxylates and amines are pointing in different directions.



in the 2D separate images you mean? Flip them around, the stereochemistry isn't even indicated (I am not trying to be discreet and gloss over a similarity that is blatantly lacking if shown in a more specific rendering of some kind) Otherwise, the carboxylate/carbmethoxy group spins & rotates freely too:

As for the amine: the nitrogen lone pair orients forward or backward as it isn't constrained in either of those compounds (cocaine, MPH or their two analogues given), in fact it alternates between one or the other depending on whether it is binding to DAT or SERT (in front and back bridged phenyltropanes, however, it is constrained; not in any pictured in my previous post, however; but this is known to heighten selectivity) this has to do with orbital hybridisation.



Dresden said:


> A study found this
> 
> 
> 
> 
> 
> 
> to be a stimulant but not a psychedelic.  No word on possible neurotoxicity.



Not to overlook this, do you have the study to cite Dres? Quite interesting.


----------



## adder

Nagelfar said:


> beta-CFT (the prototypical PT; the fluoro makes it closer to coke @ SERT than Troparil) with methylnaphthyldate (the naphthyl making it, similarly, closer to cocaine @ SERT than MPH)



I suppose that they can bind in a very similar manner no matter whether the most stable conformations of both have all major functionalities overlaid or not, the interaction at the receptor can surely heavily alter the conformation so that ring flip of ~90 degrees around the C-C bond may not be a problem at all. The problem is that simple programs that make corrections for the most stable conformations do so for isolated molecules or a set of several molecules at best. Our deliberations here on utilizing the known SAR's and/or attempting to connect the dots and extend them unfortunately lack a major component of the information which is receptor models. So it's always just pure assumptions that never get tested. Still, even quantum chemistry calculations that seemingly take into account a lot of factors often fail to represent what happens in reality as it's always based on approximation.


----------



## DotChem

aced126 said:


> This is a big finding and I'm surprised I didn't know about this. This stems a new set of DRIs - why haven't more of these been made by RC suppliers?


Actually, there are more like selective NDRI with the naphthyl beeing SNDRI (check out their SAR papers).  I guess the reason those were not pursued as RC markets is they are more closer to methylphenidate in term of effect but only more expensive.  The easier synthetic route is via arylation of arecoline (extracted from some nuts growing in Asia). But arecoline itself is not really cheap so there is no point

As for half life, the carboalkoxy-aryl-piperidines are actually pretty different from the phenyl tropanes.  Nocaine T1/2 is ca 5 hours while some the beta-carbethoxy-phenyl tropane have a T1/2 of up to 2 WEEKS!!! (can you imagine!! 

NB: according to original paper, rats trained to self-administer cocaine can't tell the difference between Nocaine and Cocaine lever..whcih is interesting because the same paper claim..." the compound was found to substitute for cocaine in animal models while having significantly less abuse potential itself." 


Dresden said:


> In fact, the first
> 
> 
> 
> 
> 
> 
> could be dubbed 3,4-dihydro-4-(4-methylphenyl)-arecoline!


Yes actually, they were all made from arecoline. at least the trans.


----------



## DotChem

adder said:


> ..Our deliberations here on utilizing the known  SAR's and/or attempting to connect the dots and extend them  unfortunately lack a major component of the information which is  receptor models. So it's always just pure assumptions that never get  tested...



Actually we do: the crystal structures of cocaine, dopamine,  beta-CFT, dichlorophenethylamine, methamphetamine and dopamine bound to  transporter DAT are all available (check it out on pubmed).  That is as  close as it gets from having all the information needed to "connect the  dots".  

The one issue with DAT binding to substrate (or  inhibitors) though is that it required Na+ binding first for the  substrate to be able to bind.  In the absence of Sodium, transport is  drastically diminished.  Binding of Na+ induce major changes in the  conformation of the DAT protein that can accommodate binding of DRIs or  dopamine substrate by exposing the binding site. The site thus generated  upon Na binding that can accomodate DRI ligands (or DA substrate) is  pretty flexible so diverse molecules can bind without necessary having  similar geometry. I mean diverse up to a point. That's why Cocaine, MPH  or METH can all bind and block the substrate from access.  Very very  different from these yet are selective incredebly potent DRIs like  Mazindol or 3C-PEP with a structure totally different from the tropanes  or the phenethylamines.


----------



## DotChem

more on Nocaine: according to original paper, the carbalkoxy-phenyl piperidines such as Nocaine are selective NDRI unlike cocaine, they much closer to MDPV or similar cathinones.  They would certainly make potent aphrodisiac if anything .. talking about selective NDRIs aphrodisiac, these compounds from Denmark (big pharma!) were claimed as potent and selective NDRIs about 100x more potent than MDPV (at NET and DAT; ca 100,000x more than cocaine) with less (100s times less) serotonergic (X, Y =Cl or Br).  If what they claim in the patent is correct, they may be he next flakka! 




they look strangely similar to U4 opioids with the the amide inverted !!

Edit: read 10x more potent than PVP. The reported IC50 values claimed in this patent are:
Monoamines Uptake Inhibition IC50(uM):
SERT = 0.37 ; DAT =  0.0040 ; NET = 0.0031 for the dibromophenyl above

For alfa-PVP IC50 (uM)
SERT = 2.78 ; DAT = 0.052 ; NET = 0.028


----------



## Dresden

Nagelfar,

No, unfortunately, I don't recall that citation.  I think the study was from the early '60s, though.


----------



## adder

DotChem said:


> Actually we do: the crystal structures of cocaine, dopamine,  beta-CFT, dichlorophenethylamine, methamphetamine and dopamine bound to  transporter DAT are all available (check it out on pubmed).  That is as  close as it gets from having all the information needed to "connect the  dots".



Yes, I know you can find those in articles, and not only for DAT, I came across such images of ligands bound to opioid and serotonin receptors, they are fun, but still you can't invent a molecule and put it into a model, and be sure it fits or have electronic properties as you think it does. With good imagination you can imagine how a close structural analogue might bind, but even for a not so distantly related molecule it becomes too little. I'm wondering if making a model of a given receptor to be able to use it in computations would be a costly thing to do if you had access to a biochemical lab. Certainly, a fast computer would be necessary in the latter phase, but it's interesting if simply experiments necessary to build a model would be expensive provided that you had the know-how to do it. I would guess the most expensive phase of new-drug research is the synthesis of potential ligands if it gets complex and requires expensive reagents.

Quite far from the current topic discussed, but here's an interesting article comparing affinity of intrinsic activity of analogues of buprenorphine, you could say, with t-butyl group swapped for different alkyl and cycloalkyl groups with different stereochemistry at C20.


----------



## Nagelfar

aced126 said:


> Binding is very intricate.
> 
> The way you have overlayed it, the 2 aromatic systems are orthogonal to each other. The two compounds will then pi stack differently with their residues, altering affinity. Not to mention the carboxylates and amines are pointing in different directions.



Also aced, have you read the DAT crystrallographic studies that show most DAT ligands bind to 10—12 loci, but cocaine & methylphenidate both bind to the 9—through—11 loci? (all seem to similarly bind to 1 & 7 in addition to that divergence . The major difference between them seem to be their respective 'enthropy of binding': cocaine —5.6 kcal/mol & methylphenidate —25.5 kcal/mol. Ref. _Bonnet, J.-J.; Benmansour, S.; Costenin, J.; Parker, E. M. ;Cubeddu, L. X. J. Pharmacol. Exp. Ther. 1990, 253, 1206)_

Also check out: _Blough, Bruce E.; Keverline, Kathryn I.; Nie, Zhe; Navarro, Hernán; Kuhar, Michael J.; Carroll, F. Ivy (2002). "Synthesis and Transporter Binding Properties of 3β-[4'-(Phenylalkyl, -phenylalkenyl, and -phenylalkynl)phenyl]tropane-2β-carboxylic Acid Methyl Esters: Evidence of a Remote Phenyl Binding Domain on the Dopamine Transporter". Journal of Medicinal Chemistry. 45 (18): 4029–37. doi:10.1021/jm020098n. PMID 12190324_

^Because there is apparently a domain *beyond* (but skipping, apparently, DAT loci) 12, that cocaine and possibly MPH analogs can reach: As below:






So making a cocaine analog of the above phenyltropane:






^the way the benzoyl oxy spins might gimp it in this context, at least increased flexibility might make it not as potent.


----------



## Nagelfar

[η5-(pentamethylcyclopentadienyl)]-[η6-(2β-carbomethoxy-3β-phenyl)tropane]ruthenium-(II) triflate

anyone able to draw the above IUPAC / following images in three dimensions, ball and stick rotating, i.e. animated, rendering?











21*b*:





..I was also theorizing to myself, might TACD just decrease in length the short actingness of IV cocaine, making it more prone to habituation and more compulsive / addictive?


----------



## Solipsis

I like to draw molecules of random pictures


----------



## DotChem

adder said:


> ... you can't invent a molecule and put it into a  model, and be sure it fits or have electronic properties as you think it  does. With good imagination you can imagine how a close structural  analogue might bind, but even for a not so distantly related molecule it  becomes too little. I'm wondering if making a model of a given receptor  to be able to use it in computations would be a costly thing to do if  you had access to a biochemical lab.



I am not sure if you're familiar with protein X-ray crystallography technique  used to solve drug-receptor structure! If you ever been to a dentist, you have probably been subjected to the same technique! usually he'll  order X-ray done to get a "picture" of teeth and gum, is that right?  He'll put you in an X-ray machine and get a "picture" of your teeth and  gum (ie the relative electrons density of different atoms of the organs  and their relative locations).  Hopefully no caries holes to fill!!

That's the EXACT same technique used to solve the structure of drug-receptor complexes by X-ray crystallography.
Same  technique, same principles, same machines (may be more powerful) a  dentist use to see patient teeth (the picture he gets IS NOT A COMPUTER  predicted model.  It is EXACTLY the location of teeth in real life ..the  relative electronic density of bones, teeth, gums, other tissues..etc.   Otherwise dentists would long be out of business if they were relying  only on computer imagined model of the patient teeth to work on him/her.

Now  take a drug (real compound! real powdered highly pure sample of a  compound NOT A COMPUTER imagined model, real powder!) and a sample of a  protein it binds to (like cocaine + DAT protein or meth + DAT) real  protein, such as the powdered protein you can buy in health stores only  highly purified. Not a computer model of the protein, real protein !!   Mix the drug and the protein.. hopefully, you'll get a crystalline  complex of protein+drug bound to it. filter the mix, recrystallize if  necessary to purify and put the crystal thus obtained in a X-ray machine. Put that on a  X-ray machine and record the picture of the complex (showing the  electrons distribution and hence the position of different atoms in the  complex including that of the drug.. that's what people are talking  about when you see papers saying "X-ray structure of drug receptor  complex at xyz Armgstrom resolution blablablabla.." Just like the  picture the dentist use to see teeth and treat any dental pbs..The only  thing computer does is rendered the picture. You don't have to use  computer! They used to develop the X-ray thus obtained on films.. Some  doctors still prefer the image on the film to that on computer! Here is  the basic steps







The  structure of psychostimulants in complex with DAT refer to are X-Ray  Structures. What the Nature paper is telling you is the X-ray they've  taken of cocaine molecule bound to drosophila dopamine transporter DAT protein ...Not a  computer "imagined" model!  Here is methamphetamine bound to DAT (will  post later...) 

Now having this "picture" in hand just like a  dentist, you can see where there are holes .. what part of the drug is  interacting with what parts of the receptor..etc  With that information  in hand, you can then predict what to add, subtracts or replace..etc  in the original drug molecule so as to increase binding or selectivity ...etc etc.. You then go the lab,  synthesize the molecule you've predicted, test it and use the  information to design better drugs.. more later....


----------



## Incunabula

Solipsis said:


> I like to draw molecules of random pictures



lol, me too.


----------



## adder

DotChem said:


> I am not sure if you're familiar with protein X-ray crystallography technique  used to solve drug-receptor structure! If you ever been to a dentist, you have probably been subjected to the same technique! usually he'll  order X-ray done to get a "picture" of teeth and gum, is that right?  He'll put you in an X-ray machine and get a "picture" of your teeth and  gum (ie the relative electrons density of different atoms of the organs  and their relative locations).  Hopefully no caries holes to fill!!
> 
> That's the EXACT same technique used to solve the structure of drug-receptor complexes by X-ray crystallography.
> Same  technique, same principles, same machines (may be more powerful) a  dentist use to see patient teeth (the picture he gets IS NOT A COMPUTER  predicted model.  It is EXACTLY the location of teeth in real life ..the  relative electronic density of bones, teeth, gums, other tissues..etc.   Otherwise dentists would long be out of business if they were relying  only on computer imagined model of the patient teeth to work on him/her.
> 
> Now  take a drug (real compound! real powdered highly pure sample of a  compound NOT A COMPUTER imagined model, real powder!) and a sample of a  protein it binds to (like cocaine + DAT protein or meth + DAT) real  protein, such as the powdered protein you can buy in health stores only  highly purified. Not a computer model of the protein, real protein !!   Mix the drug and the protein.. hopefully, you'll get a crystalline  complex of protein+drug bound to it. filter the mix, recrystallize if  necessary to purify and put the crystal thus obtained in a X-ray machine. Put that on a  X-ray machine and record the picture of the complex (showing the  electrons distribution and hence the position of different atoms in the  complex including that of the drug.. that's what people are talking  about when you see papers saying "X-ray structure of drug receptor  complex at xyz Armgstrom resolution blablablabla.." Just like the  picture the dentist use to see teeth and treat any dental pbs..The only  thing computer does is rendered the picture. You don't have to use  computer! They used to develop the X-ray thus obtained on films.. Some  doctors still prefer the image on the film to that on computer! Here is  the basic steps
> 
> (...)
> 
> The  structure of psychostimulants in complex with DAT refer to are X-Ray  Structures. What the Nature paper is telling you is the X-ray they've  taken of cocaine molecule bound to drosophila dopamine transporter DAT protein ...Not a  computer "imagined" model!  Here is methamphetamine bound to DAT (will  post later...)
> 
> Now having this "picture" in hand just like a  dentist, you can see where there are holes .. what part of the drug is  interacting with what parts of the receptor..etc  With that information  in hand, you can then predict what to add, subtracts or replace..etc  in the original drug molecule so as to increase binding or selectivity ...etc etc.. You then go the lab,  synthesize the molecule you've predicted, test it and use the  information to design better drugs.. more later....



I'm sorry, I guess, I didn't make myself clear. Yes, I know that those are X-ray crystallographic images of real complexes, this technique is probably the only method that can show real bond lengths, positions of atoms in relation one to another, electron density, and whatnot as opposed to calculated values, and for this reason it is definitely indispensable for many purposes like for example studying how already known ligands exactly bind to a receptor. But what I meant was to take such an X-ray image of a real ligand-bound protein complex and use it to make a virtual model to be able to virtually bind newly designed ligands. I suppose it's in many ways cheaper than making a complex of a protein and each new potentially good ligand, you don't have to synthesize all the ligands many of which will inevitably turn out useless and you're not wasting protein material which is probably even more expensive. That way using computations you can sort of strain the more promising ligands from useless ones at the very beginning of a research. Given how long the process of producing a new effective drug is, I guess that's more or less how pharmaceutical companies look for new drugs.


----------



## Nagelfar

Incunabula said:


> lol, me too.



Now; this thrread is starting to make memeingful sense.


----------



## aced126

adder said:


> Yes, I know you can find those in articles, and not only for DAT, I came across such images of ligands bound to opioid and serotonin receptors, they are fun, but still you can't invent a molecule and put it into a model, and be sure it fits or have electronic properties as you think it does. With good imagination you can imagine how a close structural analogue might bind, but even for a not so distantly related molecule it becomes too little. I'm wondering if making a model of a given receptor to be able to use it in computations would be a costly thing to do if you had access to a biochemical lab. Certainly, a fast computer would be necessary in the latter phase, but it's interesting if simply experiments necessary to build a model would be expensive provided that you had the know-how to do it. I would guess the most expensive phase of new-drug research is the synthesis of potential ligands if it gets complex and requires expensive reagents.
> 
> Quite far from the current topic discussed, but here's an interesting article comparing affinity of intrinsic activity of analogues of buprenorphine, you could say, with t-butyl group swapped for different alkyl and cycloalkyl groups with different stereochemistry at C20.



This is quite true.

There is a good deal of research currently going on in Pharma to develop softwares to predict which molecules are going to hit the target well, a sort of computer-simulated version of high-throughput screening. This means they can chop down the number of molecules they need to actually synthesise by orders of magnitude, which as you mentioned is the main area of expense.


----------



## aced126

DotChem said:


> I am not sure if you're familiar with protein X-ray crystallography technique  used to solve drug-receptor structure! If you ever been to a dentist, you have probably been subjected to the same technique! usually he'll  order X-ray done to get a "picture" of teeth and gum, is that right?  He'll put you in an X-ray machine and get a "picture" of your teeth and  gum (ie the relative electrons density of different atoms of the organs  and their relative locations).  Hopefully no caries holes to fill!!
> 
> That's the EXACT same technique used to solve the structure of drug-receptor complexes by X-ray crystallography.
> Same  technique, same principles, same machines (may be more powerful) a  dentist use to see patient teeth (the picture he gets IS NOT A COMPUTER  predicted model.  It is EXACTLY the location of teeth in real life ..the  relative electronic density of bones, teeth, gums, other tissues..etc.   Otherwise dentists would long be out of business if they were relying  only on computer imagined model of the patient teeth to work on him/her.
> 
> Now  take a drug (real compound! real powdered highly pure sample of a  compound NOT A COMPUTER imagined model, real powder!) and a sample of a  protein it binds to (like cocaine + DAT protein or meth + DAT) real  protein, such as the powdered protein you can buy in health stores only  highly purified. Not a computer model of the protein, real protein !!   Mix the drug and the protein.. hopefully, you'll get a crystalline  complex of protein+drug bound to it. filter the mix, recrystallize if  necessary to purify and put the crystal thus obtained in a X-ray machine. Put that on a  X-ray machine and record the picture of the complex (showing the  electrons distribution and hence the position of different atoms in the  complex including that of the drug.. that's what people are talking  about when you see papers saying "X-ray structure of drug receptor  complex at xyz Armgstrom resolution blablablabla.." Just like the  picture the dentist use to see teeth and treat any dental pbs..The only  thing computer does is rendered the picture. You don't have to use  computer! They used to develop the X-ray thus obtained on films.. Some  doctors still prefer the image on the film to that on computer! Here is  the basic steps
> 
> 
> 
> 
> 
> 
> 
> The  structure of psychostimulants in complex with DAT refer to are X-Ray  Structures. What the Nature paper is telling you is the X-ray they've  taken of cocaine molecule bound to drosophila dopamine transporter DAT protein ...Not a  computer "imagined" model!  Here is methamphetamine bound to DAT (will  post later...)
> 
> *Now having this "picture" in hand just like a  dentist, you can see where there are holes .. what part of the drug is  interacting with what parts of the receptor..etc  With that information  in hand, you can then predict what to add, subtracts or replace..etc  in the original drug molecule so as to increase binding or selectivity ...etc etc.. You then go the lab,  synthesize the molecule you've predicted, test it and use the  information to design better drugs.. more later....*



What do you take adder for? Of course he, and most people in this forum, know what X-ray crystallography is.

You've made the bolded part sound quite trivial, but in reality this is far from being an easy job.


----------



## Solipsis

Incunabula said:


> lol, me too.



Haha ^ sorry for fucking the thread but this cracked me up


----------



## Nagelfar

Is this co-ordination as inane as the cat pic or? I know nothing about co-ordination chemistry; but I am trying to get a DAT allosteric modulator to work as a DRI


----------



## sekio

Only metal centres (e.g. Cr(CO)3) will pi-coordinate like that, nags.


----------



## Nagelfar

sekio said:


> Only metal centres (e.g. Cr(CO)3) will pi-coordinate like that, nags.



I took this from a patent in my decade long sifting of phenyltropanes; almost looks sulfur "co-ordinated" but not with any connected placement of anything else; perhaps the proper terminology for what this exact methodology is, is unknown to me in this case, any clue?


----------



## Solipsis

Nagelfar said:


> I took this from a patent in my decade long sifting of phenyltropanes; almost looks sulfur "co-ordinated" but not with any connected placement of anything else; perhaps the proper terminology for what this exact methodology is, is unknown to me in this case, any clue?



That is a cyclohexyl, not an aromatic ring so no pi-interaction. Are you sure it's not a different sort of context that explains the "S" ? What does the patent say referring that image?
(Even if it was sulfur, I don't think that behaves in any such way in coordination chemistry - as said you need something like iron for that.. sulfide would be 2- and you need something that is cationic without real covalent binding tendencies to coordinate I think)


----------



## RandomClean3

*They are structurally similar.*

If you look at both molecules, yeah, it's hard to find similarities. But we know the ester bond on cocaine can be replaced entirely by a carbon bond and it retains activity, therefore, it's not part of the pharmacore. Also, we can ignore levo-methylphenidate only focus on dexmethylphenidate since it's the active enantiomer. So if you draw cocaine with that change (which I believe it's some analogue, I know the chlorinated version is) you get this.




Now, if you look at the connection between the carbonyl carbon and the amine, you notice it's a perfect match, they both go through 2 chiral carbons with the same chilarity leading to the same functional groups. The benzene is not static given that in both cases it's attached to a secondary carbon, and you can see a 6 member ring in the cocaine analogue analogous to the piperidine in the phenidates. Sure, it's not a perfect match, that's why cocaine is a sigma agonist and a serotonin reuptake inhibitor and methylphenidate isn't. But the similarity is there, and it's pretty considerable given both tropanes and piperidines are found constantly in stimulants and I suspect they may be bioisosteres. So yeah, they are pretty similar, the phenetylamine skeleton of MTP is deceiving since it's activity is not related to that. More similarities can be found in other ''dirty drugs'' like pethidine (serotoninergic and very weak dopaminergic) and even ibogaine if you wanna get creative


----------



## RandomClean3

Dude, that's old, the first is nocaine. The entire family is being investigated as less addictive analogues for addiction, depression, obesity, etc. But they don't seem very promising to be honest, they pretty much follow the same pharmacore in a more planar form, and oxazoles are bioisosteres to esters, so it makes sense they tried it out.


----------



## RandomClean3

The S is sometimes used as substituted. They leave the ring alone with no double bonds since it's possible to replace with an oxygen double bond.


----------



## Solipsis

Ah I only know that as a diagonal line crossing the bond of an aromatic ring, but that makes perfect sense!

I think the name 'nocaine' is very pessimistic


----------



## Nagelfar

Solipsis said:


> Are you sure it's not a different sort of context that explains the "S" ? What does the patent say referring that image?



US6479509 B1, Frank I. Carroll, Research Triangle Institute 4229 (phenyltropane) series

Sift through those images; that is the only one with an "S" like that, the rest are all arene/aryl, definitely aromatic and why would this be a cyclohexyl in context is beyond me.



RandomClean3 said:


> The S is sometimes used as substituted. They leave the ring alone with no double bonds since it's possible to replace with an oxygen double bond.



Thanks RC3; probably the explanation, but it's weird how they throw that in there (but they also have circles/double bonds interchangeably to show the aromaticity)


----------



## Nagelfar

RandomClean3 said:


> So yeah, they are pretty similar, the phenetylamine skeleton of MTP is deceiving since it's activity is not related to that.



A lot of people overlook that for sure, so confusing and aggravating to explain to some who are "sure they know" what they're talking about; I have even argued with licensed prescribers that MPH is *not an amphetamine* (they were insisting it was)

and thanks for that elucidation it was wonderful.


----------



## aced126

Also another thing to note is that the stereochemistry at the alpha carbon of MPH is akin to that of levo-amphetamine.


----------



## DotChem

aced126 said:


> What do you take adder for? Of course he, and most people in this forum, know what X-ray crystallography is.


No the intent is not to imply whether adder (on anybody on this forum) is or is not aware of x-ray crystallography technique.  The reason I posted is that lots of people easily make no distinction between computer predicted structural models of drug-protein and X-ray determined structures.  The 2 are not the same!! I guess it is because the representation as computer images are the same! So it is very important to make difference.



aced126 said:


> You've made the bolded part sound quite trivial, but in reality this is far from being an easy job.



No! actually it is quite trivial once the X-ray of the target protein is solved. Even easier if the X-ray of the complex target protein+bound drug is solved.  The hardest part is to get the X-Ray of the protein and the MOST DIFFICULT part of this is to get pure crystals of protein or protein+drug complex!  The reason beiing that most of of the interesting proteins targeted by drugs are trans-membrane proteins, like G-protein coupled receptors that bind most neurotransmitters or transporters lite DAT SERT, or ion channels like GABA, NMDA..etc etc.  

They are all transmembrane proteins in their native form in the cells and it is very difficult to crystallize them without destroying them!! Unlike small organic molecules.  Why is that? because they fall apart the minute you take them outside their natural environment ie cells membrane lipid bilayer.  I mean the 3-D conformation of your protein collapse. The original 3-D tertiary structure the one of the native protein in the cell. You need a lot (i mean really a LOTS of trial and error of conditions, salts, detergents, temperature...etc etc) to get the right conditions if at all. Lots of interesting proteins like GABA channels are still near impossible to solve 

It is like you want to have your cake and eat too: you have to use detergent (aka soap) to free them from the cell membrane but soap is exactly what you use to destroy their 3D and solubilize them in the first place! That's how you wash away food craps!  So this is the hardest part of all that business: isolate your protein (or protein-drug complex) with its 3D native conformation intact.  Depending on the protein, that can take a graduate student anywhere from 3 to 5 years to get good crystals of his target protein suitable for X-Ray IF AT ALL!!!  

Oh I forgot another hard part: get the MONEY to fund your project (good luck asking gov give you money to make better cocaine!!!)

While we were talking on the DAT-cocaine complex X-ray structure, here is paper published 2 days ago by a Pharma in Danmark who use exactly the same technique I was talking about but with Serotonin transporter to design SSRI starting with SERT-citalopram X-ray structure, ($$paying article$$).. enjoy the read

The same technique can be used to design DRI starting with DAT X-ray...


----------



## DotChem

Solipsis said:


> Haha ^ sorry for fucking the thread but this cracked me up


 
Have you met cathy noon? I bet you have Metcathinone..


----------



## DotChem

I think one should be cautious on MPH SAR: unlike amphetamines the  nitrogen of MPH piperidine is not really necessary for DA uptake  inhibition: replacing the N with an oxygen atom (or even a Carbo atom to  get simple cyclohexyl (like Methyl 1-cyclohexyl-phenylacetate) gives  molecules that are as potent as methyl phenidate as DA uptake  inhibitors!!  The pharmacophores) that seem to be important are the Aryl  (substitued with 1 or 2 halo is best) and the COOMe.  Even the COOMe  can be replaced by a simple CH2CH3 and still retain potent DA uptake  inhibitors. I am not sure if that is the case with amphetamines!! 



> Synthesis and evaluation of dopamine and serotonin transporter inhibition by oxacyclic and carbacyclic analogues of methylphenidate https://www.ncbi.nlm.nih.gov/pubmed/12672255


 This is as good as MPH (the one with a O is actually more potent!! cf ref )


----------



## sekio

No, but it's known to be the case with the cocaine analogues.


----------



## Nagelfar

DotChem said:


> I think one should be cautious on MPH SAR: unlike amphetamines the  nitrogen of MPH piperidine is not really necessary for DA uptake  inhibition: replacing the N with an oxygen atom (or even a Carbo atom to  get simple cyclohexyl (like Methyl 1-cyclohexyl-phenylacetate) gives  molecules that are as potent as methyl phenidate as DA uptake  inhibitors!!  The pharmacophores) that seem to be important are the Aryl  (substitued with 1 or 2 halo is best) and the COOMe.  Even the COOMe  can be replaced by a simple CH2CH3 and still retain potent DA uptake  inhibitors. I am not sure if that is the case with amphetamines!!
> 
> This is as good as MPH (the one with a O is actually more potent!! cf ref )



sekio QFT; I think my point was glossed by, by some (always is), that MPH is a cousin of cocaine and not amph.


----------



## Nagelfar

RandomClean3 said:


> The S is sometimes used as substituted. They leave the ring alone with no double bonds since it's possible to replace with an oxygen double bond.



Wait, are you telling me that:






...would work as an aromatic? ortho-oxy cocaine acts like the phenyltropane class in heightened efficacy (apart from whatever change in affinity) because the closeness of the oxygen to where the oxygen substrate site on DA is placed where the receiving loci on DAT are. Being right on the ring may be even closer with the benzoyloxy spacing; it also increases electronegativity which is shown to increase MAT ligand binding across the board.

...would this be stable?





If not then this maybe:


----------



## sekio

That pyran heterocycle isn't aromatic, sadly.


----------



## Nagelfar

sekio said:


> That pyran heterocycle isn't aromatic, sadly.



Ah, so "S" as for 'substituted in all, even unworkable, ways in this schematic of what's able to be patented for this kind' (thus RC3's insight of it's double bonds being able to be omitted in this case is useless because for the most part aromatic consistence need be maintained in that part of the pharmacophore: bit of a paradox, but so too is writing them the hexyl with circle and hexyl with double bonds for a benzene interchangeably on very same page, side by side, in one patent)


----------



## sekio

Hey Nags - $VENDOR is selling troparil, and I've reason to believe it's legit...  thoughts? D'ya think these are going to be the Next Big Drug Problem?

Also, yeah, that markush structure looks pretty... lazy. Fo sho. Might as well just have scrapped the whole thing and written "R" on the patent for all the confusion it generates.


----------



## Pomzazed

Offtopic but i cant resist!

LOL! Sekio, i really like the idea of the variable $VENDOR! So nice method of censoring!
What happen if we substitute the piperidine ring with a phenyl? As cyclohexyl is said to have activity


----------



## Nagelfar

sekio said:


> Hey Nags - $VENDOR is selling troparil, and I've reason to believe it's legit...  thoughts? D'ya think these are going to be the Next Big Drug Problem?



Not a clue. However, if it is as reinforcing as some suggest, and safer in the ways that have been assumed (non-cardiotoxic, non-neurotoxic a la amphetamine etc.) it might be a "safe" problem.



sekio said:


> Also, yeah, that markush structure looks pretty... lazy. Fo sho. Might as well just have scrapped the whole thing and written "R" on the patent for all the confusion it generates.



Yes esp. when my area of interest involves mostly these RTI patent's that F. I. Carrol et al. seem to pump out, with a like consistency, every time, for decades. ;-p As long as I notice it, I can make sure it doesn't filter it's way through to the compilation on WP I am doing of them.


----------



## Nagelfar

I don't know what's going on with the library computers and snag.gy lately, but I can't screen capture the compounds I draw;

I was mixing the benztropines and the PT benztropines and getting:
(1R,2R,3S,5S)-3-[2-(diphenylmethoxy)ethoxy]-2-[3-(diphenylmethoxy)propyl]-8-methyl-8-azabicyclo[3.2.1]octane

I wonder.


----------



## Pomzazed

> but I can't screen capture the compounds I draw;
> (1R,2R,3S,5S)-3-[2-(diphenylmethoxy)ethoxy]-2-[3-(diphenylmethoxy)propyl]-8-methyl-8-azabicyclo[3.2.1]octane




Here; drew it for you!
( looks like an squid or jellyfish or so in 2D-skeleton lol)


----------



## Solipsis

That squid has huge cojones


----------



## DotChem

^^ would make nice detergent!  (hydrophilic head + hydrophobic tail = soap)


----------



## Nagelfar

It's the aryltropanes & benztropanes together; should have "Pirenzepine"-esque muscarinic acetylcholine receptor M1 affinity but like the above two cross the BBB perhaps.

if you check out the quinazolinamines the allosteric modulators were the longer ones, like _J Pharmacol Exp Ther. 2016 Mar;356(3):624-34. doi: 10.1124/jpet.115.230722. Epub 2016 Jan 14._ has for the aryltropanes and "Compound 276"


----------



## Pomzazed

So no mention of the chirality at the center in diphenyloxy- part?


----------



## Solipsis

There is no chirality there, well I mean not in your unsubsituted structure above - here I guess there would be an ambiguous ~ line cause I can't see what X and Y are.
I guess other chirality than the axial/equatorial susbtitution of that whole moiety were not made relevant here.


----------



## Bagseed

Well if x and y are not the same, there should a centre of chirality, no?


----------



## Solipsis

Not sure, man. I'd have to see some context and I didn't dive into that if it was even provided fully in a link. Maybe it is just potentially different as in not necessarily the same, but that would still be quite premature to start talking about the chirality, hey other than that you definitely have a point.

Synthesis and monoamine transporter binding of 2-(diarylmethoxymethyl)-3 beta-aryltropane derivatives. is an article that should clarify things... but I have no access


----------



## Bagseed

Well if we say that x = flourine, y = chlorine, then the two phenyls are not equal hence the diarylmethoxy carbon is asymmetric. Do I overlook anything?

Of course if x = y, then said carbon is not chiral...


----------



## Nagelfar

Do you mean if it's alpha or beta oriented? Because benztropine is levo, unlike cocaine; at the 3 ring position.

Funny fact from WP:

"...In veterinary medicine, benzatropine is used to treat priapism in stallions."


----------



## Bagseed

the discussion is about the diarylmethoxy carbon, not the tropan


----------



## Solipsis

You are right, but my point was: chirality is drawn if it is relevant, and at that stage of consideration it is only very generally shown that there are possible substitutions that are not necessarily equal but they may be equal or not present at all. There is nothing said of what they may be, so it seems irrelevant or premature to point out that there are _potential_ chirality issues there. I think, like hydrogens it is not drawn until it really becomes a relevant matter. Anyway that's my take on it. Even if the chirality is not ambiguous anymore it is not necessarily drawn, unless it matters in the context. Look at the alpha carbon of amphetamines. Often enough ignored, cause it is not always significant in all matters.


----------



## Pomzazed

Solipsis said:


> You are right, but my point was: chirality is drawn if it is relevant, and at that stage of consideration it is only very generally shown that there are possible substitutions that are not necessarily equal but they may be equal or not present at all. There is nothing said of what they may be, so it seems irrelevant or premature to point out that there are _potential_ chirality issues there. I think, like hydrogens it is not drawn until it really becomes a relevant matter. Anyway that's my take on it. Even if the chirality is not ambiguous anymore it is not necessarily drawn, unless it matters in the context. Look at the alpha carbon of amphetamines. Often enough ignored, cause it is not always significant in all matters.



Sorry for introducing confusion. You are right that diphenylmethoxy- part is NOT chiral, due to having two identical (phenyl) group. It is just prochiral, The questions about chirality I asked is for in-case that the phenyls are asymmetrically substituted. (Eg, one Phenyl plus one chlorophenyl) from that jellyfish-like molecule


----------



## sekio

yes, then it'd be chiral because the quaternary carbon that bridges the two would have 4 differing substituents.


----------



## Nagelfar

Pomzazed said:


> Sorry for introducing confusion. You are right that diphenylmethoxy- part is NOT chiral, due to having two identical (phenyl) group. It is just prochiral, The questions about chirality I asked is for in-case that the phenyls are asymmetrically substituted. (Eg, one Phenyl plus one chlorophenyl) from that jellyfish-like molecule





sekio said:


> yes, then it'd be chiral because the quaternary carbon that bridges the two would have 4 differing substituents.



I took it from "compound 276" from Singh's 1999 coke antagonist paper: i.e.





and the 12 series phenyltropane benztropine analogs, i.e.





-----------------

(1R,3R,5S)-8-methyl-3-(9-{naphtho[2,1-c]phenanthren-1-yl}phenanthren-3-yl)-8-azabicyclo[3.2.1]octane

^Again, can't draw it from the library again, but a mixture of all of the possible ligands by length of arene/aryl and phenyl/methylenes of the phenyltropane that have affinity. (maybe not together, LOL)


----------



## Pomzazed

The first one; cis-diphenylethene one may be light sensitive! It looks like some molecular probe that switch to trans when exposed to visible or IR, but revert to cis after shortwavelength UV lol :D


----------



## roi

May or may not have fentanyls-like potency


----------



## DotChem

MDMADMTDOB free base


----------



## white55




----------



## Solipsis

Oooh... I tried ETH-LAD last sunday so I can certainly appreciate this idea - how about the benzoyl amide though? That's said to be ridiculously long-lasting IIRC.

These 1-subbed lysergamides are a mystery: they shouldn't be active themselves and also don't seem to produce enough metabolite in time to really account for everything normally. LSD et al themselves seem really strange in that tiny quantities are necessary to successfully make it into parts of the brain to lodge themselves there.
So I think the question is: do these 1-subbed ones somehow favorably deliver enough those tissues - do the pro-drugs get stuck in the CNS' 5-HT2a and then get 1-deacylated making it virtually irrelevant what portion gets deacylated overall? I think what is suggested from the data is that as if the dosages aren't tiny already for LSD, what matters mostly is some even tinier dose that successfully gets lodged. Maybe that skews some perspective on what is needed to achieve that and maybe it is the source of confusion about 'not enough metabolite LSD being present to explain the potency of such pro-drugs'? Or was Nichols just wrong about the activity of these pro-drugs themselves or is it just that LSD dosage is so overstated when street acid is advertised?

Is 6-Cyclopropyl-LAD reactive / unstable? I think I remember only the cyclopropylmethyl in literature...


----------



## sekio

I'm pretty sure that the 1-alkyl LSD analogs are deacetylated rapidly in the blood and thereby act as prodrugs and nothing more.


----------



## Bagseed

But how come that the diethylamide isn't also cleaved enzymatically quickly to give lysergic acid?


----------



## sekio

The diethyl amide is more sterically hindered than the one on the indole nitrogen. Also, because the indole group is aromatic and that disrupts the conjugation of an amide group, the amide C-N bond on the indole is longer than the one "up top", rotates more easily, and is thereby more easily hydrolysed.


----------



## Bagseed

thanks


----------



## adder

This thread inspired me to draw a few 7-sulfonylbenzodiazepines. I'm pretty sure we know nothing about SAR that would make them inactive for some reason solely due to the sulfonyl group. The advantage is that unlike with halogens or nitro group, this group is not a dead end and can be modified with a variety of functional groups, aliphatic, cyclic, aromatic etc. which might be tuned to be selective for certain receptor subtypes.


----------



## DotChem

and  replace it be a C.. you get this molecule: It is extremely potent NDMArA  about 30x more potent than K as NMDAr antagonist (Ki 3HTCP binding =  27nM v Ket Ki = 860nm) according to this patent here.   It doesn't look like any schedule dissociative at least the structure  or can it be seen like ring restricted K analog or something?..but  anyhow, it looks it might have an unbelievably long half life (>10  h???) considering there is no obvious "metabolizable" functional group  to chew esaily by metabolic enzymes..But who knows?


----------



## adder

If -NHMe and -H at the junction between cyclohexane & indane rings are cis, it's quite like dizocilpine without the second aromatic ring.


----------



## Solipsis

:D so what was their plan with this 'treatment' for cerebrovascular disorders... administer it with a whopping dose of an equally long-lasting benzo?... mk-801 type trips seem a bit hardcore to give to a patient...

I will always be amazed at how the pharmacophore of NMDA antagonists seem to be based on NMDA but also not based on NMDA. Or from a different angle: how the PCP site would have evolved to apparently have similarities to the main active site with its pharmacophore, but also to develop what seems like a specialization so that there can exist an overlap in ligands active at both sites, but not necessarily. I guess the real PCP site ligands are more aromatic or even aliphatic etc rather than having polar groups like carboxyls. Anyway maybe I am off with this interpretation.. but suffice to say it has puzzled me

Someone should really build an LSTM network AI and feed it all known relevant data and get it to come up with novel drugs for us 

wtf is this endogenous ligand's structure: https://www.ncbi.nlm.nih.gov/pubmed/2887250 for the PCP site?
Are all endogenous ligands in the brain basically 'designed' to not pass the BBB? I mean: are there endogenous brain neurotransmitters known that could be active when administered, is the BBB made to transport some compounds unilaterally or would you never find any such administerable drug because it would leak out of the brain if it could also get in there / or get metabolized really quickly before it could get anywhere?


----------



## Nagelfar

Solipsis said:


> wtf is this endogenous ligand's structure: https://www.ncbi.nlm.nih.gov/pubmed/2887250 for the PCP site?
> Are all endogenous ligands in the brain basically 'designed' to not pass the BBB? I mean: are there endogenous brain neurotransmitters known that could be active when administered, is the BBB made to transport some compounds unilaterally or would you never find any such administerable drug because it would leak out of the brain if it could also get in there / or get metabolized really quickly before it could get anywhere?



That paper was from 1987, and the PCP site is still considered an 'orphan receptor site' without adoption, last I knew. Was this paper disproven shortly thereafter perhaps?


----------



## SkyblueMolly

This is a molecule of N-Propargyl-Methiopropamine. 
It's an analogue of deprenyl, an MAO-I.


----------



## yoyoman

The first one 4-benzylpiperidine is an oddball, it sometimes gets 'good' when you take the dose up almost feels like the mao kicks in and theres too much DA.  Its a weird one cause its 5 carbons away unlike most good stimulants there's always that PEA/amp pattern of benzene ring 3 carbons to the Nitrogen.  I read somewhere (maybe here, don't remember if its reliable) that you could replace the N in ritalin with an O and it would be nearly the same.  Wonder if you can do it with amphetamines?

Its been my dream to come up with a molecule that acts like ethylamphetamine but isn't. Maybe not exact but close enough.

In the last pic i meant "ethyl to hide the hydrogen" (could be methyl etc)


I was on some random chemical research site in the USA and they had 3-CF3-amphetamine for sale... what would happen? 3FA with one fluoro is pretty strong at dopamine release (feels like it).  There's a high demand for a 2FA/2FMA substitute, I wonder what swapping for a Chlorine or Bromine might do.. make it less active there (there by making it more like standard amphetamine?)


----------



## Pomzazed

phenpropanol is a sedative...


----------



## white55

Would this monstrosity get cleaved to eth-lad and 3-ho-2'oxo-pce?


----------



## Bagseed

hard to say what happens... the carbonyl seems very sterically hindered which may slow down metabolism.


----------



## Nagelfar

Solipsis said:


> Are all endogenous ligands in the brain basically 'designed' to not pass the BBB? I mean: are there endogenous brain neurotransmitters known that could be active when administered, is the BBB made to transport some compounds unilaterally or would you never find any such administerable drug because it would leak out of the brain if it could also get in there / or get metabolized really quickly before it could get anywhere?



I don't think so much designed to 'not pass BBB' as just naturally respect the format as endogenous. For example, a lot of exogenous chemicals from plants serve to poison or otherwise dissuade animal predators, and are more of BBB crossing as an attack at the foreign target.


----------



## white55

Bagseed said:


> hard to say what happens... the carbonyl seems very sterically hindered which may slow down metabolism.


one can hope  (or take them together)


----------



## DotChem

when you cross coke and foxy..
	

	
	
		
		

		
		
	


	




 just add a 5-methoxy!! somebody applied to patents this!!  makes you wonder why??.. https://pubchem.ncbi.nlm.nih.gov/compound/58450104#section=Top


----------



## white55

Most of these benzos are pretty obvious, but should all be active and probably enjoyable for people who like them, first some that are likely to have sane potencies:

n-methyl clonazepam - people like clonazepam and n-methyl 1,4 classical benzos are usually considered better than the desmethyl versions, potency should be a bit higher than clonazepam but still not insane like clonazolam






n-methyl nifoxipam - this one has already been made and tested (it's in the same patent as nifoxipam), apparently it's stronger than flunitrazepam (so the potency is approaching the insane side but hey..) but has a higher ld50....






the nitro analog of midazolam - should be pretty awesome, midazolam is already very well liked and replacing Cl with a nitro group tends to make things even better..... not sure about potency, oral midazolam has pretty low bioavailability and is thus relatively weak, the iv version however is a completely different ballgame, could likely work as a nasal spray which should be close to iv without any needles






flualprazolam - a stronger and more hypnotic xanax, what is there more to say.... oh and since norflurazepam is a thing it should be a relatively straight forward synth (if you like working with dangerous chemicals anyway)






None of these are anything spectacularly innovative but since they are all so close to well liked pharma benzos with small modifications to make them more enjoyable and/or potent they should all be good.


----------



## SteveSmoker

Don't you just love the THClmolecule composition?


----------



## white55

Few more

al-lah - a lysergamide allowed by the Koran, should probably be active too






tfm-lad - probably a bitch to make, wonder if it's active






2f-eth-lad - another bitch to make






n-methyl clopremazepam - some more weirder benzos


----------



## sekio




----------



## Solipsis

lol






- Give me some of that new spice, I don't want any goddamn old spice
- Stop talking

ah 1992, the day people started extracting their own spice at home guided by subliminal messaging


----------



## Nagelfar

Solipsis said:


> lol
> 
> 
> 
> 
> 
> 
> - Give me some of that new spice, I don't want any goddamn old spice
> - Stop talking
> 
> ah 1992, the day people started extracting their own spice at home guided by subliminal messaging



....and who said Columbus wasn't looking for new drugs?


----------



## DotChem

break the C-N bond, merge the pyrrolidine ring, replace the methylenedioxyphenyl by an indole, add a fluoro at the 7-position of the indole.. you get this:





Maniacamine! Now this compound is about 2000x more euforik than cocain! according to this patent .. guess that would be the LSD of stims.. would need blotter! .. Amazing!


edit: actually it is ONLY 200x .. here the SAR on this class


----------



## Solipsis

Was it checked for being a MAOI or do those tend to be more analogous to releasers?


----------



## DotChem

Yeah..It is a weak MAOI relative to MA activity: IC50 MAOI > 150x higher than IC50 for MAT so more likely no significant MAO inhibition within MAT doses range.

 Releaser more pvpcoke-like than AMPH about 100x more potent than its congener pvp as SDNRA.  But unlike pvp, it is not selective NDRA but SNDRA so it is more like a cross between mdma and pvp or coke!  All the class regardless of the aryl as long as it is 2 or 3 -pyrrolidinyl..unlike pvp where all the congeners are pretty much all selective NDRA..Quite interesting!


----------



## Nagelfar

DotChem said:


> and  replace it be a C.. you get this molecule: It is extremely potent NDMArA  about 30x more potent than K as NMDAr antagonist (Ki 3HTCP binding =  27nM v Ket Ki = 860nm) according to this patent here.   It doesn't look like any schedule dissociative at least the structure  or can it be seen like ring restricted K analog or something?..but  anyhow, it looks it might have an unbelievably long half life (>10  h???) considering there is no obvious "metabolizable" functional group  to chew esaily by metabolic enzymes..But who knows?



WP article I just made for your bringing to my attention the above _N_-methylhexahydrofluorenamine


----------



## DotChem

shhhttt! @Nag...That is a trade secret ...just kidding!!! Actually, this and related compounds are from the Tricyclic class of NMDAr antagonists. They're pretty different from the arylcyclohexylamines, the adamantanes , the morphinans or the dipheylethylamines class of dissociatives NMDAr antagonists   Maybe when you have time, you should create a separate WP entry for those if you're interested since they're pretty distinct class of NMDAr antagonists.  More SAR data can be added later.   

Here is the paper and reference on that particular compound with more NMDAr data on the whole series of related structures (the patent reference + the pubmed on WP).  The most active compound discovered was the cis isomer ie cis-N-methylhexahydrofluorenamine with IC50 0.009uM almost 100x ketamnie. Maybe you should use that one on the WP page you setup and link up to the paper for analogs since it is the most optimized among the group.  

Now having said that, this compound is insanely potent dissociative.  It is in the range of the ridiculously potent NMDAr antagonist Dizocilpine aka MK-801, the standard NMDArA used to induce experimental full-blown schizophrenic dissociatives psychosis in lab rats!!..with doses in humans of 1mg or less (insane)!! But at this doses, there're is probably no aminergic ie no stim activity like with K, dck or 3meopcp..etc.. just pure dissociative!.


----------



## DotChem

for some reason, images I post on imgur.com dont show up here... Am I doing some wrong on that website imgur? may be they dont allow pic of "drugggg" molecules??


----------



## roi

Imgur allows everything (legal-ish), you must have deleted it yourself. 50% of their traffic is hardcore porn, molecules are nothing lol






doxdoxylamine


----------



## DotChem

that's what I thought..lol guess I might have accidentlly deleted the post. will try again or use photobucket but they fcuk up that site  it is so slow to load anything now..


----------



## Nagelfar

DotChem said:


> that's what I thought..lol guess I might have accidentlly deleted the post. will try again or use photobucket but they fcuk up that site  it is so slow to load anything now..



If all your links deleted at once, maybe they changed their url subsectioning methodology and it just undercut everything in your account (i.e. they're still there, the links just all broke here @ BL due to them now being under a bad url in your posts).


----------



## Dresden

I feel like drawing something cool.


----------



## Dresden

Ibuprofen is truly a wonder drug.


----------



## Pomzazed

wonder how? it eats my stomach lining


----------



## adder

yoyoman said:
			
		

> I was on some random chemical research site in the USA and they had 3-CF3-amphetamine for sale... what would happen?



I missed this post earlier and I guess 3-trifluoromethylamphetamine deserves a fair warning - it's norfenfluramine, an even more cardiotoxic metabolite of fenfluramine than the parent compound!


----------



## sekio

If ibuprofen eats your stomach, no diclofenac for you.


----------



## DotChem

Drug Design 101:
Chapter 1: STIMS
Take EPH here:
Now cut the bond between the C-alfa of the piperidinyl and the C-alfa of the Ph-CH-COOEt, merge the piperidinyl at the beta carbon with the C-alfa carbon of the PhCHCOOE to get a quaternary carbon..add a para substituted fluoro..you get this:
looks a little bit like arecoline skeloton
with extra Phenyl and saturated isnt it?

Now  this compound is the single most potent stim that gets as close as it gets to  cocaine..I mean almost carbon copy pharmacologically (same MAT inhibition ratios,  distribution profile, logP, polar surface area..etc except it is at least 50X  times more potent than cocaine (the 4-Bromo probably even more  100-200x??  way more potent and faster onset of action than MPH for sure.. Don't  ask me how do I know..research it and you let me know!! (disclaimer:  you can go to jail if you live in US or Canada because it is analog of  schedule substance!! )
Oh! one more thing: it lasts longer than Ck or MPH (the COOEt beeing now attached to a quaternary carbon is more metabolically stable toward esterases hydrolysis .. way more stable than EPH or ck possibly T1/2> 8-10 hours at least 6 I bet!


----------



## sekio

that compound is actually the meta- isomer of desmethylpethidine/meperidine/Demerol, it's an opioid i think?


----------



## LaGaFàNi

Been thinking about arylcyclohexylamines that could be potentially cool to mess around with. Most are NMDA centered (Ket-Like), some are more PCE like (the 4-HO-4'-Methyl-PCE I guess?) Which one do you guys think would be the most interesting and/or worthy of a synth? And what pharmacology profile they might have?


----------



## Solipsis

How about just 3-MeO-PCPy? Or is that boring :D

Making something ket-like and interesting structurally is even something of a challenge, let alone the real challenge: making something that acts on hyperpolarization channels a lot like K does so that you can get real anaesthetic qualities and some 'holing' going on.

Something PCE like should be much more doable.


----------



## LaGaFàNi

2-HO-2'-Oxo-PCPy sure is holing material, the 2-Meo-2'Oxo-PCPy should be even better at it! Also I was wondering about the 2'-Methyl groups, they might replicate (to some extent) the Oxo group when at the glutamate receptor, like the chloro group does with Ketamine.


----------



## DotChem

sekio said:


> that compound is actually the meta- isomer of desmethylpethidine/meperidine/Demerol, it's an opioid i think?


No actually this (and similarly substituted 3-phenylpiperidines with a secondary amine NH) have no opioid activity but are potent SNDRIs (IC50~2-5nM v Coacaine ~140nM.  But yeah. it looks like meperidine or more precisely nor-meperidine but substituted on the 3 position. While meperidine is an opioid, Nor-meperidine has NO opioid activity at all. 


> Norpethidine is a controlled drug because of its potential uses  in manufacturing both pethidine itself and a range of N-substituted  derivatives, but it has little opioid activity in its own right.  Instead, norpethidine acts as a stimulant...(norpethidine  wikipedia)


Also, moving the N from the 4 to the 3 position kills opioids activity in this series even with a tertiary amine like in meperidine. So theses are pretty much totally devoid of opiod..(would post ref SAR later
But on the other hand, nor-meperidine (and related 3-PP) are potent SNDRIs. Comparable to phenmetrazines which are 3-phenyl substitued piperidines also. More exactly morpholines! But unlike phenmetrazines (like 3FPM) which are DA/NE releasers, the Carbetoxy makes them very much MPHcokePVP-like with DAT current reversal...


----------



## malmet

I recently acquired a gram of the above molecule. MEPEA (no bromine at the 5-position) is slightly active at 300mg, so perhaps this compound is a little more interesting. Depends on how good bromine is at accepting a hydrogen bond (which is what the OMe group is doing here in mescaline when in docks with 5-HT2A, if I understand correctly). -SMe seems to work, as in 3-thioescaline, and bromine isn't far off from the methylthio group in steric bulk and polarizability...


----------



## Dresden

Bromine does not accept hydrogen bonding.  That only occurs on the FON--with fluorine, oxygen, and nitrogen.


----------



## LaGaFàNi

N-(4-Fluoro-Phenylpiperazine)-5-Meo-Tryptamine
5-Meo-PFPT

Quite straight forward if some ching wants to try it, just need 5-HTP, reduce it to N-cyanide, react it with 4FPP, then methylate 5-HO.


----------



## Dresden

^--Very interesting.

I know that 1-(3-chlorophenyl)-4-(2-phenylethyl)piperazine






has been reported in the literature to be a **ridiculously** potent DRI.  

Makes me think of 1-(3-chlorophenyl)-4-(2-(indol-3-yl)ethyl)piperazine


----------



## LaGaFàNi

Thanks, I appreciate.

Edit:  it might just be better than the foxy lady
Last edit: China should try to synth these N-(sub'd-phenylpiperazines)-4/5-sub'd-tryptamines instead of throwing out shite like u-48800. I'd love to try it out à la shulgin.


----------



## LaGaFàNi

If not already posted:


----------



## LaGaFàNi

4,13-BiDesmethyl-3,6-DiAcetyl-Morphine


----------



## LaGaFàNi

I guess it's equipotent to coca-mama; give them rhesus monkeys some new flashing material!

Please come up with some IUPAC tho, I wouldn't dare.


----------



## LaGaFàNi

Deleted for personal reasons


----------



## LaGaFàNi

Deleted for personal reasons.


----------



## noror

Metylenodioxycocaine......
Any thoughts?


----------



## LaGaFàNi

Come on guys I post some groundbreaking design of some never seen "family" of new stims and all I get is MDcoke reactions.


----------



## Bagseed

maybe it's because calling pyrrolidine piperidine and writing an enol as a stable structure doesn't give you much credibility chemistry wise?


----------



## LaGaFàNi

Still the design was quite promising; and I blame lack of sleep for the bad vocabulary.. and only one was a faulty one


----------



## Nagelfar

DotChem said:


> Drug Design 101:
> Chapter 1: STIMS
> Take EPH here:
> Now cut the bond between the C-alfa of the piperidinyl and the C-alfa of the Ph-CH-COOEt, merge the piperidinyl at the beta carbon with the C-alfa carbon of the PhCHCOOE to get a quaternary carbon..add a para substituted fluoro..you get this:
> looks a little bit like arecoline skeloton
> with extra Phenyl and saturated isnt it?
> 
> Now  this compound is the single most potent stim that gets as close as it gets to  cocaine..I mean almost carbon copy pharmacologically (same MAT inhibition ratios,  distribution profile, logP, polar surface area..etc except it is at least 50X  times more potent than cocaine (the 4-Bromo probably even more  100-200x??  way more potent and faster onset of action than MPH for sure.. Don't  ask me how do I know..research it and you let me know!! (disclaimer:  you can go to jail if you live in US or Canada because it is analog of  schedule substance!! )
> Oh! one more thing: it lasts longer than Ck or MPH (the COOEt beeing now attached to a quaternary carbon is more metabolically stable toward esterases hydrolysis .. way more stable than EPH or ck possibly T1/2> 8-10 hours at least 6 I bet!



DotChem, could you draw this? Demerol-like isomer? Did you edit out the image? I think I've probably drawn it in theory before


----------



## LaGaFàNi




----------



## DotChem

Nagelfar said:


> DotChem, could you draw this? Demerol-like  isomer? Did you edit out the image? I think I've probably drawn it in  theory before


EDIT
I removed the image bc the country i live in just blanket  ban any and all phenidates, their isomers, analogs and salts of isomers,  analogs of isomers, isomers of analogs, salts of isomers of analogs, analogs of salt of isomers, isomers of salts of analogs of isomers..blablablablabla a couple of days ago..so technically it is illegal  designing/suggesting anything that has ester, piperidine and phenyl in  it that may or may not have stim activity..(I'll edit this post later as  well.. DM me if you interested..

Here is really OLD paper on this


----------



## Nagelfar

^tropane demerol/loperamide intermediate, changed the HO on lope to aryl. since it is otherwise carbmethoxy


----------



## sekio

I wonder if endo-ethano-MPTP is toxic? Otherwise, maybe making the tropane-for-piperidine swap on demerol or MPPP would be a Good Plan.


----------



## sekio

> so technically it is illegal designing/suggesting anything that has ester, piperidine and phenyl in it that may or may not have stim activity..(I'll edit this post later as well.. DM me if you interested..


It's not illegal to draw or propose structures by the way. It's illegal to manufacture banned drugs, but banning the drug doesn't ban the literature discussion of it!


----------



## Solipsis

I don't think MAO-B can even handle tropane alkaloids?

What about inhibiting MAO-B with the 3-propynyl desmethyl analogue of peth / mppp? :>


----------



## sekio




----------



## Nagelfar

sekio said:


>


----------



## Pomzazed




----------



## sekio

Nagelfar said:


>



yeah well 
	

	
	
		
		

		
		
	


	




In b4 methylenedioxy analogs of this


----------



## Pomzazed

lol now that's look more and more like ligand for metal ions^

Edit: lowest energy conformation by MM-64 on above formentioned sekio's molucule with a metal ion
(I use a Cu2+ as representative for soft metal which likes N lone pair alot)


----------



## sekio

now thats interesting... put somethig radioactive in there and you have a radioimaging drug


----------



## Pomzazed

All the ligating sites are lone-pair of tertiary N, im not sure if large radioactive elements are too "soft"

What likes N are only like Co, Ni, Cu, Zn, Pd, Ag....

Others like Li, Na, K, Mg, Ca, Fe, etc doesnt like N so much, they are way too "hard"
While commonly radioactives like Th, U, Np or like are too "soft", they more like S or As or alike


----------



## noror

Drawing pictures of random molecules is indeed very important......But guys why do u drawa metylenodioxy ring on everything besides regular cocaine. I posted this earlier with no responses but I'm seriously wondering why noone ver did this( I even checked wikipedia page tropane anologues). Could someone with some experience speak up...pls?


----------



## Pomzazed

^ read the 1st post in this thread why methylenedioxy goes everywhere (and also my second post of MDbuckyball for answer


----------



## noror

Well I read them and it does not answear my question about why noone bother for mdcoke


----------



## Solipsis

http://www.bluelight.org/vb/threads/196430-Cocaine-like-analogues-of-MDMA-or-methylone

Apart from that, if it's just for silliness there is really no logic or rule to which compound has been drawn and which has not.

Where do you even want the MD?

Like this?


----------



## noror

Maybe? I guess as much opposite to the primary substitution as it gets. What would be the effects?
Does anyone consider this interesting?
Like imagine super short acting mdma with an unimaginable rush?
Mephedrone on steroids?
Does such assumptions make any sense?
I know that with chain extended cathinones adding the MD does not make much diffrence(alfa-pvp/mdpv) so how about coke?
Just posting ideas guys I'm an udergraduate atm.


----------



## Solipsis

First SAR rule of all: SAR does not carry over from one sort of drug to a relatively unrelated other drug. There is no reason why they would respond in the same way to a subtitution unless you know that they bind to a receptor in some same way spatially.
Remember the primitive lock and key analogy for drugs in receptors and realize which drugs actually act on which receptors and whether it actually makes sense to try and make a key that fits well in all.

Unfortunately even drugs that seem related in certain ways may turn out to bind upside down to a receptor compared to each other... this again would ruin any plans you might have had to make a hybrid that bridges the 'gap'. What you need is two drugs that behave similarly and even bind similarly, so that you can enhance that binding with a well-placed chemical group. There is often little tolerance for what sort of group must be or can be placed somewhere to make a drug better... ahh if it were only that easy right? No drug designers really put the art in 'the art of science' i guess... although that stuff *can* be simulated and calculated etc..

So hybridizing two drugs is really very rare and afaik only tends to happen sometimes with drugs that share *some* pharmacology and even then it is a tradeoff: you are basically making one type of drug worse at something by trying to turn it more into another one.
Think of breeding animals... you got your liger for example, but there are quickly limits you encounter trying to breed two types of animals that aren't that related like a parrot and a crocodile, and even if you could do that - it would be a lottery winner if it would then have a fighting chance in nature let alone if it can survive in the local environment where you want to keep it as a pet (you sadist bastard). Not too good an analogy [what about genetic engineering / modification for example?] well that is screwing with the chemistry at a another level.. with drugs you are already at that deepest level.

MDMA is not super related to cocaine, it's an empathogen and acts promiscuously on triple monoamines in various ways including as releaser while cocaine is a reuptake inhibitor with a preference for dopamine.

Since cocaine doesn't act as releaser that way, you can't really enhance that hypothetical activity to make it more MDMA-like, at least not simply that way...

There are 4'-subtituted analogues: https://en.wikipedia.org/wiki/List_of_cocaine_analogues#para-substituted_benzoylmethylecgonines
And looking at these my best guess would be that the above molecule may retain some activity as DRI although possibly not very good.. but who knows it is not enough info to really go on..

This looks more like a supercharged coke:
https://en.wikipedia.org/wiki/Salicylmethylecgonine

But hey it wouldn't be the first coke analogue that sounds amazing on paper but sucks ass according to people who try it - like worse than inactive the way I read it.

Talk to nagelfar, he has been posting cocaine analogues like a coke-fuelled message posting rabbit, but I don't know if he has relevant info on this topic. Just wait here for everyone else to chime in too though.

Also: if you check out the way cocaine docks into DAT for example, you can sort of check out what amino acid residues are around that para position, what might be a better way to hang on to the cocaine molecule, where there is tolerance for substitution etc.

I don't know how e.g. MDPV docks but apparently that part of the drug is not involved with critical parts of it binding and activation. If it doesn't really matter much, as you put it, then on the other hand you also don't have much potential to supercharge your molecule with a modification and 'put it on steroids'.


----------



## noror

Wow dude thanks! It's super interesting. If u don't mind may I ask what do u study/studied and does medicinal chemistry aims for that kinda stuff as disuscussed here? But that was off topic a little bit, I only wanted to add that cocaine(being a stimulant) does not primarily acts on dopamine. Instead it acts primarily on norepinehrine than dopamine than serotonin with a ratio of 7:4:3 where higher number means more affinity. Btw it's a feature that all drugs considered as stimulants/euphoric stimulants share like METH. Anyway thanks for ur answer, it's very elaborate.


----------



## Dresden

It might be great.  It might not be.  The only way anyone can know for sure is to make it and try it, which is dangerous (the trying it part), difficult (the synth part), and possibly illegal (?).


----------



## Solipsis

Ah right.. yes the affinity for NET is stronger.. the dopaminergic activity is thought to be relatively very important though, DAT is more studied and the profile in general for the monoamines / catecholamines determines the sort of effect. The balance is important, at least IMO, I don't like drugs that are quite norepinephrinergic...

I studied chemistry but dropped out, the way it looks now ADD played a serious role but no idea what it would have been like without that. Considering how I function now, I like to think that I could have finished it fine but who even cares. One of my best friends (even before college) did Drug Design... I still have his quite nice Medicinal Chem book.

I haven't been seriously active in any of these fields for quite some years though, there are guys here who instead are on the top of their game and they definitely should have the final word.

Coke is one of the drugs I dislike most apart from shunning ones entirely like deliriants.


----------



## DotChem

Cyclodrones: 

beta-keto arylcyclohexylamines (bk-ACHs) 

bk-PCP






Not what you may think: they have NO NMDAr activity (pretty much zero) !!.. but pure stims more like PVPs .. here is the MXE congener

bk-MXE: 




look like hexedrone with the hexyl cyclized .. or alfa-alfa disubstituted cathinones with the dimethyl cyclized via a Pr group


----------



## DotChem

sekio said:


> It's not illegal to draw or propose structures by the way. It's illegal to manufacture banned drugs, but banning the drug doesn't ban the literature discussion of it!



Isn't is called "aiding and abetting".. if you design, draw, suggest a synthesis route for a potentially illegal substances and somebody go ahead manufacture and distribute it and get busted in the process: you go to jail !


----------



## Solipsis

Two important things:
- Synthesis discussion is not allowed here and definitely not supporting a manufacturing scheme with such discussion.
- Who really is to say which compounds are _potentially_ illegal, that is quite difficult to prove in court IMO. Close analogues and the analogue law... then yes sure of course. But fuck the 'you could have known it would _become_ illegal' argument. It's already enough of a minefield. Nobody can guess what is going on in the minds of lawmakers and honestly I don't really want to. Let them pass laws and not suggest hypothetical ones you cannot even break hypothetically or help someone else break hypothetically.. 8(

Aiding and abetting applies to supporting perpetration of a crime. What's going on here is suggestion only of novel routes to follow - in terms of design only - but definitely not something like a map to perpetrate a crime entirely like successful and profitable synthesis of a compound entirely indicated as a scheduled substance. Let alone the international nature of the forum, of course we wouldn't explicitly endorse or support something clearly illegal somewhere but this is all a fresh and grey area and internationally speaking it will be even greyer. Grey... not crime.

Oh and actually another thing on top: if this would be aiding and abetting, where would one draw the line with legit research articles which also describe 'potentially' illegal substances or even fully illegal substances? All we're doing here is conducting intellectual discussions. I even hardly think it needs a disclaimer to say that when people abuse this information to break the law it's not our fault. Nothing at all says that this forum or thread is set up for that exact purpose, unsurprisingly because that is not what it is set up for.

in my honest post. 

(if someone were to chime in and say: I want to make compound X or Y from this thread, can you please instruct me in detail how to do that exactly... then it would quickly become a whole different matter.)


----------



## sekio

> if you design, draw, suggest a synthesis route for a potentially illegal substances and somebody go ahead manufacture and distribute it and get busted in the process: you go to jail !



Where I'm from, you can publish all the synthesis information you want, you just can't actually do the synthesis without the correct paperwork. If someone wants to break the law by manufacturing drugs without a permit to do so, the blame for doing so falls squarely on _them_. Neither whomever published the synthesis, nor the person who sold the clandestine chemist his glassware, nor the landlord who leased the building, nor the company who made the chemist's lab coat are responsible in the slightest... it's the person or persons using the flasks and chemicals to make the drugs that are breaking the law. It's because the chemists who do the synthesis are usually government-associated or audited by the gov't and have special licenses to work with controlled substances and precursors legally. Or, you can always do the chemistry and publish whatever you want if you find a new, as-yet-unbanned drug or class of drugs... almost every illegal drug is banned well after they have been made and distributed for a few years, rather than immediately at the time of discovery. There was actually a period in time that fentanyl analogs were not explicitly illegal...

If publishing drug synthesis could lead to legal liability you'd see a whole bunch of ex-pharma chemists in jail (from everywhere... Allan & Hanburys, Parke-Davis, Pfizer, National Institutes of Health/NIH, etc), John Huffman (inventor of JWH-xxx series cannabinoids), Albert Hoffman, the Shulgins, etc. I mean, half of the new "research chemical" drugs are cribbed from the patent literature, usually with a whole synthesis right there on the same page...  so there's a pretty strong case to say that _even if you're actually doing illegal chemistry with no regard for the law_, you can publish whatever you'd like. If you're doing bad things you'll end up arrested. There's no law against incriminating yourself. ...


----------



## DotChem

You're absolutely right: the law applies to the "manufacture, selling,  possession, possession with intent to sell or consume the controlled  substances and/or its salts, analogs, isomers thereof (in countries  where there is analog laws).  It applies only to the person(s) actually  making, consuming or trading (not conceiving!).  Kind of reassuring.. It  would have been one heck of a Police State to lock people up for  imagining and drawing a molecule.  The reason I edited a post I made earlier on  possible MPHs that I was musing about was that I was kind of concerned  about designing or discussing in particular phenidates and/or analogs.  Because lately for some reasons this particular class has come under the  target of law: 2-3 days ago, UK just banned Ethyl Phenidate (following  the methyl, isopropyl,..etc), Canada did the same with half a dozen  phenidates 3 weeks ago, US feds are in the process of passing new  synthetics law in a month or so...So I suppose better get away from this  class.. actually I wonder why phenidates: could the pharma makers of  Ritalin loosing market shares to the RC competition?!?.. who knows?
^^ re: synthesis route: I am talking in general not necessarily on BL.. of course talk abt synthetic methods is off limits even tho instinctively the first thing that come to my mind when I see a random molecules drawn is: "geez, 4 chiral centers, how da heck you make that!??"


----------



## Blue_Phlame

I like reading about this kind of discussion, kinda makes me want to earn an advanced degree in organic chemistry, and feel like a wizard making potions.
 Makes me want to go back into a lab.


----------



## Solipsis

Usually with chiral centers they use left vs right hands to explain things, with 4 chiral centers you would need a human centipede to explain... which, fun fact, is why the mad doctor in the movie (you know, the 'eat shit and die' one) wanted to make em.

Some reactions involve an intermediate step where basically one of the 4 substitutions of a chiral center leaves and is replaced by another (sometimes in one fell swoop, depending). This can scramble your chirality when that intermediate loses its chirality if the leaving group leaves in a separate step and when there is just no preference for the new group to bind from the back or the front. So I think you need the type of reaction where the new group comes from one side, for various possible reasons.

The planning strategy is also amazing (well in general for more or less complex molecules IMO) and I guess like solving a Rubik's cube: by protecting and deprotecting reactive groups - preferably making groups not reactive anymore as in the end-product asap when possible - and looking ahead all the way to the end and each step making sense because they anticipate the other steps.

Not sure if that's quite right, posted cause curious to see if it is. I definitely didn't advance to synthesis of 4 chiral center type compounds, and it seems unlikely that a lab would bother to make it unless economically viable or worth it for some particularly reason. If potent enough one could imagine that they would not bother to make it entirely enantiomerically pure but only narrow it down a bit if that saves so many resources that it is still plenty efficient.


----------



## Dresden

Enantiomers are difficult to separate, but as the number of chiral centers per molecule increases (for example, diastereomers), the widely differing physical properties of the resultant mixture's molecules usually make them a snap to separate out.


----------



## sekio

Enantiomers aren't actually that difficult to separate, nature has given us all sorts of high-e.e. chiral compounds we can use to make separation media and do derivatizations with to produce disastereomers. (e.g. react a DL-alcohol with L-(O-acetyl)lactyl chloride to make (D,L) and (L,L) pairs which have differing physical properties... or use sparteine to sep. chiral carboxylates, or camphorsulphonic acid to do amines, etc)

And we also have enzymatic reactions that can produce compounds in high yield and ee, if you know where to look to get the right enzymes....


----------



## Dresden

Difficult is a relative term in chemistry especially.


----------



## Nagelfar

Solipsis said:


>



noror, the reason is, the 3-benzoyloxy (of cocaine) already gives it more 5-HTT affinity than, say the 3-phenyl (troparil), perhaps a phenyltropane with the methylenedioxy, but there seems to be an issue with binding a ring with oxygen, the napthyl seems to have good affinity. Also, releasers (substrates) like MDMA, and uptake inhibitors like cocaine, MPH, PTs, are different in the mechanism of action.


----------



## Nagelfar

Just a thought.


----------



## adder

Diastereomers can often be separated by such simple means as column chromatography on unmodified silica gel. As for the separation of enantiomers via derivatization with a chiral auxiliary - this leads either to preferential formation of one diastereomer or mixture of diastereomers with different physical properties and thus can be resolved using extraction, crystallization, chromatography etc. (an example being separation of amphetamine enantiomers with D- or L-tartaric acid by the formation of a diastereomeric salt). But derivatization with chiral auxiliaries don't always work for all compounds, so we have asymmetric synthesis and many methods thereof. Chiral pool synthesis is a method based on the use of enantiopure substrates that will react in a stereospecific manner, but this can be very expensive. Chiral auxiliaries can be also incorporated temporarily into the structure to differentiate between faces of double bonds in a chemical reaction (e.g. Evans' oxazolidinones are a great example of this and their use revolutionized stereoselective aldol reactions) or two alkyl groups or two protons of a methylene unit. Chiral auxiliaries can be recovered after their job is done, but their use requires those additional steps of incorporating them into your compound and then getting them off. So far the most optimal approach in my opinion is the use of chiral ligands binding to metal atoms in organometallics which impact the stereochemical outcome of a reaction but other than that are essentially spectator ligands, a great example of this is stereoselective catalytic hydrogenation of double bonds in alkenes, ketones, and imines, again a reaction that changed a lot in organic chemistry and pharmaceutical industry (look up the synthesis of L-DOPA). The goal of any organic reaction developed is to end up useful for the industry which deals with bulk quantities of chemicals and then it is more practical to obtain your chiral compound in asymmetric synthesis rather to have to separate isomers at a late stage during multi-step synthesis.


----------



## Pomzazed

Sorry, synthesis discussion is not allowed here.
Btw, what will happen when you mix those is a crap with mixed composition (aka organic lab junk crude)

You have 2 phase of rxn there, one nonpolar consisting of thinner n gasoline, with iodine preferentially dissolve in that phase
one aqueous with pyridinium carboxylic acid (salt from nicotinic pyridine position and HCl
Dropping in P4 in that the intermediate PI3 would suddenly react with water to HI,
Which should does...nothing on 2-carboxypyridinium chloride you have in aq phase.


For the first reaction in the quote, younwont form oxime just be "mixing" them only and do nothing else (eg removal of water or like). Ahem, but lets assume you already have the oxime, the condition of working up you provide will break (hydrolyse) it apart back to starting material (liquid) so you wont retain a thing on your filter paper.


Btw, synthesis does not work like "just put this in and put that in, mix, shake, filter", that would give weird junk product. aka. "Street Drug cooking", which is a very different thing than real org. Syn.

Lets say crocodyl then, they put random crap in and get a crude product with some psychoactive compd in that, but then whats inside? At least 50+ random toxic craps like iodinated pdts, leftover phosphorus cmpd, which gives ppl crocodyl syndrome (...flesh rotten and limb falling off) 

That is very different than "desomorphine" which is properly made, characterize ans tested!


Other comparative example is like when you want to make a cake, instead you put whole egg with eggshell in (bcos it has egg content), then throw raw rice grain in(bcos it has starch) dump sugarcane(bcos of sucrose and glucose, why not.) etc, then put in a blender(mix) and throw these mixture directly to open flame(need heat to cook).... and wishing you will get the nicely baked cake.... 

That's imposiburu... but its the same kind of logic how "drug cooker" and "organic chemist" works differently.

Im not posting to discourage you, instead I just want to say that if ink you have an idea and interest in these thing, first gonna study the basic how-to in chemistry (gen chem plus org chem would somewhat suffice) and you then can satisfy yourself  and start having idea of creation of novel stuffs.

Like, you learn basic food cooking on how to prepare ingredient, how to fry, how to boil, how to bake, etc first, then your imagination of making new food menu can kick in with high possibility.

Not... cooking just need ingredient and heat, so lets mix random food ingredient and throw them to open flame! (And get a burnt charcoal as result)


----------



## Solipsis

We clearly need 'instant meals' but you'd probably get F'ed by the DA marketing that..


----------



## Kenn Bish

Pomzazed said:


> Sorry, synthesis discussion is not allowed here.
> Btw, what will happen when you mix those is a crap with mixed composition (aka organic lab junk crude)
> 
> You have 2 phase of rxn there, one nonpolar consisting of thinner n gasoline, with iodine preferentially dissolve in that phase
> one aqueous with pyridinium carboxylic acid (salt from nicotinic pyridine position and HCl
> Dropping in P4 in that the intermediate PI3 would suddenly react with water to HI,
> Which should does...nothing on 2-carboxypyridinium chloride you have in aq phase.
> 
> 
> For the first reaction in the quote, younwont form oxime just be "mixing" them only and do nothing else (eg removal of water or like). Ahem, but lets assume you already have the oxime, the condition of working up you provide will break (hydrolyse) it apart back to starting material (liquid) so you wont retain a thing on your filter paper.
> 
> 
> Btw, synthesis does not work like "just put this in and put that in, mix, shake, filter", that would give weird junk product. aka. "Street Drug cooking", which is a very different thing than real org. Syn.
> 
> Lets say crocodyl then, they put random crap in and get a crude product with some psychoactive compd in that, but then whats inside? At least 50+ random toxic craps like iodinated pdts, leftover phosphorus cmpd, which gives ppl crocodyl syndrome (...flesh rotten and limb falling off)
> 
> That is very different than "desomorphine" which is properly made, characterize ans tested!
> 
> 
> Other comparative example is like when you want to make a cake, instead you put whole egg with eggshell in (bcos it has egg content), then throw raw rice grain in(bcos it has starch) dump sugarcane(bcos of sucrose and glucose, why not.) etc, then put in a blender(mix) and throw these mixture directly to open flame(need heat to cook).... and wishing you will get the nicely baked cake....
> 
> That's imposiburu... but its the same kind of logic how "drug cooker" and "organic chemist" works differently.
> 
> Im not posting to discourage you, instead I just want to say that if ink you have an idea and interest in these thing, first gonna study the basic how-to in chemistry (gen chem plus org chem would somewhat suffice) and you then can satisfy yourself  and start having idea of creation of novel stuffs.
> 
> Like, you learn basic food cooking on how to prepare ingredient, how to fry, how to boil, how to bake, etc first, then your imagination of making new food menu can kick in with high possibility.
> 
> Not... cooking just need ingredient and heat, so lets mix random food ingredient and throw them to open flame! (And get a burnt charcoal as result)


Does carboxypyridinium chloride produce pyschotactive properties? what would happen if a 3 cyclohexane carboxaldhyde  was added?


----------



## Kenn Bish

Is there a way to make is pyschotsymatic


----------



## DotChem

"The Light"...


----------



## Bagseed

DiBT... I wonder how active that would be... as shulgin said, "butyl is futile"... but maybe the more compact form of isobutyl would fit the receptor better than n-butyl...


----------



## malmet

Inspired by selegiline and tranylcypromine.






Conformationally restricted DiPT...






...and something a bit different.


----------



## Solipsis

I think DPT is called 'the light' already? Otherwise I have some editing to do of the DPT thread title in PD iirc.. 

DiPT already has such low potency and DALT is not suggesting either that there is much beyond them. Perhaps 5-HT1A is more tolerant to these effects but it seems to make more of a stimulating spiritual experience rather than psychedelic if you'd make the 5-MeO of this.

Isobutyl may be more 'compact' but it is also more bulky in a fat and inflexible way rather than slim way while n-alkyls can at least try to fold into a pocket. So I think the butyl idea applies to basically all of them and I think he has more homology rules of thumb...
Not sure what would be up with the di-tert-butyl though, that seems hard to make? It should be possible but quite hard since it's so crowdy...

The methyl propargyl is a nice idea... two doesn't work because of interaction between the pargies.

I am already horrified by the PTC drugs china made so please no tranylcypromine stuff, lol  The latter two aziridines have been proposed before in this thread. Just saying because if you search well you could find some talk about it 

@Kenn Bish:
- Again: nothing focused heavily on synthy stuff, use this thread correctly or not at all plz.
- Some of it like the 'psychosomatic' part doesn't even make sense. I guess you meant psychoactive.
- No reason why analogues of benzoic acid would be psychoactive, at best I think an idea could be the pyridine analogue of acetylsalicylic acid: aspirin.
- We draw pictures of random molecules, not see what we can make... anyway you would first have quite a long time of learning chemistry before touching any synthy stuff, we do help with chemistry understanding but not by helping with your irl 'projects'. The things you ask about: that's not how that works, and guessing isn't the way to go anyway. As was already said regarding the crocodil: stuff like that just makes toxic gunk and has nothing to do with properly making something.
This is a harm reduction forum, we're not here to support someone improvising on already questionable one-pot meth synths.
- While we're not gonna help with the synth, a tip is: first plan your synthesis from beginning to end and separate it in steps, with intermediates. Understand how every one of those steps work, what it's called and what it would require.
- I guess people will help if you ask more generally about the psychoactivity of certain analogues if you leave out the synthesis stuff like about the iodine and phosphorus.


----------



## Kenn Bish

Solipsis said:


> I think DPT is called 'the light' already? Otherwise I have some editing to do of the DPT thread title in PD iirc..
> 
> DiPT already has such low potency and DALT is not suggesting either that there is much beyond them. Perhaps 5-HT1A is more tolerant to these effects but it seems to make more of a stimulating spiritual experience rather than psychedelic if you'd make the 5-MeO of this.
> 
> Isobutyl may be more 'compact' but it is also more bulky in a fat and inflexible way rather than slim way while n-alkyls can at least try to fold into a pocket. So I think the butyl idea applies to basically all of them and I think he has more homology rules of thumb...
> Not sure what would be up with the di-tert-butyl though, that seems hard to make? It should be possible but quite hard since it's so crowdy...
> 
> The methyl propargyl is a nice idea... two doesn't work because of interaction between the pargies.
> 
> I am already horrified by the PTC drugs china made so please no tranylcypromine stuff, lol  The latter two aziridines have been proposed before in this thread. Just saying because if you search well you could find some talk about it
> 
> @Kenn Bish:
> - Again: nothing focused heavily on synthy stuff, use this thread correctly or not at all plz.
> - Some of it like the 'psychosomatic' part doesn't even make sense. I guess you meant psychoactive.
> - No reason why analogues of benzoic acid would be psychoactive, at best I think an idea could be the pyridine analogue of acetylsalicylic acid: aspirin.
> - We draw pictures of random molecules, not see what we can make... anyway you would first have quite a long time of learning chemistry before touching any synthy stuff, we do help with chemistry understanding but not by helping with your irl 'projects'. The things you ask about: that's not how that works, and guessing isn't the way to go anyway. As was already said regarding the crocodil: stuff like that just makes toxic gunk and has nothing to do with properly making something.
> This is a harm reduction forum, we're not here to support someone improvising on already questionable one-pot meth synths.
> - While we're not gonna help with the synth, a tip is: first plan your synthesis from beginning to end and separate it in steps, with intermediates. Understand how every one of those steps work, what it's called and what it would require.
> - I guess people will help if you ask more generally about the psychoactivity of certain analogues if you leave out the synthesis stuff like about the iodine and phosphorus.


I deleted the posts so I was hoping that would help so is it pyschoative in any way having a piperdine ring? Or a pyridine ring considering pcp has a piperdine ring and nicotine does have a pyridine ring? Or does it work completely different


----------



## Solipsis

That's also fine 

Not sure if I recall a piperidine compound in your earlier posts but it doesn't really matter:

These rings are just building blocks of molecules - you call them groups or moieties - on their own they don't really imply psychoactivity or other activities (there may be exceptions, like the metabolism can depend on those building blocks but never mind those)... so no, it doesn't work like that ^.

The activity is mainly a product of the exact shape of the *total* molecule and the electronic properties of each of the moieties. To interact with for example receptors in the brain they sort of lock on as a key in a lock (binding). 

Modifying one group (by adding it etc) can have consequences for how the entire molecule binds, whether it changes a lot or not depends on how well it matches the shape and properties of the receptor, plus some subtle things which determine whether the binding even has an activating effect on the receptor.

The methylenedioxy addition to a molecule like the fun on the first page of this thread is misleading: it's meant to partially be ironic / a joke. For particular drugs, adding a methylenedioxy is meaningful and appropriate - mainly empathogen or stimulant phenethylamines... adding it to random other drugs or molecules is just taking it way too far as ridicule, so don't take that seriously.
Some molecules posted here are jokes for some reason or another while others are more serious ideas / suggestions which could actually be psychoactive in interesting ways. 

There are countless compounds which are not psychoactive that have piperidine or pyridine rings so call that insignificant / coincidental.

Changing say the phenyl ring of amphetamine / meth to a pyridine ring is not generally a bad idea though. There are what are called bioisosteres: you can replace some moieties / groups by particular others which resemble them so much that the biological activity is more or less similar. It depends on various factors whether that idea then actually works or not, but it's one valid approach to modifying drugs.

Another approach is borrowing ideas from one drug in a particular class and applying it to another in the same class in a smart way. To do this though you have to understand which significant structures are shared and that they actually bind in similar ways spatially.


----------



## Kenn Bish

Solipsis said:


> That's also fine
> 
> Not sure if I recall a piperidine compound in your earlier posts but it doesn't really matter:
> 
> These rings are just building blocks of molecules - you call them groups or moieties - on their own they don't really imply psychoactivity or other activities (there may be exceptions, like the metabolism can depend on those building blocks but never mind those)... so no, it doesn't work like that ^.
> 
> The activity is mainly a product of the exact shape of the *total* molecule and the electronic properties of each of the moieties. To interact with for example receptors in the brain they sort of lock on as a key in a lock (binding).
> 
> Modifying one group (by adding it etc) can have consequences for how the entire molecule binds, whether it changes a lot or not depends on how well it matches the shape and properties of the receptor, plus some subtle things which determine whether the binding even has an activating effect on the receptor.
> 
> The methylenedioxy addition to a molecule like the fun on the first page of this thread is misleading: it's meant to partially be ironic / a joke. For particular drugs, adding a methylenedioxy is meaningful and appropriate - mainly empathogen or stimulant phenethylamines... adding it to random other drugs or molecules is just taking it way too far as ridicule, so don't take that seriously.
> Some molecules posted here are jokes for some reason or another while others are more serious ideas / suggestions which could actually be psychoactive in interesting ways.
> 
> There are countless compounds which are not psychoactive that have piperidine or pyridine rings so call that insignificant / coincidental.
> 
> Changing say the phenyl ring of amphetamine / meth to a pyridine ring is not generally a bad idea though. There are what are called bioisosteres: you can replace some moieties / groups by particular others which resemble them so much that the biological activity is more or less similar. It depends on various factors whether that idea then actually works or not, but it's one valid approach to modifying drugs.
> 
> Another approach is borrowing ideas from one drug in a particular class and applying it to another in the same class in a smart way. To do this though you have to understand which significant structures are shared and that they actually bind in similar ways spatially.


Huh very facinating I'm assuming that there is no effect or drug high associated with carboxypyridinium chloride but is metabolized to aspirin? That's what I've collected is this a new Chem or been done before? Thanks for all your help!


----------



## Nagelfar

Solipsis said:


> We clearly need 'instant meals' but you'd probably get F'ed by the DA marketing that..



My DA also markets me confirmation-bias psychotic-delusions, but usually only when I flood my nucleus accumbens with it. ;- P and don't get me started on district attorneys.


----------



## sekio

"carboxypyridiniumj chloride" is ill-defined, there are 4 possible isomers, all are likely to be unstable (lose HCl to the free pyridine) ... and 3-carboxypyridine is actually nicotinic acid. That's a B-vitamin, precursor to niacin. Not generally considered to be psychoactive.


----------



## DotChem

Bagseed said:


> DiBT... I wonder how active that would be... as  shulgin said, "butyl is futile"... but maybe the more compact form of  isobutyl would fit the receptor better than n-butyl...


..the 4-OH-di-nButyl is  pretty much dead as per Sasha unlike the di-(iso)Propyl .. but who knows how the di-isoButyl will behave? the SAR of  psycheldelics is kind of tricky both PIHKAL and TIHKAL (doesn't make lots  of sense! at least at first glance ): you go from more  potent to less potent: Me>Et>Pr, iPr>Bu etc both with  Tryptamine and PEAs.. but then back up  to incredibly more potent than anything with even bulkier  Methoxybenzyl>Bromobenzyl>Benzyl>...etc (mono-substituted!)  like with the NBOMe  series.  With a secondary NH .. Not sure about the  N,N-dibenzyl (Nichols might have try them for sure since that would  seems  the logical SAR ..monalkyl --> dialkyl -> substituted-benzyl -->di-benzyl..etc etc
Here  is a lecture by Pr Nichols on youtube explaining the rather interesting  SAR of 5HT2a agonits psychedlics (starting  @ ~19:00 (a bit old 3 years  ago.. but worth watching!!.. 







Solipsis said:


> I think DPT is called 'the light' already?  Otherwise I have some editing to do of the DPT thread title in PD iirc..


No don't edit.. DPT is nicknamed "The Light". I should've use  different nickname.. The idea was to increase metabolic stability of DPT (therefore the experience of "The Light")  by branching the propyl but  obviously it may kill the 5HT2a activity altogether..


----------



## Pomzazed

sekio said:


> "carboxypyridiniumj chloride" is ill-defined, there are 4 possible isomers,....



This quote refers to what I replied to his original message (which was removed) talking about mixing niacin and HCl and other thing else, so I replied that to him, as it does nothing but only forms a salt.


----------



## JK25

My grandmother drew a picture of a penis once on a storm drain.


----------



## WSH

(C60-Ih)[5,6]fullerene, a doping drug for soccer players


----------



## serotoninsoldier

4‐(5‐fluoro‐2‐methoxy‐2,3‐dihydro‐1H‐inden‐1‐yl)‐6‐
methyl‐6,11‐
diazatetracyclo[7.6.1.02,7.012,16]hexadeca‐
1(16),2,9,12,14‐pentaene







so i generated some fragments for lsd from the 5tvn pdb, then i grew that fragment until i reached this and the simulation said it had about the same affinity for 5ht2b as lsd. but idk it looks pretty bulky lol.

this one is prob better


----------



## Solipsis

Hi welcome 

The diethylamide moiety plays a key role and causes exceptionally slow dissociation from 5-HT2A and 5-HT2B, so affinity is not the only thing...

Please design a selective 5-HT2A agonist haha :D - well not like NBOMe shit but selective to somehow skip 5-HT2B but not 2A... [although LSD may not be an agonist per se at 2A but a mixed agonist/antagonist there due to it's weird sticky behavior].

I guess this one is no good, probably better the oxazolidine or to constrain the oxygen onto the ergoline skeleton rather than the precious diethylamide ;D :






(8β)-6-Methyl-8-(N-ethyl-4-methyl-4-oxazolin-2-yl)-9,10-didehydroergoline

What did you simulate with?


----------



## aced126

Solipsis said:


> *The diethylamide moiety plays a key role and causes exceptionally slow dissociation from 5-HT2A and 5-HT2B, so affinity is not the only thing...*



Source for this?


----------



## Solipsis

here, I'll google it for ya 

http://www.cell.com/fulltext/S0092-8674(16)31749-4

Explains why this moiety is particularly intolerant to modification: the snagging effect / self-trapping would be delicate. Too big changes and you don't just get lower binding rates but also increased dissociation rates since the size of the group may prevent it from becoming trapped by it's own induced conformational change. My earlier wording was wrong though I think: both of those factors determine affinity?
However, I doubt that simulations can predict this trapping/snagging effect on dissociation rates so what I meant to say is affinity prediction from binding energies alone is probably not the only factor for SEsoldier


----------



## WSH

WSH said:


> (C60-Ih)[5,6]fullerene, a doping drug for soccer players



How long do you guys think it would take until the FIFA makes this compound illegal for doping soccer players?

I've heard that both Messi and Ronaldo take this!


----------



## Solipsis

Let me just revive this classic from page 1 real quick :D






Should roll...


----------



## Nagelfar

WSH said:


> (C60-Ih)[5,6]fullerene, a doping drug for soccer players



Nah, what's going to happen is that the Koreans (some Asian country, but I am guessing Korea, or Japan; very possibly a mainland China government Olympic "world-fair" type gimmick in near future) are going to create a nanobot foosball table; *and this is going to be the actual ball*

The game will be telecast through an electron microscope.


----------



## Dresden

N,N,N-tri-((indol-3-yl)ethyl)amine.


----------



## Nagelfar

Would this be a crystal salt when protonated, maybe one that sparkles? ;-j

But seriously, how would the conductive electromagnetic character of having gold metal atoms work in regard to something like a nitrogen carrying ligand substrate? Any literature to this effect? I know both chromium and rhenium work (one twice as well, one about a tenth as well, due to electro-static difference influencing their structure) on cocaine analogs. (Let's forget the multi-billion dollar/pound/euro/yuan per milligram price tag, for gold, anyway)


----------



## Solipsis

Nitrogen carrying somewhere randomly on the complex / molecule is one thing, the bond between gold and nitrogen seems like it would easily cleave the carbon-nitrogen bond and send the nitrogen off with the gold if you're not careful.

The carbon-gold complex: you need one or various coordination ligands to go with that gold... it won't do single carbon bond due to oxidation states i think. Amphetamine is way too intolerant to those kinds of modifications I think, you can't tag it so easily or if you would I think you'd rather go for the 2-position or something.

With chromium etc: that is definitely a different kind of coordination complex with cocaine - a pi-stacking one with the metal sandwiched in between some aromatic ligand, ferrocene-style... or at least pi-bound to cocaines phenyl ring on one side. So that is not normally bound to a phenyl ring but coordinated from the side because of the pi-electron cloud...

You could try something similar with chromium sort of transition metals, but I don't think gold tends to be bound that way ^ my guess is that it is just too big and the charge too spreaded or something, for that.

Just thinking out loud, i don't think i finished coordination chemistry iirc.


----------



## sekio

Yeah, the chromium/rhenium complexes are "half-sandwich" (_maybe "open faced sandwich"?_) compounds where the metal center "sits" on top of the phenyl ring, like an egg on toast. There's no direct sp3 bonding going on like the stuff Nagelfar depicted with the C-Au and N-Au bonding.

You might be able to make a complex from a gold(II) atom and a pair of 4-thioamphetamines minus the S-protons (deprotonated version of 4-SH-amphetamine, desmethyl-4-MTA) though.


----------



## Nagelfar

sekio said:


> You might be able to make a complex from a gold(II) atom and a pair of 4-thioamphetamines minus the S-protons (deprotonated version of 4-SH-amphetamine, desmethyl-4-MTA) though.



Would, being a pair, it function as a dimer and be virtually non-functional until metabolization, then?

below: W/O the OTf bracketing it all (have to learn to make that in chemicalize):






^Though, the inhibition binding of the MPH/cocaine reuptake site and the substrate site are probably sufficiently different, that's why Rhenium and not Chromium, should still fit, being bigger, if it still works properly, I'd like to see this tried.


----------



## JK25

nuke said:


> This is the official been-up-tweaking-for-two-days-and-though-a-methylenedioxy-ring-on-everything-would-make-a-better-drug thread.
> 
> Please put your pretty pictures in here and talk about them so that they do not clutter the rest of the forum.




Imagine how complex and big the molecular structure of only 1 entire human being must look like.  From head to toe.  I mean starting from the point of the first piece of the first part of the first piece of cell-membrane of the first cell on the longest hear to the last point of the last piece of cell-membrane of the last cell on the last toenail.


----------



## Nagelfar

Apparently trithiapentalene has a 'Pimentel–Rundle three-center' resonance model and a "10-π aromatic structure" similar to naphthalene. So seeing as the N-desmethyl, 2-acyl, 3-naphthyl is the most potent phenyltropane known, how would the above work?


----------



## DotChem

Pramipexotamine : D2R agonist + SDNRI Reuptake Inhibitor + SDNRA Releaser .. 





may be Amphetaxole; AMPH+Pramipexole  or Amphetazole : sounds more correct since technically it is an azole. I Wonder why Prami is called Pramipexole and not Pramipazole since it is a benzothiazole.  May be trade name by original makers for marketing purpose (sounds nicer!..


----------



## Dresden




----------



## Solipsis

https://en.wikipedia.org/wiki/3-Methylamphetamine



> 3-Methylamphetamine (3-MA; PAL-314) is a stimulant drug from the amphetamine family. It is self-administered by mice to a similar extent to 4-fluoroamphetamine and has comparable properties as a monoamine releaser,[1] although with a more balanced release of all three monoamines, as opposed to the more dopamine/noradrenaline selective fluoro analogues.[2]
> 
> 3-Methylamphetamine has been investigated for military and para-military use as a less-lethal psychochemical weapon.[3]



might be a bit too close to 4-methylamphetamine for my taste

I wonder how much 'psychochemical' weapons have ever been used?


----------



## Midnight Sun

get to it, china 
there's something for everyone in the nitazene class


----------



## Pomzazed

Change that fluorophenylmethyl group to fluorophenylketo, or alike for additional CB1 activities


----------



## Midnight Sun

Pomzazed said:


> Change that fluorophenylmethyl group to fluorophenylketo, or alike for additional CB1 activities



supposedly linking the two ring systems with a carboxyl only serves to increase opioid potency on these... although, was putative CB1 activity ever investigated at the time -- probably not... 

good eye -- the similarities between cannabinoid ligands and some opioids I have always found fascinating


----------



## Frigyeslayman

What does this make? It sounds like a pcp synthesis 

5.3g of Bleach (sodium hypochlorite) (chlorine) and acetic acid (lemon juice)  and salt None Iodized  this is cyclohexane Synthesis 

sodium carbonate is added with rapid stirring distilled

3.93g of potassium cyanide

8.17ml of piperine  is added after it is created into piperdine (black pepper works) then cooled on ice heated in microwave 

Magnesium turnings(irosply alcohol and wash containing magnesium sulfate) were added dried 30ml of (ether,gasoline,alcohol) and then bromozine-arisol (any type of fragrance)

Then toluene is added (or acetone) and sharpie ink /(calcium chloride)
add 10.3ml of anhydrous (baking soda) add 

several grams of ammonium chloride and sodium hydroxide is added (drain cleaner) ice again then dilute 3 times with hydrocloric acid cool in the freezer until it's dry then unfreeze into a liquid


----------



## Dresden

Lsd binds irreversibly to serotonin sites, causing them to buckle over the molecule, trapping it in.  The neurons must die and be replaced by an LSD naive receptor site, if that ever really happens, that is.  The conformation of the receptor after binding with LSD otherwise never occurs when plain ole 5-HT aka serotonin binds to it.  I wish had jotted down a source for this information, but I didn't.  All I know is that this comes from vnew research, during which the active binding site for LSD was mapped.  The two ethyls lie perfeftly on the top portion of the drug-receptor site.


----------



## Solipsis

Dresden said:


> The neurons must die and be replaced by an LSD naive receptor site,



Not the neuron dies fortunately, but the receptors do get internalized and metabolized (along with LSD) and recycled)... also this does not happen to every one of them, some LSD molecules do wiggle loose and get dissociated again from the receptor before internalization.


----------



## Dresden

O-Methyl Haoma Extract (from the plants ma huang or ephedra after chemical modification)

Note the similarity to Preludin (phenmetrazine).


----------



## Dresden

Of course, I don't expect anything to top this chemically derived haoma extract, better known as methamphetamine.






(S)-2-METHYLAMINO-1-PHENYLPROPANE.

Ahh, clean-burning propane...


----------



## Dresden

PSI-N-ETHYL-SHIVA






SHIVA

And finally, a good alternative to MDMA:






PCA (whose effects were 'well tolerated' according to one old study)






2C-SHIVA has already been synthed and tested.  It was found to be a stimulant but not a psychotomimetic.


----------



## aspiringdrugdesign

7-acetyl-mitragynine





7-AcO-Mitragynine

I don't know all that much about drug design nor pharmacology (yet, I really want to learn more) -- would either of these make a much more potent mitragynine analog? My logic was that being that acts on opioid receptors, something that causes opioids to be more potent (morphine -> heroin with diacetyls), it would also work for mitragynine? I chose the 7 position as a 7-HO-Mitragynine is more potent than regular mitragynine. 

Can someone explain why I'm correct/incorrect? I want to learn more about SARs and all that jazz.


----------



## Dresden

beta-chloro-methamphetamine

I realize aliphatic chloros are to be avoided, as they can N-chlorinate DNA, but some such as clindamycin are still prescribed, and let's face it, the typical user of a drug like this usually isn't the most health conscious.


----------



## aspiringdrugdesign

Also, "indolibut"? Lmao, I don't know if this would work at all -- would it?


----------



## aspiringdrugdesign

Sorry to double post, but has there ever been any thiophene or benzofuran analogs of LSD? If not, why?


----------



## Bagseed

might be pretty hard to synthesize.. lysergic acid after all is a compound you get from nature.


----------



## Pomzazed

Dresden said:


> beta-chloro-methamphetamine
> 
> I realize aliphatic chloros are to be avoided, as they can N-chlorinate DNA, but some such as clindamycin are still prescribed, and let's face it, the typical user of a drug like this usually isn't the most health conscious.



I still avoid this one, the tendency to form reactive aziridine is too strong. (leaving group at beta position to a nucleophile)
(This is even a topic of study in Org.chem: see here for brief idea - Wiki )
The formation is assisted by attacking of lone pair from beta-position to kick away the leaving group forming reactive three-membered ring.

This is the principal of design of mustard gas, both sulfur and nitrogen mustard; which is much more stronger alkylating agent than a normal "chloroalkane" should have


----------



## aspiringdrugdesign

Thought of these before giving a further look into this thread -- I saw someone propose the first one, which would be incredibly difficult to synthesize the diathiol -- or might not even be possible -- but what about the bottom two? Do you think those would be possible? An MDMA sulfur analog.


----------



## aspiringdrugdesign

Fluoro DragonFLY


----------



## LeviathanBaphomet

Ethoxetamine





Acetoxetamine


----------



## Dresden

PARVATI [2-amino-1-(3,4,5-trifluoropheny)-propane]


----------



## Dresden

3C-DMT


----------



## Bagseed

using that nomenclature, 3C-DMT would be a,n,n-trimethyltryptamine, which is already a thing..

is there any chance that your molecule would be active anyway?


----------



## Dresden

HOT n' BLACK


----------



## Dresden

Of course there's a chance 3C-DMT could be active.






STARBUCKS


----------



## aspiringdrugdesign

Does anyone have any insight on my mitragynine idea? I'm genuinely curious


----------



## Nagelfar

aspiringdrugdesign said:


> Does anyone have any insight on my mitragynine idea? I'm genuinely curious



OK, let me explain why your logic here is the same as the 'methylenedioxy on everything' fallacy:
---
Morphine skeleton substitution pattern and it's numbering system:




---





^Codeine, which is 3-methyl-morphine (morphine with a methyl-ether on the three position)

way less potent than morphine & needs to me liver de-methylated (heptatic first pass metabolized) to even become morphine. It is inactive (compared to morphine activity) because the methyl's specific location blocks the mu-opioid receptor binding site with its specific/particular molecular conformation.

---

Heterocodeine (6-methyl-morpine)






^This is a methyl on the 6 position of the morphine molecule. It doesn't block the binding site, and though it is still de-methylated by heptatic metabolism, it is six times more potent (or thereabout) than morphine because it is more structurally stable and less labile (the word "labile" can be thought of in terms of its anagram "liable" as in 'liable (to metabolize)', quicknesss with which it breaks down.
---
heroin is 3,-6-acetyl (di-acetyl, or acetylated in two separate beginning places, a split in the branches each having one acetyl; as different from bi-acetyled, acetylated twice along the same branch in some sequence), now it is 1 and a half times the potency of morphine because of logP from the acetyl, it is a prodrug, most prodrugs are *less* potent because it has to become the drug, the heroin branches immediately cleave to morphine (for the most part), omitting the 3 position, and getting 6-MAM, is even more potent still, but it is more work for not so much benefit to selectively acetylate just the six position when a good yield will also react with the three position that goes bye-bye anyway upon crossing the BBB.

Now the kratom active metabolites, how they fit the G-coupled protein receptor at mu, is different than the phenathrene morphanins.

This answer help?


----------



## aspiringdrugdesign

That was actually a really good read! So are SARs not really dependent on the receptor being binded to, only the structure class being modified? I really want to learn more about them or how to even understand changes in structure and their effects, but I'm unsure where to start.


----------



## Solipsis

Both: SAR is what makes a difference for a drug's binding to a receptor, sometimes this is generalized when a 'structure class' binds so comparably that SAR follows analogous tendencies. But you should try to not isolate one factor too much to focus on and hope or assume that the rest will stay the same. Things like lipophilicity and metabolic stability will always still be a factor and may surprise you by throwing your assumptions about a SAR pattern out of whack.
SAR is about biological activity which is not limited to pharmacodynamics [at the receptor].

Whether it is a good idea or not to take a structural modification like methylenedioxifying out of context really depends IMO: in doing so you may (intentionally or not) be taking a standard approach like creating an ester and it might actually not be such a bad idea..

The methylenedioxy has mythical status for the empathogen / stimulant PEA world but it otherwise not such a common structure so often it will be silly to attach it onto some very different drug somewhere.

Acetylating hydroxies on mitragynine may not really be useful for the lipophilicity reasons you'd acetylate opiates (actually not sure), but it might allow you to protect a group that is known to make the compounds unstable and the reason kratom extracts apparently don't have a long shelf-life (in the case of esterifying 7-hydroxy). So making the black tar heroin version of kratom alkaloids could actually be interesting? Even if inadvertently. However having to inject that seems like a terrible prospect so you would have to extract and purify to make a powder to make it snortable cause otherwise by taking it orally the acetoxy will be metabolized too much and your only benefit then may be the shelflife.

The logic that mitragynine is an opioid may be more irrelevant than dodgy/bad when the acetylation is aimed at things like shelf-life of isolates or the log P (and thus things like absorption, pharmacokinetics etc). IMO it is not comparable to 'put a methylenedioxy on everything' because that is aimed at the SAR more often focused on: the pharmacodynamics i.e. what happens at the receptor.

Esterifying is still not exactly universally applicable, but it is also not as case-dependent as whether a methylenedioxy has any business being on a molecule.

On an unrelated note, and nagelfar might love this:






Meteloidine, an alkaloid found not only in Datura/Brugmansia but I think also in Australian Erythroxylum species. AFAIK it is not known what alkaloids like these do.






This is 1-hydroxytropacocaine I thought is found in E. Novogranatense (which I am growing a couple seedlings of), though wiki claims it is found in E. Coca.


----------



## Kenn Bish

In the cumene process for acetone production it says propene.

is it propylene gycol or propane/butanone?


----------



## Pomzazed

It is really propene (propylene gas, for common name) ala H2C=CH-CH3

It is the second smallest alkene, after ethene (or so called ethylene) and is a gas at room temperature and pressure.

Didferent chemical from propylene glycol and propane or butanone...

Wiki "propene" and look for brief


----------



## Kenn Bish

Pomzazed said:


> It is really propene (propylene gas, for common name) ala H2C=CH-CH3
> 
> It is the second smallest alkene, after ethene (or so called ethylene) and is a gas at room temperature and pressure.
> 
> Didferent chemical from propylene glycol and propane or butanone...
> 
> Wiki "propene" and look for brief


See I read the articles all of them and they seemed to switch what they were talking about,but what is propylene gas?


----------



## Pomzazed

Yes, but you will need different condition. I assume this is not synthesis discussion because conditions to control for cumene process are for industrial plants and not easily achievable in unprepared lab.

The difference is that for propene, you use acid to protonate it making it the C3 carbocation
In case of isopropyl alcohol, acid also protonates the hydroxyl group, the dehydration to C3 carbocation.

After then the C3 carbocation reacts with benzene forming cumene, later steps are all the same.

What to control is the condition (say, temp and pressure), the toxicity of benzene, the {##^*%%}smell of cumene,
The explosive cumene hydroperoxide, the corrosive and toxic of phenol etc. 

I work in a professional org. synth wet lab, and never have an idea to "run" this process in my lab scale!


----------



## Bagseed

why would you synth acetone anyway? it is easily available.


----------



## Nagelfar

Solipsis said:


> On an unrelated note, and nagelfar might love this:



Absolutely, thank you, as you know I'm always looking for metabolites, bio-synth precursors and relatives, and synth analogues of the like compounds


----------



## Solipsis

Actually, here pure acetone is restricted for private persons due to its use in explosive making so it is not really an innocent topic nor is it a pointless synth for people involved with that in countries like these. Not accusing you but assuming that this is not the only time you have a synthy question try a less inappropriate forum for that? A hydroxide like sodium hydroxide is a base though not an acid.


----------



## Kenn Bish

Solipsis said:


> Actually, here pure acetone is restricted for private persons due to its use in explosive making so it is not really an innocent topic nor is it a pointless synth for people involved with that in countries like these. Not accusing you but assuming that this is not the only time you have a synthy question try a less inappropriate forum for that? A hydroxide like sodium hydroxide is a base though not an acid.


Thank you for informing me,and I know just through I'd ask anyway.


----------



## DotChem




----------



## JK25

DotChem said:


>





This is what is left of my brain.


----------



## Midnight Sun

a very simple kavain analogue:




a little more involved, but adopts a conformation more resembling barbiturates:


----------



## Nagelfar

Kenn Bish said:


> Is no one going to answer my question is there are way to make phenols fumes none corrosive and what is the procedure for C3 carbocation just want a answer cause my mind is still racing on these questions.



The C3 locant of what molecular/chemical structure? Depending on the QSAR, the process is *entirely* different. Each molecule is highly *relative* depending on the constituent parts, a C3 position is the numbered position for that *individual* structure counted around from a center point. (or am I mistaking the question, anyone back me up / refute me here?)


----------



## Dresden

N-methyl-N-ethyl-5-methoxytryptamine (from melatonin)


----------



## DotChem

^ without the Me?? straightforward synthesis by reduction of melatonin?? isnt it?


----------



## DotChem

3-Methoxy-4-aza-Phencyclidine .. aka 3MeO-4-Aza-PCP (aka PCPridine aka Azacyclidine ..


----------



## Midnight Sun

I don't know if it would work but I thought to break up/unconstrain the piperidine moiety of allylprodine (for safety's sake given the subpar QC standards in many clandestine labs) -- anyway, the end result vaguely resembles tapentadol.  I couldn't help but note how at least in two dimensions there is also an overlay with diarylethylamines (the most relevant to this being lefetamine) however I think in those particular cases the phenyl rings are oriented differently in 3D space

On that note there's also a passing resemblance to methadone:




Either of these two despite their differences more or less overlay allylprodine in 3 dimensions albeit in different ways so they probably are active to some extent.  *shrugs*


----------



## adder

> Can acetone be synthesized with hydrochloric acid isopropyl alcohol and benzene then neutralizing the phenol with sodium hydroxide?



No, acetone won't be obtained, nor will phenol form from these reagents. To obtain acetone from isopropanol you need an oxidant.


----------



## aspiringdrugdesign

Dopamine-NBOMe, Epinephrine-NBOMe

AFAIK, this has never been done before? I don't have too solid of an understanding how it would work, but would either?


----------



## WSH

aspiringdrugdesign said:


> Dopamine-NBOMe, Epinephrine-NBOMe
> 
> AFAIK, this has never been done before? I don't have too solid of an understanding how it would work, but would either?



What are you going for, 5-ht2a or their usual receptors like D2 and alpha-adreno?


----------



## aspiringdrugdesign

Could it have affinity for both? Or do the SARs not work in that manner? Doesn't 25I have strong affinity for both serotonin and dopamine? I have a very limited knowledge of all this stuff though.


----------



## WSH

aspiringdrugdesign said:


> Could it have affinity for both?



Yes, they have the hydroxys in the right places and are also at least secondary amines, so they might also hit their "usual" receptors.

---

I wonder if something piperidine-like could work at 5-ht2a:






Or more nbome-like:







The distance from the nitrogen to the benzene ring should be in the ballpark of ~5 angstroms* which is the basic pharmacophore for pretty much *all* 5-ht receptors (unsurprisingly, since the unselective 5-ht receptor agonist serotonin has the same basic pharmacophore, with an additional 5-hydroxy and the Pyrrole, which *both* have the effects of primarily increasing the intrinsic activity at 5-ht2a and secondarily also increasing the affinity).

But I actually don't think that a high intrinsic activity is necessary (look e.g. at LSD which has a rather *low *IA and it's still one of the best)

* compare e.g. to serotonin and escpecially the *conformationally restrained* LSD, which is *clearly showing* both the* optimal orientation* of the conformationally flexible aminoethyl side chain of serotonin and also the *optimal distance* between the *center * of the aromatic ring and the nitrogen atom, which is pretty much *exactly 5 angstroms*. Note that the aminoethyl side chain of serotonin is flexible enough to create distances of 5 up to *even more than 6 angstroms *, which shows the importance of a *conformationally restrained* molecule like LSD in showing that the* most efficient* pharmacophore has a distance of  pretty much *exactly 5 angstroms!*


----------



## aspiringdrugdesign

I'm only beginning to take organic chemistry this semester -- does the halogen (iodine in this case) affect the distance between the nitrogen and the benzene? 

Do you think that the dopa/epine-NBOMe molecules would be able to cross the BBB? And would they have psychoactive effects?

I'd really like to be able to learn more to better understand what you were just talking about with pharmacophores and conformational restraining, do you have any suggestions?

Sorry for all these questions haha, I really find all this stuff super interesting.


----------



## Bagseed

if you can buy 2-propanol, how on earth are you not able to get acetone? the oxidizing agents needed to oxidize isopropyl alcohol are certainly harder to get (toxic stuff like chromium compounds) than acetone itself which is a pretty standard solvent.

ps if your friend is "in organic chemistry", he should know this because this is something you learn in the first few lectures of any elementary OC class...

sounds to me like you wanna do some shady kitchen one pot drug synthesis without any chemistry knowledge and experience whatsoever. please don't get yourself or other people hurt or killed...


----------



## sekio

> also in the halform reaction is acetone produced as a byproduct of chlorination of the isopropyl alcohol



Hypochlorite may oxidise isopropanol to acetone but it sure won't be selective. The haloform reaction on isopropanol would actually lead to chloroform and sodium acetate.

The problem with synthetic methods to make acetone from isopropanol at home is that you almost certainly need compounds that are much harder to get than plain old acetone. You could use Jones reagent (chromic acid in water) but that requires conc. sulfuric acid and sodium or potassium dichromate (& distillation setup to purify the resulting pdt). Swern needs dry ice and DMSO/oxalyl chloride. Hypochlorite is not selective. Classical dehydrogenation catalysts all need vapor phase reactions. etc.

If you don't have time to learn these things on your own, why would you expect anyone to spoon feed you and hold your hand?


----------



## aspiringdrugdesign

Never seen or heard of any 25x beta ketone analogs, have they been tried before?

 Also, why aren't there really any analogs of cathinone or just any phenethylamine with different beta substituents?


----------



## Incunabula

aspiringdrugdesign said:


> Also, why aren't there really any analogs of cathinone or just any phenethylamine with different beta substituents?



Yuo mean like this....

https://en.wikipedia.org/wiki/BOD_(psychedelic)

https://en.wikipedia.org/wiki/Βk-2C-B

http://www.bluelight.org/vb/threads/776091-The-Small-amp-Handy-BOHB-(beta-hydroxy-2C-B)-thread


----------



## aspiringdrugdesign

Sorry, I poorly worded what I meant -- other than that beta-methoxy, there doesn't ever really seem to be anything besides ketones on the beta position. Is there any particular reason? I've seen a couple beta hydroxys, that beta methoxy, and that's about it beyond ketones.


----------



## DotChem

Ibogaine little brother -- DMT big brother 






Happy Summer ends !


----------



## Kenn Bish

also in the esterfication process of ethyl acatate would 5% acetic acid work and would hydrochloric acid work as a catylist?


----------



## aspiringdrugdesign

This isn't really a synthesis thread, is it? :/


----------



## Kenn Bish

aspiringdrugdesign said:


> This isn't really a synthesis thread, is it? :/


No it's not but these are just questions stuff like actual meth synths are not aloud.


----------



## Solipsis

Regardless, it's off-topic and not appropriate for this thread. 
I think this one would be a bit more suitable, if you try to keep questions in one post (edit, don't make new posts too much): http://www.bluelight.org/vb/threads...mistry-Pharmacology-Odds-N-Ends-Thread-Part-3
...But still barely depending on how synthy your questions are and how many questions you can fit in your "one-off". There is chemistry involved in this forum, plenty of it... but I've never known it to be the place to ask pure chemistry or synth questions one after another unless on-topic to some thread. Making acetone is hardly on-topic to anything... this is a drug harm reduction site. 
There are entirely other dedicated chemistry fora for pure chem or synthy stuff. The point is that normally such questions are ultimately relevant to drugs and how they work or are made, so it can easily arrive at synthesis discussion which is not allowed (some harmless parts are condoned only in certain context). If not, then typically people are recommended to follow more proper ways of education, for the sake of everyone.

It's not up to me though to what extent the questions are welcome or where but not in this thread please. thnx


----------



## aspiringdrugdesign

Zero basis on anything, is there anyway to speculate activity just from the molecule?


----------



## Solipsis

Maybe as a sort of hexylpropine / aminorex analogue with aromatic alpha substitution and cyclization (so conformational rigidity)?
2-DPMP / pipradrole / prolintane analogies are even more  remote but who knows it might fit the pharmacophore for DRI activity..
Is my guess


----------



## aspiringdrugdesign

That's super cool I drew something loosely related, I didn't have any particular thought process or intuition in drawing that!

I'm about a month into my first OChem course, is aromatic alpha substitution just a substitution of an aromatic ring on the alpha position? With conformational rigidity, would that be like axial/equatorial orientation?


_________________________________
The beta, alpha and N- substituents are just placeholders so I didn't have to make an amph, meth and cathinone version of each idea I had






4-nitrile-phenethylamine





4-nitroso-phenethylamine




4-sulfinyl-phenethylamine




3,4-sulfoxyl-phenethylamine (is that the correct nomenclature?)
Would that be active or is it too bulky do you guys think?




Xenethylamine? xenylethylamine/4-phenyl-phenethylamine

_________________________________










Cyclic variants of caffeine, would either of these have any activity do you guys think?
_________________________________________________________________________






MDMA analog of lorcaserin, a 5HT2C agonist with affinity for 5HT2A as well





Lorcaserin-NBOMe, unless I am misunderstanding, this would work, no?





Lorcaserin-NBOH (same manner of thinking behind the previous analog)





Lorcaserin-NBMD




Lorcaserin-NBF
__________________________________________________________
Didn't realize how many I just made lol, oops





PNU-181731-NBOMe (what a mouthful)




PNU-181731-NBOH




PNU-181731-NBMD




PNU-181731-NBF


----------



## aspiringdrugdesign

2CB-Lorcaserin hybrid, am I wrong in thinking that since they bind to the same receptors they should have similar patterns?





Have silicon derivatives ever been made of psychoactive drugs?


----------



## Solipsis

Lorcaserin is apparently a shit experience so I wouldn't really care to pursue it.. 

I am not sure what you mean by 'similar patterns', but for starters you would have to know exactly how they bind - in what spatial orientation. I have found differences in binding orientation between what appear to be very analogous drugs to be very surprising and that would totally ruin SAR assumptions and hybrids like you are talking about. But, if you do know that they bind in a certain analogous orientation I think hybrids can be fair ideas since the function of groups and their positions have an okay chance of matching.

We're talking hybrids of compounds with at least partially matching activity here. Making hybrids of drug molecules that aren't really in the same category very rarely works because the modifications aren't tolerated by either 'side' which gives you something in the middle which is accepted by none of the receptors. bk-2C-B is one of the rare exceptions and it takes advantage of the fact that within the realm of PEAs there is already an overlap of psychedelics and stimulants. It is another thing to try and find a completely new overlap!

Silicium no never heard of that. @ the MDMA idea: while silicium can bind strongly to oxygen, the methylenedioxy bridge there on the left is a really tricky thing. It is a sort of acetal which are normally unstable but here it is stabilized by conjugation and resonance with the adjacent aromatic ring. I think it has been shown to tolerate very little change like messing with the methylene function. What I am saying is: the silicium doesn't necessarily have to go exactly there in the molecule if you want to make a replacement... it could be a bad idea or there is the off chance that it turns out particularly great. Still: not sure if there is a reason to take such chances.

N-benzyl functions like NBOMe or NBOH can make for pretty selective 5-HT2A agonists when PEAs or very closely related compounds are fit with them, but that seems to be a sort of exception. Even fitting psychedelic tryptamines with them doesn't seem to work and many of those are 5-HT2A agonists too.
I think that means it doesn't bode well for trying to use it for other serotonin receptor subtypes since even for 2A it is so particular. Maybe though there is a way to make adjustments to try and find an analogy for tryptamines that *does* work. It would require investigating how they bind different spatially to the receptor so that you can try to model it. Possibly you can use a similar group meant to bind to the same part of the 2A site, but it may need to be bound differently to tryptamines than would be casually guesstimated, or it may take an extra spacer.


----------



## aspiringdrugdesign

Ooo, I was hoping for a reply 

I know SARs don't cross categories very well, but isn't Lorcaserin a phenethylamine that's been sort of cyclized? Or does just that small change throw off the SARs?

Ah, I forgot how hard it is to change the MD bridge, someone was telling me about that when I thought of a thio version for MDMA. Perhaps instead of going for the MD, you could change the molecule to have some silabenzene to look for some new change in activity. The reason to take such a chance is discovery  although my way of going about it probably isn't the best.

My thought process behind the N-benzyl functions for at least the lorcaserin was the phenethylamine backbone in it, although now I realize the SARs may not be applicable anymore. I know there is a rule for morphines or opioids, something about the spacing of the amine and a few other groups that need to be in specific spots for optimum activity -- is there anything like this for phenethylamines or tryptamines? Is there a good place to go or find a book where I can learn more about SARs, and receptor binding? I'm not too knowledgeable about all of that!


----------



## aspiringdrugdesign

Did someone say something about hybrids?


----------



## Soulfake

Some random molecules, some more and others less serious. Please make the Fencamfamine+Tilidine fusion in the middle and the cannabinoid left on the bottom!
If anyone can say/guess something about the molecules I´d be thankful for a comment  

edit: what about a fun-thread called "which of those molecules would you take if you were forced to choose one?" ?


----------



## Soulfake

Some more molecules, I´d be really interested in the Fentanyl and Phenibut analogues & the Isopropylmorphenate analogue of Isopropylphenidate (one of the best stimulants that was banned way too quickly :´/ )


----------



## aspiringdrugdesign

@Soulfake:

Would that thiophene in your phenibut analog be considered bioisosteric (proper term?) with benzene in the same position?


----------



## Solipsis

The one on the bottom right already exists, it is called nicomorphine.. just swap its pyridine rings with the thiophene of that phenibut analogue 

Yeah I don't know why those rings wouldn't be expected to behave more or less bioisosterically to phenyl rings, but there may be exceptions when there is really very little tolerance for the changes in bond angles and orientation. Here I don't think those aromatic functions actually play a very active role in the pharmacodynamics and more in absorption etc.

Morphenate is the anion of morphine, so you'd have to go with morphenidate or something :D

fun pics


----------



## aspiringdrugdesign

Are bioisosteric groups always bioisosteric? Or are they like SARs where it may change from drug category to drug category? Could a thiophene analog of phenibut, or phenethylamine be guaranteed to have some level of activity (possibly less due to worse binding) or does it not work that way?


----------



## Solipsis

By definition, one group cannot be the exact same as another. Bioisosteric groups have [very] similar size and polarity properties to another, but like I said earlier: there will be exceptions. It will vary between drug categories but also within a drug category on various factors.
It will probably become a problem when you try to swap a group that is very critical to receptor binding, one that has multiple interactions with residues on the binding site. Then the variations in size, orientation and polarity / electronegativity can be a problem... basically when the difference between the generally bioisosteric groups in one situation is exactly something the binding depends on. If you change that, you change exactly what is not tolerated.

I don't think I would ever really guarantee with SAR stuff, seems like bad practice. I think you can mostly talk about likelihood, and very likely activity would be when you swap a bioisosteric group like that and computational models show good binding to the same receptor plus the new group is expected to give the same or better bioavailability plus is not known to be really prone to degradation like in the stomach or by hepatic or other enzymes.


----------



## Soulfake

Solipsis said:


> Morphenate is the anion of morphine, so you'd have to go with morphenidate or something :D



I read about the Methylmorphenate in the Methylphenidate analogues article at Wikipedia https://en.wikipedia.org/wiki/List_of_methylphenidate_analogues

Did you mean morphinane? 

Some more random molecules, I feel that one of those Tilidine-Fencamfamine/-Phenmetrazine fusions could be a really good substance.
I wonder how that giant Phenibut-ring would be metabolized/hydrolized. The nicotinoyl-Gabapentin could be better absorbed/transported through the BBB similar to nicotinoyl-GABA (Picamilon)


----------



## Pomzazed

Wow those cyclic polyamide gabapentinoids!

Btw, those looks like some molecules that can break cell membrane to a pore, or some potent ion channel blockers


----------



## adder

Soulfake said:


> I read about the Methylmorphenate in the Methylphenidate analogues article at Wikipedia https://en.wikipedia.org/wiki/List_of_methylphenidate_analogues
> 
> Did you mean morphinane?
> (...)



Well, the fact that Wikipedia has something doesn't make it true. Most likely the name was made up by some RC vendor or an enthusiast got carried away while writing the article. Morphenate is the C3-O(-) anion of morphine.


----------



## DotChem

Sex aphrodisiacs:
(1-Benzofuranyl-2-keto-cyclohexyl)methylamine aka Benzo-FuKCamine (not Fuckamine, Fukcamine!).. inspired by BTCP


----------



## Midnight Sun

*beating a dead horse*

O I am so curious as to how the sulfur would interact with the binding site


----------



## Soulfake

adder said:


> Well, the fact that Wikipedia has something doesn't make it true. Most likely the name was made up by some RC vendor or an enthusiast got carried away while writing the article. Morphenate is the C3-O(-) anion of morphine.



Yeah of cause, I know you can write wrong stuff in Wikipedia and it will stay there as long as no moderator or other person corrects it. Maybe someone can correct the "Methylmorphenate" into another name that isn´t misleading/wrong (I would do it but I don´t know what the correct name derived from it´s chemical formula would be).



Pomzazed said:


> Wow those cyclic polyamide gabapentinoids!
> 
> Btw, those looks like some molecules that can break cell membrane to a pore, or some potent ion channel blockers




What do you mean with "break cell membrane to a pore"?

The gabapentinoids are ion (calcium) channel blockers so that would probably be the effect of this stuff too (if it would hydrolyze, if not I guess it would be too bulky to do anything at all. But I guess it isn´t that easy as you would probably see dimers/cyclics/esters etc. of illegal drugs sold as research chemicals at least in countries that don´t have any analogue laws)


And another few random chems


----------



## adder

Soulfake said:


> Yeah of cause, I know you can write wrong stuff in Wikipedia and it will stay there as long as no moderator or other person corrects it. Maybe someone can correct the "Methylmorphenate" into another name that isn´t misleading/wrong (I would do it but I don´t know what the correct name derived from it´s chemical formula would be).



The situation with this compound's name is more complicated than I thought. Typically compounds get non-systematic names at a later stage of research when their potential utility is more evident, before that they may have a codename (like PAL-287 for 1-(2-naphthyl)-2-aminopropane), but RC vendors run very rapid _testing_. Apart from the Wikipedia link to the Pubmed page on this "methylmorphenate", which by the way has no information on it aside from the structure and doesn't name it as "methylmorphenate", there is no information regarding its pharmacological properties in reviewed articles in scientific journals that could be accessed by a quick search using its systematic name. On the other hand Google search reveals quite a lot of results on "methylmorphenate", almost all linking to sites where the compound is marketed or discussed as an RC drug. There is one scientific paper though, very recent, on methylphenidate analogues as RC's and it includes "methylmorphenate". It looks like the compound may have been first synthesized and named by some RC vendor. At this point there is basically nothing we could do to change the name considering the already widespread use of it. Nonetheless, there is no chance that it could be confused with codeine (which could be called methyl morphenate although that would be a very weird name) as it's exclusively discussed with structurally related stimulants.

article access page link


----------



## Pomzazed

@soulfake,

See "Macrolide" type antibiotic for general mechanism idea I'm talking about, and how they kill bacterial cells.


----------



## DotChem

No-so-random molecules..New RCs: Benzothiocaine...
Now this molecule here:




is  as close as you would get to c0ciane in terms of pharmacological  profile (10-20x more potent!) without the sodium channel  blockade-cardiovascular effect (probably has longer half life since no  obvious "metabolic handle" to metabolize and get rid of it by the body.. maybe  6hours+..but who knows??) .. It doesnt look like any banned substances tho  (may be very very remotely pcp or similar arylcyclohexyl amines like  ketamine or maybe BTCP..but it has 0 NMDA dissos effects! zero!). Here is the  original paper that described it: edit: oh btw, unlike BTCP which is selective DRI but not NMDA antagonist this one is more balanced SNDRI
nb: why I am posting this? for the sake of harm reduction, at least it won't give you cardiac arrest since it is not cardiac sodium channel blocker afaik . don't ask me how I came up with the name Benzothiocaine, I made it up ..Google won't help you   :D


----------



## aspiringdrugdesign

thoughts?


----------



## Bagseed

cannabinoid?


----------



## cj187

These seem obvious but I can't find any information about them. They're probably active, but maybe too difficult to synthesize.


----------



## Volsam

cj187 said:


> These seem obvious but I can't find any information about them. They're probably active, but maybe too difficult to synthesize.



^^^ They look yummy! :D

Look very similar to 2C-G-3 that has very nice comments and active at 16-25mg. Considering these two having a sulfur on 4th position, it might become up to 4 times as potent, so probably will be active at 5-10mg, am I right?..8)

And what about benzofuran (and dihydrobenzofuran) analogs of those (oxygen instead of a sulfur), were they ever made?..


----------



## cj187

Here are two obscure chems briefly mentioned in Shulgin's lab notes:





"Active 25-30mg. 5 hrs. Good eyes-closed                              visuals."





"doesn't have much re alteration of consciousness, but marvelous visuals - in light, squinting needs dark glasses, but no dilation. Wine cellar -> 100ft vision [with] detail."

Clearly this one should be active too:






I would think that this would work too:






What if you put a halogen at the 6 position of instead of an alkyl group? 2-FA and 2-FMA are considered worthwhile drugs by many people. Perhaps you could do the same thing with the psychedelic phenethylamines.


----------



## Soulfake

I wonder why you shouldn´t be able to use a weak fentanyl-derivate which has a similar potency to Morphine, Oxycodone etc. as a recreational drug, why are people always into the strong fenta analogues? I imagine a weak one with a long half life to be really good.


----------



## Soulfake

Some carisoprodol-analogues. I wonder why none of those muscle relaxers have made it to the rc-marked, same with Gabapentin or Pregabalin-Analogues (which seem to be relatively easy to make, like esters, pro-drugs or small molecular changes, just look how simple the "rules" are with Gaba/Baclofen/Phenibut/Tolibut/Gabapentin/Pregabalin/GABOB etc.). I'm very sure many people would buy it even if not too many use them recreationally but as more people know about it more will test it out and it'll get a similar place to benzos in the relaxing-rc category. Of cause they are more dangerous chemicals than benzos but well, the train seems to have left as they sell stuf like NBOME, fentanyl-analogues, Bromadol etc. even in pure form, so a few muscle relaxers won't hurt the whole thing.


----------



## DotChem

Soulfake said:


> I wonder why you shouldn´t be able to use a weak fentanyl-derivate which has a similar potency to Morphine, Oxycodone etc. as a recreational drug, why are people always into the strong fenta analogues? I imagine a weak one with a long half life to be really good.



What's the point of developing one with morphine or oxy potency.. It can never be cheaper than the last 2, right? But just in case: IIRC the metabolite of fenta (without the phenethyl chain is as potent as morp or it is the metabolite of carfenta (have to check my notes). Nice structures (I like the last one especially if you make it bis-2-thiophenyl, furans are hard on the liver)


----------



## aspiringdrugdesign




----------



## Midnight Sun

Soulfake said:


> Some carisoprodol-analogues. I wonder why none of those muscle relaxers have made it to the rc-marked, same with Gabapentin or Pregabalin-Analogues (which seem to be relatively easy to make, like esters, pro-drugs or small molecular changes, just look how simple the "rules" are with Gaba/Baclofen/Phenibut/Tolibut/Gabapentin/Pregabalin/GABOB etc.). I'm very sure many people would buy it even if not too many use them recreationally but as more people know about it more will test it out and it'll get a similar place to benzos in the relaxing-rc category. Of cause they are more dangerous chemicals than benzos but well, the train seems to have left as they sell stuf like NBOME, fentanyl-analogues, Bromadol etc. even in pure form, so a few muscle relaxers won't hurt the whole thing.



I love carisoprodol and would like to see more analogues, but carisoprodol is not very potent which is probably the greatest blockade to seeing analogues come to market -- second to that would be the fact that carisoprodol itself is hit or miss with people.  Remember nifoxipam?  





Barbiturates on the other hand... those suffer from impotency issues too, but not as bad as carisoprodol (I have to eat >2g to get anywhere with cariso) and they're more universally well-liked, albeit more lethal.  Thing is at least in the US there's a catch-all on in the analogue act which schedules any derivative of barbituric acid.  Now... desoxy analogues like desosecobarbital above are exempt since barbituric acid isn't used or made in the synthesis  -- they act as prodrugs to the real deal, though  perhaps being prodrugs would help temper the fine line between strong high and lethal dosage?





> What's the point of developing one with morphine or oxy potency..  It can never be cheaper than the last 2, right?



so people stop dying?

Make no mistake: fentanyl does NOT have a manufacturing cost anywhere NEAR the retail or bulk price.  Because the strong potency is common knowledge the chinks charge according to effective dosage which you can't blame them for doing.  OTOH if China wants to keep pissing strong opioids into the world supply they should start pumping out dipipanone or nitazene analogues instead


----------



## DotChem

^ guess I didn't make my post clearer: I mean why not just take morphine  or oxydocone if the idea is to supply opioids (fentanyl analogues) with  morphine or oxy potency! Sure the manufacturing costs of fentanyl are  near zero compared to the retail price. But it can never be cheaper than  opiates derived from poppys seeds (you just plant the shit and harvest  it like potatoes or broccoli!) IMHO, the whole issue is due to  PROHIBITION which is really where most of the retail or bulk price for BOTH  synthetic and natural opiates is.


----------



## doxylamine

aspiringdrugdesign said:


>



Haha, "Dopa-but"


----------



## aspiringdrugdesign

doxylamine said:


> Haha, "Dopa-but"




I wonder if it'd do much


----------



## CodyV17

(4R,4aR,7aR,12bS)-9-methoxy-3,4a-dimethyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one (4-methylhydrocodone)




It is very similar to hydrocodone and oxycodone, except the hydrogen at 4a in hydrocodone and hydroxyl at 4a in oxycodone has been replaced by a methyl group. Would this compound be active, and where would the potency lie? My guess is less than hydro/oxycodone.


----------



## DotChem

can you believe it? now this simple molecule is a mu opiod agonist 2x more potent than morphine.. (the cis stereoisomer not the trans)





looks vaguely like tramadol cyclized


----------



## Pomzazed

That one still looks like stripped down mophine.
Is the N-methyl version better or no?


----------



## DotChem

equipotent.. but the N-phenethyl is 2xfentanyl (about 100-200x morphine).. alkyl or benzyl substituted at the dihydrofuran 3-position (4 position of piperidine) are antagonist .. trans stereoisomers are inactive


----------



## doxylamine

First contribution to this thread. Long time lurker and has given it me many laughs so time to return the favour! Had to include some methylenedioxy versions as part of the running joke here, naturally  These are all based on either GHB-Phenibut or Tranylcypromine-Phenibut hybrids, with some other substitutions whacked on to include other well-known goodies. I'm sure you can figure them out haha. Some of these aren't very neat, first time using the specific chem sketch application and on my mobile with a dodgy touch screen. Anyway, enjoy! 

EDIT: Gah, sorry the images are so huge. Will resize next time.


----------



## Pomzazed

^ the ones where hydroxyl and amino are attached to same carbon is not stable, 
It will spontaneously lose ammonia and become an aldehyde.

Search Hemiaminal (not hemianimal!)


----------



## aspiringdrugdesign

That 2c-b-fly/cyclopropyl GABA mashup is pretty interesting


----------



## Soulfake

DotChem said:


> ^ guess I didn't make my post clearer: I mean why not just take morphine  or oxydocone if the idea is to supply opioids (fentanyl analogues) with  morphine or oxy potency! Sure the manufacturing costs of fentanyl are  near zero compared to the retail price. But it can never be cheaper than  opiates derived from poppys seeds (you just plant the shit and harvest  it like potatoes or broccoli!) IMHO, the whole issue is due to  PROHIBITION which is really where most of the retail or bulk price for BOTH  synthetic and natural opiates is.



I would love to just take same oxy or morphine but it is nearly impossible to obtain for me. The only time I got the chance to try morphine was when some friends brought those substitol capsules from Vienna that are used for opioid addiction there. 10 years ago I got a few oxy tabs but since then I never found it again. So for the RC-market some light opioids would be nice, desmethyl-Tramadol and AH7291 where quite popular and why not use some light fentanyl analogues (or similar light analogues of other kinds of usually strong opioids), they are cheap and easy to make and there are many different possible variations. Of cause some synthetic "natural looking" opioids would be the best (similar to the cannabinoids) but vendors just are too greedy to sell something that pricey and bulky if they can sell comparatively small amounts of stronger opioids that are also cheap to make.

Some analogues of the n-methylcarfentanyl which has about the potency of morphine:


----------



## clubcard

cj187 said:


> These seem obvious but I can't find any information about them. They're probably active, but maybe too difficult to synthesize.



The problem is the synthesis. There all manner of likely compounds (and those look very good) but if you like to draw, extend to synthetic references. S can be a pain since it exhibits +2, +4 & +6 oxidation states. I have also struggled with the synthetic route. As a rule-of-thumb only 3 'pots' is the maximum. I spent a good 5 years reducing the synthesis of the reversed-ester of tilidine from 5 steps to 2. In fact, it was a 2016 paper that dealt with the issue. Consider U-47700. With the right precursors (acid chloride and 1,2,2-trimethyl aminocyclopropan-2-diamine). The former is a 'fine chemical' and the latter is commercially available.

I think that is the important thing. We can conceive of all manner of compound with very likely good activity but the mechanical losses when making a sample make some things expensive and the sheer precursor costs make bulk unattractive. For what it's worth, the aromatic is VERY likely to have activity but adding those methoxy groups makes it impossible.

Use Chemoffice to see if precursors are available.

CC

PS the thiophene analogs of mephedrone and related p-Me cathinones has been studied. Reaxys gives a lot of refs but once again, good luck finding the precursors and dealing with the stench during manufacture. I got the 2-Me benzaldehyde that was a pitch black liquid that smelt of dead people. That it went forward as a PS amazed me. The furan would be interesting. Reaxys also threw up the O analog of clomethiazole. The furan is more potent, longer lasting, is pH neutral for parenteral administration but as long as thiamine (hydrolysis of B1) is OTC, anyone with thionyl chloride can make Heminevrin. The hydrochloride produces big fluffy crystals but supplying something that managed to kill Keith Moon is obviously a set for disaster.


----------



## DotChem

inspired by the many thio on this page... thio 4-FPM .. 




Now since sulfide are easily oxidized (even by simple exposure to ambient oxygen in air.. thio-4FPM-1-oxide:





Now this group (sulfoxide) looks like one found in modafinil type stimulants used by military..so could be good nootropic functional stim cross between FPM+Modafinil.. but who knows? 
....for completion don't forget the S,S-dioxide: 




nb: these are new untested compounds afaik (if you happen be in situation to be able to synthesize'em (pretty easy actually!) .. give me credit and send me my 3% patent royalties ..


----------



## aspiringdrugdesign

DotChem, perhaps a second phenyl group in a similar manner to modafinil would make it even more similar.


----------



## DotChem

^ Yes it would for sure where do you want to add extra phenyl? but you may loose 4-fluorophenmetrazine-like activity + increase lipophilicity


----------



## aspiringdrugdesign

I was thinking one carbon down from your sulfone group there, or perhaps replacing one of the ketones on the sulfur. Would that be too hindered if it were to replace a ketone?


----------



## Solipsis

Don't forget unifiram, although I guess that is different being a sulfonamide... Could trigger a sulfa allergy but not sure.

I think sulfones are bioisosteric to, if anything, ketones so a better analogue in the category perhaps would be: 






1-methylaminoethyltol-4-ylsulfone (which prolly isnt iupac..  1-methylaminotol-4-ylsulfonylethane then? ill settle for that).

"Ketone" applies to carbons (C=O), not to (other) heteroatoms. 

@ADD: that would make it a hybrid which tend not to be winners at least when you make too big sacrifices and you often would in order to bridge that gap hybrids bridge. Also you can't replace a sulfone oxygen with a phenyl ring because it would not be a good valency for sulfur.

I love the sulfoxide / sulfone discussion  Some of these may indeed be unrealistic due to the synthesis and I also guess unifiram is pricey for a reason?? But hey challenges are fun


----------



## aspiringdrugdesign

If sulfones are bioisosteric to ketones (now I know ketone only applies to oxygen), have any cathinone/sulfone derivatives been attempted? Is that still quite a difficult synthesis? I'm only finishing my first organic chem course, just touching on benzylic substitution right now.

Perhaps an alkene branch connecting the phenyl and sulfone then? It'd have to be two carbons long then though, that might change things. 

I like these discussions too, it helps me learn more


----------



## Pomzazed

I studied JWH analogs during my master degree, the ones with sulfonyl(sulfone group), sulfinyl(sulfoxide group) are more prone to heat in comparison with parent carbonyl derivative, and likes to break into SO2 gas if trying to vaporize, in solution it is stable enough.

Synthesis is kinda straightforward but a little bit more steps than ketone, but that cant be discussed here.


PS. For these sulfur-y JWH analogs, I discourage anyone grabbing this idea for drug abuse purpose, it is unsafe regarding decomposition product and is not as efficient as ketone ones(per in vitro testing for binding).
PS2. The sulfide analog (just plain -S- linking) is prone to aerial oxidation, and parent molecule without alkyl tail on indole-1-position STINKS. (Similar to diphenylsulfide mixed with mothball and some dumpings)


----------



## Solipsis

aspiringdrugdesign said:


> If sulfones are bioisosteric to ketones (now I know ketone only applies to oxygen),


 Not really, the term ketone applies to C=O specifically, not to be a stickler: the point is it refers more to the C= part than the oxygen, a thioketone is C=S  not S=O. Has nothing to do with the isosterism





> have any cathinone/sulfone derivatives been attempted?


Yes I recall that but it is not a public matter afaik nor was I interested to try





> Perhaps an alkene branch connecting the phenyl and sulfone then? It'd have to be two carbons long then though, that might change things.



Am gonna go out on a limb here and say I think it would be unstable and have a tendency to polymerize.

Wow JWH compounds... both interesting and worrisome, toxicologically speaking a nightmare as far as RCs go: Hoffman may have decently studied his JWHs but the pharmacophore / general structure spawned an endless list of analogues involving all kinds of functional groups. I thought it was already both "brave" (fascinating I mean, also foolilsh) and reckless to guinea pig yourself when rather simple stim homologues etc became available many years ago, extending or swapping a group here and there hoping to make no significant toxicological changes. Cannabinoids are nuts in that regard and it is no surprise various are found to be toxic.


----------



## Pomzazed

^
Hehe by test i dont mean abuse or like, it was a proper academic study in university, but that was like many years ago.
I studied on the noncarbonyl bioisosterism of those compounds (including even C=S) The activity was tested using cultured cell lines.

What i said is (C=O) cannot be just swapped with (S=O), or (C=S) in every cases, if it functions as linker at that position its swappable, but once it contributes to binding there are some differences, the sulfinyl are Chiral group, with chiral center at S, and the =O and lone pair electron of S cant be flipped. The shape will be trigonal pyramid regarding to S, and carbonyl it is trigonal planar regarding to C. While thiocarbonyl is much more polarizable and it displays alot of (+)C—S(-) character instead of C=S

Interesting note is that the N-despentyl thiocarbonyl of JWH are deeply colored, and the solution turns from light yellow to deep red as concentration increases without transition via any orange color.

Isostere; is not always a fixed rulee that functional group A and be replaced by group B; depends on the molecule and how that position contributes to binding. For example in the case of modafinil, unlike my above examples, the S=O are replaceable by C=O and still retain quite some activity.


----------



## Solipsis

I know  was more like.. speaking of which...

Hmm is the carbonyl of cathinones too involved with binding? I also don't know whether that different geometry would be permitted.

I don't ever see C=S in drugs or meds, is that typically metabolically safe?..

Uh I think that weirdly sometimes compounds are yellow when diluted in solution but red when concentrated, this even applies to certain yellow food pigments. I don't really know what could cause that, additive mixing of light for example can be really weird, sometimes when you see a color it is a product of two other colors mixing while the one you see is not emitted at all technically... the way our eyes work is particular.
Best explanation I have is that the red wavelengths with rising concentration add up way heavier than the yellow wavelengths when appearing darker, overwhelming simply because red is arbitrarily darker in our perception than yellow? - might be similarly true with bilirubine in urine though with brown?

Nope bioisosterism is not a rulee-fixe  but compounds in this thread are so hypothetical that often predicting that stuff could go a bit far, though sometimes ppl like to go far with analysis because it is interesting or they feel like it

Chems right? Can't vacuum with them, can't be (and therefore not think) without them


----------



## Pomzazed

idk if thiocarbonyl is metabolically safe, I just tested in vitro.

Yellow to red in solution is not strange as the concentration rise, just lift up the amplitude of the wavelength, and the baseline will rise up and cover the other color, this applies to many red pigment (which diluted to yellow)

The weird thing is that my compound transit without orange in between, unlike most pigment.
This only happens in halogenated solvents like DCM or similar too, in toluene it has orange in the middle...

Interesting note is that thiocarbonyl of benzophenone is very deep blue, and transit to cyan without “light blue”inbetween too, when diluted with DCM. I GUESS it has something to do with the highly polarized C=S bond as (+)C—S(-) and the high dielectric constant of halogenated solvent! (No proof yet)


———
In cathinones, i think it involves, =O (or -OR, -OH) in beta position affects alpha1 and alpha2 binding, see adrenergic agents.


----------



## DotChem

aspiringdrugdesign said:


> I'm only finishing my first organic  chem course, just touching on benzylic substitution right now.


 May I suggest you take Biochem next: basic fundamental biochem like  Lehninger Principles of Biochem dealing with proteins structure &  function.  It would be very useful if you plan career in medicinal  chemistry/drug design in future.. good luck



Solipsis said:


> Hmm is the carbonyl of cathinones too involved with binding? ..


 
Not critically afaik.. Prolintane  (the fully reduced Pyrovalerone analog is  as good  stim as PV). But in that case tho, the carbonyl CO of PV is replaced by  CH2.  That  doesn't affect binding but changes pharmacokinetics as one might expect: absorption, duration of effect, metabolism..etc since the molecule has  now different  physicochemical properties (ex: pKa of PV ~7.8-8; pKa prolintane  ~10.2!! ). 
As to replacing CO by SO2 in cathinones, I am not sure if alfa-aminosulfones  are very  stable: unlike RCO, RSO2 is a relatively good leaving group (in the form   of RSO2- ; pKa of  sulfinic acid usually < 5) so it would behave somewhat like an acyl  aminal: NCHOAc very unstable in aq solution ).. but who knows? unless  you make and test them!.. 


Solipsis said:


> I don't ever see C=S in drugs or meds, is that typically metabolically safe?..? ..


There are few drugs  having C=S for example: for example the one used to treat alcoholism, Disulfuram:  pretty smelly, very nauseating shit.. but it works for compulsive binge drinkers. The C=S is actually pretty benign  metabolically (not too hard on liver). It gets converted to C=O via  first oxidation of the sulfur and 2. hydrolysis with a sulfonate as  leaving group to give the corresponding ketone CO.




Pomzazed said:


> I  studied JWH analogs during my master degree, the ones with  sulfonyl(sulfone group), sulfinyl(sulfoxide group) are more prone to  heat in comparison with parent carbonyl derivative, and likes to break  into SO2 gas if trying to vaporize, in solution it is stable enough.


3-sulfonyl  (as well as 3-acyl) N-unsubstituted indoles are pretty unstable in aq  solution (especially in acidic media).  Indoles behave like enamines:  the 3 position is highly reactive towards electrophiles.  It is very nucleophilic  (and even more so for 3-acy or 3-sulfonyl): In aq sol , it would pick  up a proton to give indolenium ion which may loose a proton to go back  to starting acyl(sulfonyl) indoles or competing reaction the RCO (or  RSO2) undergo attack by water to generate RCO2H or RSO3H and correspond  deacetylated (desulfonated) indoles .. I wish I could draw pic w/ e flow  to see what I am talking about.. but I am sure you get the point: My  former boss was expert in indole chemistry.  One the method is liked is  protection indole 3-position by PhSO2 and then removed protecting group  by mild acids once something done elsewhere. However, keep in mind,  3-acyl (or sulfonyl ) indoles are more stable when the indoles NH is  substitued by alkyl, or acetyl..or tosyl..etc etc so the JW cannabis  series should be ok since they all substituted on NH ..


----------



## DotChem

re: sulfone or sulfoxide bioisoteres. as ^^ mentioned, it all depends what one wants to achieve; sometimes it works sometimes not. With sulfo methadone for example ie Methiodone, it doesnt work that well. In that case the ketone CO of Methadone replaced by a Sulfone.. 
I've seen sulfones (SO2CH2CH3) used as bioisosters replacement of esters (CO2CH2CH3) where the issue is the ester susceptibility to hydrolysis (and hence shorter half-life) and the binding not that much affected.. talking about which makes me think of this:




or this 





(nb: afaik these are new compound.. if you happen be in position access them.. give me credit and send me my 3% patent royalties


----------



## pharmakos

Pomzazed said:


> idk if thiocarbonyl is metabolically safe, I just tested in vitro.
> 
> Yellow to red in solution is not strange as the concentration rise, just lift up the amplitude of the wavelength, and the baseline will rise up and cover the other color, this applies to many red pigment (which diluted to yellow)
> 
> The weird thing is that my compound transit without orange in between, unlike most pigment.
> This only happens in halogenated solvents like DCM or similar too, in toluene it has orange in the middle...
> 
> Interesting note is that thiocarbonyl of benzophenone is very deep blue, and transit to cyan without “light blue”inbetween too, when diluted with DCM. I GUESS it has something to do with the highly polarized C=S bond as (+)C—S(-) and the high dielectric constant of halogenated solvent! (No proof yet)
> 
> 
> ———
> In cathinones, i think it involves, =O (or -OR, -OH) in beta position affects alpha1 and alpha2 binding, see adrenergic agents.



Perhaps the orange phase happens imperceptibly quick?


----------



## aspiringdrugdesign

DotChem said:


> May I suggest you take Biochem next: basic fundamental biochem like  Lehninger Principles of Biochem dealing with proteins structure &  function.  It would be very useful if you plan career in medicinal  chemistry/drug design in future.. good luck



I'm taking analytical chem and the second OChem class at my university next semester, I believe the biochem classes start the semester after that. It's my major after all!


----------



## clubcard

DotChem said:


> re: sulfone or sulfoxide bioisoteres. as ^^ mentioned, it all depends what one wants to achieve; sometimes it works sometimes not. With sulfo methadone for example ie Methiodone, it doesnt work that well. In that case the ketone CO of Methadone replaced by a Sulfone..
> I've seen sulfones (SO2CH2CH3) used as bioisosters replacement of esters (CO2CH2CH3) where the issue is the ester susceptibility to hydrolysis (and hence shorter half-life) and the binding not that much affected.. talking about which makes me think of this:
> 
> 
> 
> 
> or this
> 
> 
> 
> 
> 
> (nb: afaik these are new compound.. if you happen be in position access them.. give me credit and send me my 3% patent royalties



Use Chemaxiom to check cLogP and pKa values. The on-line version is free. Unless the molecule is uncharged at physiological pH then it won't cross the BBB and if the cLogP is low, it won't accumulate in the brain. ChemOffice allows you to overlay versions and Discovery Studio does the docking calculations.... oh, and Reaxys lets you know if it's already been tried....

But truly interesting. Sulfonate is generally a bioisostere of a ketone but a sulfone, due to the extra lone-pairs in S end up an odd shape... and are chiral.


----------



## Soulfake

A simple cocaine analogue with the tropane ring changed into norbornane:


----------



## DotChem

^ interesting .. 



clubcard said:


> .. oh, and Reaxys lets you know if it's already been tried....



am afraid I can't afford the ~ US$20,000 Elsevier Co charge for access to Reaxys!!). Even if I do, I won't spend a penny since I don't think it is useful!  Just waste of money (It is no better than pubmed literature search (ncbi.nlm.nih.gov) FREE and surechembl.org patent literature FREE! + uspto.gov FREE + .etc


----------



## DotChem

Dissociatives:  this molecule is a potent NMDA antagonist which bind to PCP sites ..It is ~20x more potent than ketamine)!  looks like pretty simple molecule but different from any other NMDA antagonist structure (legal or not..). Unless I miss something?


----------



## clubcard

DotChem said:


> ^ interesting ..
> 
> 
> 
> am afraid I can't afford the ~ US$20,000 Elsevier Co charge for access to Reaxys!!). Even if I do, I won't spend a penny since I don't think it is useful!  Just waste of money (It is no better than pubmed literature search (ncbi.nlm.nih.gov) FREE and surechembl.org patent literature FREE! + uspto.gov FREE + .etc



Reaxys is worth the money. What takes 5 minutes with can take 5 hours without. It is merely a question of how much your time is worth?

The sulfone substitutes in ketobemidone and it's x15 derivative. Finding the paper ON the FULL ketobemidone QSAR would be impossible without Reaxys because the titles of papers and patents nor keywords help. I suppose if you guessed the answer and searched of keywords, you might get lucky, but it is a British patent, so see if you can find it....

Sulfones also work in the cathinones. The twin problems are the synthetic cost and the lower LOogP... and unless you pack under dry nitrogen, they seem to polymerize.


----------



## adder

Reaxys does give you fairly neat tools to input information aside from searching with words and phrases, i.e. you can query with structures and reaction schemes which is very nice and if you're looking for a very specific reaction, searching with Reaxys is usually the fastest. But the structure editing tool is far from perfect IMO, the best structure editor is in Java and thus basically useless on modern browsers, all the rest is rather uncomfortable to use especially when you want to mark specific R groups and obtain information how broadly some reaction has been researched, but it can be done even if sometimes it requires a few queries instead of one. You definitely have no way of searching through articles like this with Scholar Google, you have to input specific words to get a list of publications and then look through those publications to see if they contain the reaction or compound you're looking for (which is rather pointless if you're given such a job to do, you should be given a more appropriate tool IMO). But still, Scholar Google is what I use at home to find articles on specific topics, IME it works pretty well and you can still find a lot of more rare articles in organic chemistry this way as well. If you're looking for some general information on some reaction as a general method, then Scholar Google is definitely enough, you find an article which links to a review and then it's easy to find more information available through references and knowing names of researchers through the search engine again. You never know if it's exhaustive, with Reaxys you can't be sure either, but it's what most people in academia use (I guess). Anyway, if you carry out research and have to compile data, then that's when Reaxys is indeed indispensable when you have to check if your compounds have already been synthesized and if yes, compare analytical data from the literature with yours, good luck doing that with Scholar Google. :D No matter how clumsy the structure editor in Reaxys may feel, it's million times faster to find specific data for a given organic compound with Reaxys than with any search engine which accepts only words and phrases. I don't really use PubMed too often nowadays, so I can't say much about it.

All in all, I would definitely not invest into Reaxys either unless I ran a private company and did research that required certain functionalities Reaxys does offer.


----------



## Nagelfar

Soulfake said:


> A simple cocaine analogue with the tropane ring changed into a norbornane:



Already done, in a Frank Carroll patent (U.S. Patent 6,479,509). I dug through all this to find anything new, and spotted it some time ago. I've been digging out unique cocaine analogs for ten years; but if you find anything I haven't, let me know. P.S.  nice image overlay of 'em, I took 'public domain' chemistry image rational and put it to my WP page , hope you don't mind, if you do: let me know or just take it off yourself, (otherwise perhaps you could make me another with transparency. hehe. ;-p)


----------



## Soulfake

Thanks for adding it to Wikipedia  Everyone can use my images, no problem.

I use Marvin Sketch from the Marvin Suite chemistry programs, it´s really a great tool (it shows if you draw false structures, you can draw molecules and the program gives you the full chemical name, 3d-alignments/overlays and much more. You can download it for free at https://www.chemaxon.com/products/marvin (you have to register first but it´s fast)

Some more random analogues and one molecule that probably would be extremely toxic but it would be fun to know how it would behave in the body, which metabolites would form etc. 







I wonder why no pyrrole cannabinoids make it to the market, there have been JWH-307 and JWH-147 some years ago and both were quite effective and enjoyable (in contrast to the overly potent new cannabinoids). I imagine a AB-Pinaca or AB-Fubinaca pyrrole analogue to be very nice. You could create a whole new generation of different cannabinoids by using the pyrrole base structure.

The main problem is that mostly cannabinoids with the tert-butyl (makes all/most cannabinoids way too strong) and the ester unit (makes it last only a few minutes until it´s hydrolyzed) are being sold, if they would change it to isopropyl + amide you would have (in most cases) much safer and more enjoyable cannabinoids. They sell the overly potent ones at the same price and producers even put the same amounts (out of stupidity) into their "herbal incense" so money can´t be the argument to produce/sell the overly strong ones. I guess most producers have no clue about the more or less subtle differences and quality of effect from those two specific configurations and just think "the stronger the better" which also causes many people to get side effects like seizures or heart problems and generally unpleasantly strong effects from the tert-butyl that are very short due to the ester.






edit: the R2-units of the last molecules are just indazole placeholders.


----------



## sekio

So are N-hydroxycathinones stable, or not? Just wondering.





Also, re: Reaxys, the only way I'd recommend it would be useful for the Average Joe is if they get complimentary access through an educational institution. Nobody's business is going to shell out $25k a year.


----------



## Pomzazed

sekio said:


> Why would ELIXIR be active? J/w as it has no nitrogen


Because GHB is active,
And 3- or 4- alkylated versions are active too, like:

HOCPCA
https://en.m.wikipedia.org/wiki/HOCPCA

UMB68
https://en.m.wikipedia.org/wiki/4-Hydroxy-4-methylpentanoic_acid


----------



## sekio

Both of those are significantly more compact that b-isobutyl-GHB (ELIXIR), and are also GHB-receptor agonists and not GABAergics (GHB is both).


----------



## Pomzazed

I am not argue on that point. Just to say it “may” be active per your question.
(Either agonist,or antag)


----------



## sekio

I don't have chemdraw with me now, but how about ethyl 4-acetoxy butyrate ? The O-acetyl and ethyl diester of GHB.

Or even GHB lactide? (cyclic diester of lactic acid with GHB)


----------



## Pomzazed

GHB prodrugs with hydrolyzable group are known, no better effect, slower onset, worse smell. The synth and effect are reported in erowid.

GHB lactic lactone seems to be having too big ring to favor formation thermodynamilcally in comparison to other possible product choice. (Lactide and GBL)


----------



## oestrogenprinsessa

i love chemdraw lol


----------



## oestrogenprinsessa

i like drawing steroids


----------



## aspiringdrugdesign

That cyan blue is pretty difficult to see @oestrogenprinsessa


----------



## DotChem

Crack cousin


----------



## aspiringdrugdesign

Dresden, don't most of these molecules exist already?


----------



## sekio

^ that, and probably 75% are inactive...


----------



## sekio

https://www.ncbi.nlm.nih.gov/pubmed/1349351
(2S,4S,6S)-2-ethyl- 2-(1-chlorophenyl)-4-(2-piperidyl)-1,3-dioxolane


----------



## aspiringdrugdesign

Dopamine with a beta 4-bromobenzene substituent. There's beta phenyl methamphetamine which has activity, so perhaps this would do something






Serotonin/phenylpiracetam mashup - I don't think this would do much but I'd love to hear your guys' thoughts






Cyclized seroracetam 





Apparently the R-isomer of methylphenylpiracetam has greater activity than phenylpiracetam itself so that leads me to the next molecule






Bromomethylphenylpiracetam! I don't see why this wouldn't be stronger than methylphenylpiracetam. Hopefully someone has some insight on any of these molecules


----------



## sakeisking

What's the deal with Bromine, from a biochemical standpoint? Why is it so prevalent in psychoactive chemicals?


----------



## aspiringdrugdesign

AFAIK, and this is from a somewhat layman's perspective, I think the electronegativity causes it to be more easily absorbed in addition to it fitting into a given receptor better. I'm sure others could give a more in depth answer but I'm pretty sure that's why!

Something I didn't take into account though, is that that bromine might be in a problematic position. 4-bromoamphetamine is neurotoxic, so if the amphetamine substructure contributes to its activity, that bromine might cause issues. Maybe a hydroxyl group or different positioning would be better.







some goofy amphetamine analogs I thought of






phenylpiracetam analogs, the hydrazine version of phenylpiracetam has been shown to have activity, and I figure the cliche methylenedioxy group might do something too, with or without that methyl group





I'll call this one imidazoracetam lol, and I think that's enough racetam analogs for now






I'm curious if this fat bastard would do anything, and if it would, what would it do?






This one is a licofelone analog influenced by zileuton -- it would probably be a LOX inhibitor, but I know even less about NSAIDs than I do phenethylamines


----------



## Solipsis

Don't think of SAR as being so caused by the parts of the sum... bromine doesn't do anything inherently. It has steric and electronic properties but even those are very circumstantial and the relevance depends completely on the rest of the molecule and the exact structure. Also is it prevalent? Compared to what? I think that is just selective perception, if you are thinking of all psychoactives with bromine in their structure suddenly it might seem like they are more prevalent than they are vs all those that do not.

Methylenedioxies however.. :>


----------



## Hodor

sakeisking said:


> What's the deal with Bromine, from a biochemical standpoint? Why is it so prevalent in psychoactive chemicals?



Bromine is both electronegative (i.e. it draws in electrons, which may be important for interacting with receptors), and relatively large (which can greatly affect a drug's potency). It is also relatively easy to both attach to and selectively detach from a molecule, meaning you can easily synthesize a brominated compound *and* use it as a precursor for e.g. a chlorinated compound. 

However, I wouldn't say that it is all that "common" in psychoactives. Sure, for the reasons mentioned above it is basically "perfect" for the 4-position in a psychedelic phenylethylamine (so you've got DOB, as well as its analogues 2C-B, 2C-B-FLY, 25B-NBOMe, and so on), but as far as other psychoactives are concerned, bromine is probably rarer than chlorine (note: fluorine, chlorine, bromine and iodine form a group of very reactive elements called "halogens" that play an important role in Organic Chemistry).

There's been relatively little interest in brominated tryptamines, for example.

With many "legal highs" or "research chemicals", people will even deliberately use fluorine instead of other halogen substituents like bromine because it is such a *small* molecule - para-Fluoro versions of fentanyl analogues, for example, probably aren't going to differ from their parent molecules all that much as far as potency and toxicity are concerned.


----------



## aspiringdrugdesign

Differently positioned serotonin/racetam mashup





Could also try this if you want the ethanamine branch to go the other way






Benzothiobut, using benzothiophene as a bioisostere






More silane derivatives, I don't know if these would work


----------



## Hodor

Solipsis said:


> Also is it prevalent? Compared to what?



Yeah, I should perhaps stress this point again:
Bromine is easily among the top ten elements found in psychoactive drugs, sure.

However, that is because psychoactive substances are almost always organic compounds, which *severely* limits the number of elements you're dealing with.

The various psychoactive organics found in nature are usually made up of just 3 or 4 elements, ex.:
DMT: carbon, hydrogen, nitrogen
THC: carbon, hydrogen, oxygen
morphine: carbon, hydrogen, nitrogen, oxygen

Sulphur and phosphorous are also pretty useful in organic chemistry at times, although phosphorous is relatively rare in psychoactives for various reasons.

Lastly, you've got a group of elements called the halogens (which bromine belongs to), which are less commonly found in natural substances, but tremendously valuable when designing synthetic compounds.

Virtually all the other elements suffer from concerns like toxicity and/or a diminished ability to form stable covalent bonds, which mostly rules them out as building blocks for psychoactive substances that anyone would actually ingest willingly.

So basically out of the ~120 known elements you've got just 10 that you'll realistically see in a psychoactive drug, and out of those, bromine is probably in the bottom 5.


----------



## aspiringdrugdesign

This one is inspired by kynurenic acid, which has some downstream effects on some of the neurotransmitters -- it also binds to some receptors but I forgot which. 

I figured since it indirectly impacts dopamine, perhaps this would do something.






Some thioamph inspired phenylpiracetam molecules, and unless I'm mistaken, those acetyl groups on the right would metabolize into hydroxyl groups






Did someone say 5-HT2A agonism? 






I'm curious if an n-thiophene function would work similarly, or not in this situation


----------



## Hodor

aspiringdrugdesign said:
			
		

> Did someone say 5-HT2A agonism?



Ralf Heim - the guy who discovered the NBOMe‘s - synthed & assayed both the 2C-x-NBOMe‘s and their DOx-NBOMe analogues.

Interestingly, the combination of an N-methoxybenzyl and an alpha-methyl-group didn’t seem to result in increased receptor affinity when compared to the plain 2C-x-NBOMe version.


----------



## aspiringdrugdesign

Hodor said:


> Ralf Heim - the guy who discovered the NBOMe‘s - synthed & assayed both the 2C-x-NBOMe‘s and their DOx-NBOMe analogues.
> 
> Interestingly, the combination of an N-methoxybenzyl and an alpha-methyl-group didn’t seem to result in increased receptor affinity when compared to the plain 2C-x-NBOMe version.



Interesting, I knew the alpha methyl group doesn't do much for 5-HT affinity, but I was basing this off of bromo-dragonFLY. Perhaps something about those furan groups would cause the n-benzyl functions to have more affinity than its counterparts





2CBCB-hemiFLY-NBOME












Some opioid antagonists I thought of





I don't think this would do much but hybrids are fun to make


----------



## aspiringdrugdesign

This isn't the thread to ask KDazzle


----------



## Nagelfar

Hodor said:


> Yeah, I should perhaps stress this point again:
> Bromine is easily among the top ten elements found in psychoactive drugs, sure.
> 
> However, that is because psychoactive substances are almost always organic compounds, which *severely* limits the number of elements you‘re dealing with.
> 
> The various psychoactive organics found in nature are usually made up of just 3 or 4 elements, ex.:
> DMT: carbon, hydrogen, nitrogen
> THC: carbon, hydrogen, oxygen
> morphine: carbon, hydrogen, nitrogen, oxygen
> 
> Sulphur and phosphorous are also pretty useful in organic chemistry at times, although phosphorous is relatively rare in psychoactives for various reasons.
> 
> Lastly, you‘ve got a group of elements called the halogens (which bromine belongs to), which are less commonly found in natural substances, but tremendously valuable when designing synthetic compounds.
> 
> Virtually all the other elements suffer from concerns like toxicity and/or a diminished ability to form stable covalent bonds, which mostly rules them out as building blocks for psychoactive substances that anyone would actually ingest willingly.
> 
> So basically out of the ~120 known elements you‘ve got just 10 that you‘ll realistically see in a psychoactive drug, and out of those, bromine is probably in the bottom 5.



So much more could be done with the transition metals than is; for constraint of the cost and specificity in the synthesis is my guess why it's not though. Speaking strictly of chelates and such; i.e. bioorganometallic chemistry


----------



## aspiringdrugdesign

Nagelfar said:


> So much more could be done with the transition metals than is; for constraint of the cost and specificity in the synthesis is my guess why it's not though. Speaking strictly of chelates and such; i.e. bioorganometallic chemistry



Could you give a few examples of transition metal containing drugs? Any nootropics or psychoactive ones? I think I've seen a few used for treating specific cancers, but I don't know enough on the subject


----------



## Hodor

aspiringdrugdesign said:


> Could you give a few examples of transition metal containing drugs? Any nootropics or psychoactive ones? I think I've seen a few used for treating specific cancers, but I don't know enough on the subject



Apparently someone made a more potent version of troparil (itself a structurally simplified version of cocaine) using a benzene-chromium-tricarbonyl complex instead of plain phenyl.






The structural configuration of this complex has been called a "piano stool" for rather obvious reasons:





Obviously more of a "proof of concept" than something we might realistically see as grey-market a designer drug, but extremely interesting nonetheless.


----------



## Solipsis

Good clarification about the bromine there 

I think alpha-methyl NBOMe's not being so good is for similar reasons as tryptamine-NBOMe's happening to not be good or antagonistic (IDK if some DOX-NBOMe's are antagonistic): the NBOMe group enhances a particular conformation of 2C-X and there is no reason why this necessarily translates to all kinds of - even closely related - agonists which may have a different spatial conformation in the receptor. The way they bind spatially may be mutually exclusive so finding an optimum tends to be a custom job. To say whether other NBOMe's pretty much couldn't (have been) good depends on that binding conformation of the parent molecule and it has to be compatible. I've seen some of those conformations of different psychedelics and some are surprisingly different, though I am not 100% sure about whether those were produced by notoriously unreliable computational models.

@ the thiophene analogue: I think it has a good chance of working fine though likely not a first-class one like a lot of NBOMe's but a second-class like NBOHs or worse. Similarly isn't there a THF analogue?

Chromium doesn't seem viable for a drug due to toxicity? Aren't there any Fe ones?


----------



## aspiringdrugdesign

Hodor said:


> Apparently someone made a more potent version of troparil (itself a structurally simplified version of cocaine) using a benzene-chromium-tricarbonyl complex instead of plain phenyl.
> 
> 
> 
> 
> 
> 
> The structural configuration of this complex has been called a "piano stool" for rather obvious reasons:
> 
> 
> 
> 
> 
> Obviously more of a "proof of concept" than something we might realistically see as grey-market a designer drug, but extremely interesting nonetheless.



Very interesting, I wonder how metabolization works with coordination complexes. I actually don't even get how the "piano stool" is bonded to the benzene ring. (it's not bonded to the center, is it?) How does that work?




Solipsis said:


> I think alpha-methyl NBOMe's not being so good is for similar reasons as tryptamine-NBOMe's happening to not be good or antagonistic (IDK if some DOX-NBOMe's are antagonistic): the NBOMe group enhances a particular conformation of 2C-X and there is no reason why this necessarily translates to all kinds of - even closely related - agonists which may have a different spatial conformation in the receptor. The way they bind spatially may be mutually exclusive so finding an optimum tends to be a custom job. To say whether other NBOMe's pretty much couldn't (have been) good depends on that binding conformation of the parent molecule and it has to be compatible. I've seen some of those conformations of different psychedelics and some are surprisingly different, though I am not 100% sure about whether those were produced by notoriously unreliable computational models.




Huh, I didn't realize that NBOMe groups were for 2Cs only! I figured it'd be applicable to a majority of phenethylamine 5-HT2A agonists, although there'd obviously be a few that don't work because of other functional groups. I read something about the NBOMe moiety working through pi-stacking interactions. What does that actually mean? Is it similar to hydrogen bonding?



Solipsis said:


> @ the thiophene analogue: I think it has a good chance of working fine though likely not a first-class one like a lot of NBOMe's but a second-class like NBOHs or worse. Similarly isn't there a THF analogue?




I wish there was a program or app that could accurately calculate receptor affinities given a molecule -- that'd be very useful 

If I'm guessing correctly, a THF analog would participate in hydrogen bonding, right? Although it wouldn't be conjugated like a benzene or thiophene ring as there's no pi electrons there. (unless you aren't referring to tetrahydrofuran?)







Is there much info on that thiophenyl group for phenethylamines? I pulled it off Aleph-6, and there's another phenethylamine I found named 3C-BZ. 3C-BZ has an oxygen in place of the sulfur, however both 3C-BZ and Aleph-6 have much longer durations than their non-thiophenyl/phenol group counterparts. Does it impact metabolization in some manner?


----------



## Tzcatlipoca

aspiringdrugdesign said:


> Very interesting, I wonder how metabolization works with coordination complexes. I actually don't even get how the "piano stool" is bonded to the benzene ring. (it's not bonded to the center, is it?) How does that work?
> 
> 
> 
> 
> Huh, I didn't realize that NBOMe groups were for 2Cs only! I figured it'd be applicable to a majority of phenethylamine 5-HT2A agonists, although there'd obviously be a few that don't work because of other functional groups. I read something about the NBOMe moiety working through pi-stacking interactions. What does that actually mean? Is it similar to hydrogen bonding?
> 
> 
> 
> I wish there was a program or app that could accurately calculate receptor affinities given a molecule -- that'd be very useful
> 
> If I'm guessing correctly, a THF analog would participate in hydrogen bonding, right? Although it wouldn't be conjugated like a benzene or thiophene ring as there's no pi electrons there. (unless you aren't referring to tetrahydrofuran?)
> 
> 
> 
> 
> 
> 
> 
> Is there much info on that thiophenyl group for phenethylamines? I pulled it off Aleph-6, and there's another phenethylamine I found named 3C-BZ. 3C-BZ has an oxygen in place of the sulfur, however both 3C-BZ and Aleph-6 have much longer durations than their non-thiophenyl/phenol group counterparts. Does it impact metabolization in some manner?



Great post! Let me begin with thank you! I theorize since sulfide/sulfamide groups are recognized by the body as poison/vile, they may have priority of excretion as a radical group over oxygen which is considered fuel for the cells. In order to prove this, a selenide in the radical group of popular psychedelics should be designed and tested as selenium is the ultimate antibody. In theory selenide compounds should have metabolic over the sulfide compounds. How this would contribute to activity and subjective tripping, I have no idea.. 
Food for thought..

Best regards, 
Tezcat


----------



## Hodor

aspiringdrugdesign said:


> Very interesting, I wonder how metabolization works with coordination complexes. I actually don't even get how the "piano stool" is bonded to the benzene ring. (it's not bonded to the center, is it?) How does that work?



Well, the benzene isn't "bonded to" the piano stool because it is part of the piano stool - it's supposed to be the seat.
I mean, you know what a piano stool looks like, right?





The seat is the benzene, the angled legs are the carbonyls, and the metal is sort of the part where the vertical rod joins the angled legs... so basically, the metal sits below the center of the plane of the benzene ring, with the metal's d-orbitals interacting with the benzene's pi-electrons.

In an ordinary "sandwich complex" the metal is, well, "sandwiched" between two aromatic ligands (the prototypical "sandwich" is the ferrocene molecule). (Benzene)chromium tricarbonyl is a "half-sandwich" complex, in which the chromium sits between an aromatic ligand (which is haptic, i.e. it bonds to the metal with multiple contiguous carbon atoms) on one side, and several unidentate ligands (which only bond with one atom each) on the other.



> Huh, I didn't realize that NBOMe groups were for 2Cs only! I figured it'd be applicable to a majority of phenethylamine 5-HT2A agonists, although there'd obviously be a few that don't work because of other functional groups.



I just looked at Ralf Heim's dissertation again, and apparently he actually synthed 2C-B-FLY-NBOMe, 2C-B-FLY-NBOH, as well as the alpha-methylated DOB-FLY-NBOMe, and assayed their activity on rat 5HT2A receptors. Potency-wise, the former two were roughly in the same ballpark, while the alpha-methylated version was significantly less active. He also compared (among others) DOB, 25B-NBOMe and DOB-NBOMe, with DOB-NBOMe being about as potent as plain DOB, and significantly less potent than 25B-NBOMe.
http://www.diss.fu-berlin.de/diss/s...000001221/3_RalfHeimPharmakologischerteil.pdf (in German)

Of course this is a 14-year-old in-vitro study on rat receptors, so take these results with a grain of salt.


----------



## Solipsis

Benzofurans (and I guess benzodifurans) are supposed to be heavy on the liver right? I was pretty concerned when people started trying 2C-B-FLY-NBOMe not that long ago, in general. Fortunately for the liver problems the dosage is so incredibly low.

Anyway: with regards to the 2C-T-X benzodifuran crossover above and its potential non-NBOMe analogue I would personally be really careful. 2C-T's have an incredibly complex metabolism already where there are signs that metabolites may play a role in both the activity and potential toxicity and interactions. Not sure you want to introduce extra challenges for e.g. the liver and perhaps inhibit parts of the metabolism with who knows what consequences. 2C-T's are a hit or miss anyway with GI problems, in my opinion you want to keep all interactions to a minimum when dealing with 2C-T's including with minor things you might not even really consider but which do matter for what your liver enzymes are up to.
Staying unusually clean and healthy might just help to get a good 2C-T-X trip. I stilll have some T-7 which I love so much. Too bad the dose-response curve can be so all over the place!

Sorry I have no molecules for you but I do like that pianochair, have had some good experiences on that.


----------



## sekio

from earlier


----------



## Swerlz

Did Shulgin ever look into the 3,5-dimethoxy-4-haloPEAs? We all know the 2,5's were good to go and i know he looked into the amphetamine 3-methoxy homolog of DOB but can't see any PEA research on the matter

Example:


----------



## Tzcatlipoca

sekio said:


> For a good introduction try flipping through PiHKAl and TiHKAL, pay attention to the dosage/activity with respect to the structure of the molecule.



Will continue doing immediately.
Thank you,
Tez


----------



## LucidSDreamr

i would be curious to search some of these on scifinder but havn't done so. I wonder if they have been explored


----------



## Swerlz

LucidSDreamr said:


> i would be curious to search some of these on scifinder but havn't done so. I wonder if they have been explored



http://www.bluelight.org/vb/threads/504286-PCP-analogs-(Cumulative)



			
				from the post said:
			
		

> 1-(1-phenylcyclopentyl)piperidine
> 
> The substance wasn't even synthesized. Any enlargement (or the contrary action) of the cyclohexane ring gives a massive decrease in activity, so no further research makes sense.


----------



## LucidSDreamr

Thanks swerlz.  I guess that rule that out.  Except for the expansion/contraction of the piperidine on PCP. has that been done?

PS, Fent Liquordale, lol   Definitely is that.  I walked down oakland park blvd in broad daylight to go to the beach from my friends house and we counted witnessing three different drug deals during a 30 minute walk.


you actually inspired me to come up with a cute name for my location


----------



## Hodor

LucidSDreamr said:


> Thanks swerlz.  I guess that rule that out.  Except for the expansion/contraction of the piperidine on PCP. has that been done?



Rolicyclidine (where PCP's piperidine has been contracted to a pyrrolidine) has been claimed to be more sedating rather than stimulating and is somewhat weaker than PCP, but still close enough to its big brother that it was placed in Schedule I (i.e. banned) back in the 70's.

https://en.wikipedia.org/wiki/Rolicyclidine


----------



## LucidSDreamr

It sounds like my cup of tea


----------



## Solipsis

*NSFW*:


----------



## Swerlz

lol great picture


----------



## JacksinPA

Dumb newbie question: how do I upload a jpeg image from my hard drive? These don't have urls to my knowledge. Other boards let you do this with no sweat.

I have a number of jpeg files that I created with my ChemDraw 17. The one I'd like to upload & discuss relates to the binary formation of VX nerve gas & how it was used by those 2 women who assassinated Kim Jung-un's brother recently.


----------



## LucidSDreamr

JacksinPA said:


> Dumb newbie question: how do I upload a jpeg image from my hard drive? These don't have urls to my knowledge. Other boards let you do this with no sweat.



the only thing i hate about Bluelight is the image thing.  You have to create an image shack account. upload your image there then paste the url into to photo button when you make  a Bluelight post


----------



## JacksinPA

Thanks. I'll have to check that out. But I am on a board with pretty much the same software & there is no problem uploading a jpeg from My Documents in Windows 7. Isn't there an option to allow this that the list owner can switch on?


----------



## LucidSDreamr

i would love it if they did


----------



## LucidSDreamr

do arylchxamines require the H on N?


----------



## Solipsis

No, cf. PCP or https://en.wikipedia.org/wiki/Rolicyclidine

However, smaller rings than pyrrolidines may pose problems - for example aziridine is likely to be mutagenic and azetidine may also be toxic. I don't know about N-alkylketamine (tertiary amine) type compounds, can't find info easily. Dimetamine would be an example of such an ACHA.


----------



## LucidSDreamr




----------



## JacksinPA

Takes a lot of steps to get those 3 iodos in the 3,4,5 positions. Unattractive from both the economics as well as logistics (read lab) POVs. Probably looking at solubility problems also.

FWIW, 1,2,3-triiodobenzene appears to be commercially available so steric issues may not be as much of a problem as I had thought.


----------



## JacksinPA

I signed up with Image Shack last night but they still haven't sent me a verification email. I did send inquiry about that & did receive a response but so far no luck. My email server is going down for main this weekend so I may have to wait.

There has to be an easier way to do this. The debate Politics board lets you upload direct from your MyDocuments in Windows 7.

Jack


----------



## LucidSDreamr

^ it takes them a little while to send the confirmation email you should have it now


----------



## sekio

Deutetrabenazine, the 1st deuterated pharmaceutical approved by the FDA.

Why not deuterated RC's? The increased "weight" of the deuterium can reduce metabolic lability by decreasing reaction rates, meaning longer half life and better BA.






PS imageshack sucks. Use imgur


----------



## JacksinPA

I got their email & they wanted $$$. Better free alternative is *postimage*. I'll post some of the structures I created using my new ChemDraw Professional 17.


----------



## JacksinPA

I tried IMGUR & could not upload the structure. Only free *postimage* works for me. See example:


----------



## JacksinPA

A one-step synthesis of this endogenous cannabanoid. Easy water wash workup. Thought vaping this stuff in a water aerosol might work for administration, it being a lipid & the lining of the lungs having lipid membranes.


----------



## JacksinPA

I modified the program's structure for ibogaine to get this. Too much work to start from scratch when you don't have to! Shorthand for this molecule is *18-MC*.


----------



## Swerlz

Shulgin did some research with deuterated 2c'd



> The effects of 4-D and beta-D are similar to one-another, both as to dosage and effect. And with both, there is a close parallel to those reported from mescaline. It is reasonable to assume that the human body handles these materials in the same manner, although no metabolic studies have ever been published.
> 
> A similar deuterium substitution pattern is of course completely feasible with TMA and related 3,4,5-trimethoxy-substituted analogues. Some studies have supported the idea that the ability to remove methyl groups from such aromatic ethers might be correlated to endogenous schizophrenia. It is possible to imagine that, in such individuals, the effects of substituting trideuteromethyl groups for normal methyl groups might result in psychopharmacological differences of action. Two reports exist that describe metabolic products of mescaline that have lost this methyl group on the 4-position oxygen. It is possible that these might be produced in abnormal quantities in mentally ill subjects. There are also similar reports of the 3-methoxyl group being demethylated in man. Here, studies with 3,5-D (3,5-bis-trideuteromethoxy-4-methoxyphenethylamine) might reveal some differences in quantitative responses in man. These are extremely minor metabolites, however. I suspect that more extensive studies will establish that 4-D, 3,5-D and beta-D all have properties indistinguishable from one-another, at least in healthy subjects.


----------



## JacksinPA

Perhaps OT so please forgive me. I have both *PIKHAL *& *TIKHAL* & actually met Shulgin at an ACS meeting in Anahaim, CA. Nice guy. Would have enjoyed talking to him longer. Believe he started out as a research chemist at Dow Chemical's former ag research facility in Walnut Creek, CA. I think he created *DOM* there in 1963. Dow was more interested in making _*Agent Orange*_ for the Vietnam War.


----------



## JacksinPA

In the middle to this nasty flu epidemic, I have 10 75 mg caps of generic *Tamiflu* sitting in my fridge at 37 deg. If I don't need it this year it should be OK for use next year. I would never think to store this kind of molecule at room temperature.


----------



## JacksinPA

SAR studies have shown that reversing the position of the carbonyl & amide nitrogen groups produces so-called* retro-anandamides* with more potent receptor binding affinity.


----------



## JacksinPA

SAR studies have produced other more potent anandamide derivatives such as *ACPA* where the ethanolamine function is replaced with a cyclopropyl amine group:






The 4_* cis*_ double bonds are required for full activity.


----------



## JacksinPA

I've been taking gabapentin for years to treat the depression side of bipolar. At 100-200 mg 2-3 times/day, it's like taking sugar pills - no noticeable effects. But when I tried 2,000 mg in one shot on a mostly empty stomach, I had quite the pleasant buzz that evening.

There's a discussion on the* Gabapentin High* thread about this drug's bioavailability & absorption limits. That got me thinking about this molecule. Basically it is an amino acid with a big, fatty cyclohexane ring in its middle. This type of molecule is called zwitterionic as it contains both an acidic & a basic functional group. That got me thinking about simple water-soluble acidic & basic salt derivatives that might significantly alter the drug's effects. The acid form could be the hydrochloride salt & the basic form could be the sodium salt. Both of these are known materials. See graphic:


----------



## sekio

Gabapentin is kid of weird in that it's not absorbed through "normal" diffusion, it actually uses the amino acid transporter to cross the BBB. Staggered dosing is much more effective than bolus dosing -  BA goes _down_ with increasing dosage.

Forming a salt of either kind is not really useful - the blood has a fixed pH of around 7.4, the stomach has a fixed pH of approx. 1-2, and the intestines have a pH of about 6-7.

So any orally absorbed drugs will likely exist as a HCl salt in the stomach and only later on, in the intestine, do they change to uncharged forms which cross lipid membranes easier.





There has been a prodrug with much higher BA which releases gabapentin upon metabolic hydrolysis, called gabapentin enacarbil. Note the bulky group blocking the ionizable NH2 present in gabapentin.


----------



## JacksinPA

It's hard to believe that you apparently can buy this plant material on the internet. https://www.uspharmacist.com/article/the-dea-changes-its-mind-on-kratom

I created these structures out of curiosity as I had not been familiar with Kratom until just now. I also was challenging ChemDraw's Name > Structure function. There are some differences between the structures of the parent alkaloid & its 7-hydroxy derivative.

Interesting reading about the pharmacology of these alkaloids. 

I was just over on the Kratom thread & *I wouldn't touch this stuff *unless somehow my life depended on it.


----------



## Nagelfar

JacksinPA said:


> It's hard to believe that you apparently can buy this plant material on the internet. ....I had not been familiar with Kratom until just now...*I wouldn't touch this stuff *unless somehow my life depended on it.



Kratom is quite widely abused, in my somewhat smaller-ish American town there are signs at headshops with just one word "Kratom", and people everywhere around have been using it for going on a decade or more. Not really at all considered unsafe, unless you consider opioid addiction in all its forms so.


----------



## JacksinPA

I was reading some of the withdrawal stories in the Kratom thread & it sounds like trying to get off heroin. I have an addictive personality but no interest in even experimenting with something that really gets the hook in you. I'll stick to my prescription benzo, gabapentin & Polish potato vodka, thanks!

I have had fun with the usual recreational drugs like _Cannabis_, _Psilocybe_, LSD, nitrous oxide, gabapentin, organic mescaline, & Polish potato vodka. But I have never felt the need to get involved with anything that involves physical addiction & the specter of having to go through withdrawal. I'm a senior citizen & my doctor keeps me on a pretty short leash, so getting hooked on something like Kratom does not sound  like a good idea.


----------



## JacksinPA

From another thread:


----------



## sekio

> something that really gets the hook in you



I suggest you read a couple stories of benzo withdrawal


----------



## JacksinPA

My DO is very happy prescribing alprazolam to me & I'm very happy using it to fall asleep after getting up to pee in the middle of the night. Why no tolerance to this after 35+ years is a mystery to me as I know I've developed tolerance to flurazepam & possibly to midazolam & fentanyl as well. Propofol is now my anesthetic of choice for anything surgical. Have used it twice in the last 18 months with very good results.

Strange about the fentanyl as I've only had it used on me (cataract surgery) twice & both times it instantly knocked me out. But a mixture of midazolam & fentanyl that they were giving me via IV during an endoscopy didn't even give me a buzz. I've had midazolam 5-6 times for colonoscopies & woke up only once when this big GI doc was poking into me hard with the 'scope, then went back to retrograde land.

While I'm aware that discontinuing even low regular doses of benzos can cause seizures & possible brain damage, I'm just glad that tolerance hasn't shown up & I can continue taking them.

Besides the lack of tolerance question, I find the fact than alprazolam rapidly puts you into REM sleep very interesting.


----------



## Solipsis

The problem only gets serious if you have reasons to use these sorts of drugs daily to (self-)medicate a persistent problem. Benzo's are so much worse than kratom in this respect and can be at least as bad or worse than serious opioids if you feel very inclined to use daily.
Just like with incidental benzo use, incidental kratom use is fine if you are relatively stable and problem-free. This is your major predisposition to addiction, not just the lack of self-control people associate with addiction. Coming off opioids feels hard and horrible but with benzo's it can feel functionally impossible especially because it can take so incredibly long to function ok again.

Opinions on kratom seem quite polarized, some people are suprisingly scared of it and others find it unreasonably harmless in all respects. The truth is somewhere in the middle, there are some positives like the ceiling effect limiting but not eliminating abuse potential. It also means people don't die but just feel like shit if they take a lot... unlike with heroin and other opiates where ultimately both of those things happen.
I know people have serious problems with chronic daily use of kratom... I can personally start to like it a bit too much when still finishing a first small batch every once in a while and don't like it to quit again but I manage and just quit it again anyway whereas I wouldn't dare with harder opioids anymore since I had problems with them. There are just a bit too many off feeling sides to kratom for me to really be okay with taking it for extremely long periods.
There are also signs that kratom does not stimulate the pleasure centers in the brain quite like morphine etc do.

It's a personal thing and not a black and white story. By all means if you are worried, avoid certain drugs to be sure... seems preferable over making an unnecessary and grave mistake.

I do like benzo's such as alprazolam or etizolam for sleep even though they are not hypnotics. The more hypnotic benzos are the more you go out like a light but the worse it also seems to be for your actual sleep quality. I think way too many elderly seem to be on drugs like these and they were a nightmare for me to take regularly (but I can safely take them only sporadically now), on the other hand I understand completely the reasons like pain and discomfort to treat... I just dread the moment I would have to constantly treat such symptoms that way, things get so lopsided it is an irreversible proces.
Benzos don't have as bad a name as many other drugs and you might not think this from just taking one every once in a while but trust me: they can be among the worst.

Anaesthetics are a different story entirely. Some can be really heavy, and such a rapid route of administration of anaesthetic doses of the drugs you mentioned leave you little time to get into a 'recreational phase'. The seizures etc can happen with just alprazolam or etizolam but typically you would need to take rather high dosages and/or quit abruptly which are both terrible anyway. I can't imagine what it is like to abuse things like propofol etc.


----------



## Soulfake

Some benzo analogues I'd like to test and a random phenethylamine-norbornane compound. I wonder why there are no methoxy-substituted benzos? Also I'm interested in the pyridine-analogues like Bromazepam and Pyrazolam as well as 3-methyl benzos like Meclonazepam, why are those so rare?
/edit the second one is Diazepam for comparison


----------



## Solipsis

Isn't the planar structure of phenethylamines pretty important?

I wonder why *1*-methyl benzos are not more available.. @ 3-methyls: meclonazepam is kinda nice but nothing special I guess - haven't tried high dosages and I am not really looking for that anyway, it was suspiciously cheap when i bought it and just served as a backup. I guess it didn't meet therapeutic standards in trials, which I would understand if only because it has little to contribute that other benzos don't do better.
It also has a chiral center there which isn't exactly something you want or need either unless it's *that* potent right?


----------



## roi

Cyclopropylpemoline appeared as "nootropic" a while ago, this might increase fun & potency.


----------



## JacksinPA

You have  the structure wrong for this molecule. See https://psychonautwiki.org/wiki/Cyclazodone. You've drawn it with the side group as oxetan-3-amine rather than *cyclopropyl amine*. It's also said to be hepatotoxic. Here is the correct structure for *cyclazodone:

*





I did a brief Google search & see it available as a 'research chemical'._* Caveat emptor.*_


----------



## aspiringdrugdesign

Currently going over organometallics rn, I'm aware this would probably have genotoxic / other toxic properties, but can anyone tell me what dangers would arise from something like this? 

I was thinking the Br would leave the magnesium pretty easily, which could brominate things that shouldn't be brominated. Is there more to it?


----------



## JacksinPA

What you've drawn is called a Grignard Reagent. Firstly, it couldn't exist as you've drawn it because the Ar-Mg-Br would react with the free amine on the end of the ethyl chain. I don't believe this would act as a brominating reagent even if you protected that amine first with groups that could be removed in a later step, like benzyl groups with can be removed via hydrogenation. I'm not familiar with any application of these reagents as brominating agents. There are simple, commercially available molecules like N-bromosuccinimide & even elemental bromine for doing that.

Grignard reagents are formed in solution of either dry ether or tetrahydrofuran & are not usually isolated but are reacted directly with things like ketones & aldehydes. With metal catalysis they  can be made to couple with things like alkyl halides.

So yes, there is a lot more to it. Just being able to draw a structure doesn't mean it makes sense or can be made or exist in the real world.

I don't know what your educational background is in organic chemistry, but Grignard chemistry is usually first-year college organic 101. If you haven't already, order a good introductory organic textbook from Amazon or your local college bookstore. Or just read this: https://en.wikipedia.org/wiki/Grignard_reaction

Whatever you wind up doing, be very careful with Grignard chemistry. You're working with volatile & flammable solvents that have to be specially purified to remove peroxides & dried before using. The Grignard reaction itself, where magnesium metal reacts with the organic halide, are many times difficult to get started due to factors such as surface oxidation on the magnesium metal you are using. And once started, they can get pretty active, so you have to work under efficient reflux condensers for proper cooling. And most Grignard reactions are run under a continuous flow of dry nitrogen. Good luck!


----------



## roi

JacksinPA said:


> You have  the structure wrong for this molecule. See https://psychonautwiki.org/wiki/Cyclazodone. You've drawn it with the side group as oxetan-3-amine rather than *cyclopropyl amine*. It's also said to be hepatotoxic. Here is the correct structure for *cyclazodone:
> 
> *
> 
> 
> 
> 
> 
> I did a brief Google search & see it available as a 'research chemical'._* Caveat emptor.*_



This thread is titled "draw pictures of random molecules" - in case you haven't noticed, the 4-fluorophenyl group doesn't exist in Cyclazadone either 

I draw a different molecule which "might increase fun & potency" (compared to, yes, Cyclazadone!).


----------



## JacksinPA

Fluorine & novel side chain or not, pemoline & likely its derivatives are nothing to play around with except to draw. See: Liver toxicity In some patients pemoline is suspected of causing hepatotoxicity,[8] so the FDA recommended that regular liver tests should be performed on those treated with it.[9] Since receiving FDA approval in 1975,[10] it has been linked with 21 cases of liver failure, of which 13 resulted in *liver replacement or death*.

In March 2005 Abbott Laboratories and generic manufacturers withdrew pemoline from the American market due to concerns about the liver toxicity risk.[11] See https://en.wikipedia.org/wiki/Pemoline Perhaps fun & potency before you die of liver failure.

Regarding cyclazodone:
*toxicity and harm potential*

The toxicity and long-term health effects of recreational cyclazodone use do not seem to have been studied in any scientific context and* the exact toxic dosage is unknown.* *This is because cyclazodone has a very limited history of human usage.*
*There exists a history of liver failure in children taking the structurally related compound pemoline[8], which resulted in its removal from the market. *Another compound related in structure, 4-methylaminorex, has been associated with pulmonary hypertension[9]; though, it is reported to induce far stronger stimulation than that of cyclazodone. While cyclazodone is 5-10x more potent than pemoline,* it is not known if it possesses the same level of hepatoxicity.*
In rodents and primates, sufficiently high doses of monoamine releasing agents cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized by reduced transporter and receptor function. There is no evidence that releasing agents are directly neurotoxic in humans. However, large doses of releasing agents may cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine.[_citation needed_]
*It is strongly recommended that one use harm reduction practices when using this substance.*
*Tolerance and addiction potential*

Addiction is a serious risk with heavy recreational stimulant use but is unlikely to arise from typical long-term medical use at therapeutic doses. Notably, the structurally related compound pemoline fails to demonstrate a potential for self-administration in primates and is considered to have reduced risk of dependence relative to those more typical dopaminergic stimulants. Caution is nonetheless advised, as with other monoamine releasing agents.
*Tolerance to many of the effects of cyclazodone develops with prolonged and repeated use.* This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about 3 - 7 days for the tolerance to be reduced to half and 1 - 2 weeks to be back at baseline (in the absence of further consumption). Cyclazodone presents all dopaminergic stimulants, meaning that after the consumption of amphetamine all stimulants will have a reduced effect.
*Psychosis*

_Main article: Stimulant psychosis_
*Based on its pharmacological similarity to other stimulants, it is likely that misuse of this compound can result in state of psychosis marked by a variety of symptoms (e.g., paranoia, hallucinations, or delusions).*[10][11] *A review on the treatment for amphetamine and methamphetamine abuse-induced psychosis states that about 5–15% of users fail to recover completely.*[11][12] The same review asserts that based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[11] Psychosis very rarely arises from therapeutic use. The combination of the prolonged use of high doses combined with sleep deprivation significantly increases the risk of stimulant psychosis.[
https://psychonautwiki.org/wiki/Cyclazodone


----------



## sekio

> can anyone tell me what dangers would arise from something like this?
> 
> I was thinking the Br would leave the magnesium pretty easily, which could brominate things that shouldn't be brominated. Is there more to it?



Grignard reagents are strong bases, they are incompatible with proton-bearing groups (-OH, -NRH or -NH2, -SH) and anything that's even slightly acidic will end up converting R-Mg-X to R-H and Mg(OH)X where X=Cl, Br, I.

So unless you had protected the amine as a phthalimide or something the Grignard would not be formable. And even if you could form it, working in anhydrous ether solvents (ethyl ether and THF are two common ones) is mandatory, with dry glassware and a stream of N2 or argon purging any moisture and oxygen out.


----------



## roi

Yeah JacksinPA, Pemoline itself is a metabolite of Levamisole iirc. Certainly not one suited for regular use.

Back on topic:


----------



## Nagelfar

roi said:


> Certainly not one suited for regular use.



It is for cokeheads.


----------



## JacksinPA

Roi

Does this have a trivial or non-commercial name besides its chemical name(s)? I don't recognize it off hand but carbamates are known to be carcinogenic & mutagenic.


----------



## JacksinPA

Potent CB1 agonist. There were 2 errors in the earlier drawing which I have corrected.


----------



## aspiringdrugdesign

JacksinPA said:


> What you've drawn is called a Grignard Reagent. Firstly, it couldn't exist as you've drawn it because the Ar-Mg-Br would react with the free amine on the end of the ethyl chain. I don't believe this would act as a brominating reagent even if you protected that amine first with groups that could be removed in a later step, like benzyl groups with can be removed via hydrogenation. I'm not familiar with any application of these reagents as brominating agents. There are simple, commercially available molecules like N-bromosuccinimide & even elemental bromine for doing that.
> 
> Grignard reagents are formed in solution of either dry ether or tetrahydrofuran & are not usually isolated but are reacted directly with things like ketones & aldehydes. With metal catalysis they  can be made to couple with things like alkyl halides.
> 
> So yes, there is a lot more to it. Just being able to draw a structure doesn't mean it makes sense or can be made or exist in the real world.
> 
> I don't know what your educational background is in organic chemistry, but Grignard chemistry is usually first-year college organic 101. If you haven't already, order a good introductory organic textbook from Amazon or your local college bookstore. Or just read this: https://en.wikipedia.org/wiki/Grignard_reaction
> 
> Whatever you wind up doing, be very careful with Grignard chemistry. You're working with volatile & flammable solvents that have to be specially purified to remove peroxides & dried before using. The Grignard reaction itself, where magnesium metal reacts with the organic halide, are many times difficult to get started due to factors such as surface oxidation on the magnesium metal you are using. And once started, they can get pretty active, so you have to work under efficient reflux condensers for proper cooling. And most Grignard reactions are run under a continuous flow of dry nitrogen. Good luck!



Ah, just learned in class today that there should be no protonated atoms like OH, NH, SH and so on with a Grignard Reagent. I wasn't actually planning on synthesizing any of this, I don't even know how -- I was just curious if it was even plausible since we went over the reaction in OChem. 

Thanks for the insight!


----------



## LucidSDreamr

How I want to shoot up:


----------



## LucidSDreamr

aspiringdrugdesign said:


> Ah, just learned in class today that there should be no protonated atoms like OH, NH, SH and so on with a Grignard Reagent. I wasn't actually planning on synthesizing any of this, I don't even know how -- I was just curious if it was even plausible since we went over the reaction in OChem.
> 
> Thanks for the insight!



what makes the H on OH or SH different than the Hs connected to carbon atoms all througout the molecule? why don't those react while OH and NH2 do react?  Always think about why something happens and you will ace organic chemistry.


----------



## JacksinPA

They also react. Different bond strengths, acidities.


----------



## clubcard

For people thinking about NMDA antagonists, the spacial position of the basic amine's lone-pair is key. 8A-PDHQ has too many isomers so the metabolism could be complex so thumbs down. Dizocilpine has similar affinity but no DRI activity so isn't euphoric. The 1,2-diphenylethyl amines are non-rigid dizocilpine analogues. I cannot remember the 'magic angle'. I think it's 107.5? but this is thinking back 5 years. Dextrophan has the aromatic and 2 methylene spacer but seems too promiscuous. A French team took tiletamine, swapped cyclohexane for a 4-thiane and added an o-methyl. That obviously leads to 4 isomers but one was very potent indeed and who knows, maybe the sulphur is oxidised so by the time it reaches the bladder, it is inactive which may improve chronic bladder damage. It was published in a European (as a whole) periodical. They made a large set but both synthetic complexity and uncertainty of the metabolism of the 4 isomers (maybe you can racemize it so you just get the trans isomers?) made it another thumbs down. The space-filling methyl in dizocilpine may overlap the French set, who knows?

So, for the sake of keeping it real, the arylcyclohexyl (smaller and larger rings are inactive) and 1,2-diphenylethyl amines are the only 2 scaffolds worth tinkering. I DID wonder about affixing an extra carbon onto the 1,2-DEAs i.e. isopropyl but once again, isomers.....


I would appreciate someone confirming that angle. It was US research that discovered it,


----------



## aspiringdrugdesign

LucidSDreamr said:


> what makes the H on OH or SH different than the Hs connected to carbon atoms all througout the molecule? why don't those react while OH and NH2 do react?  Always think about why something happens and you will ace organic chemistry.



Well it'd be due to their relative electronegativities, right? Also I'd bet their pKa values impact how readily hydrogens are given up, and what is bonded to the carbons themselves. 

What's that polymer looking thing with an opioid on it? Is that a delivery system?








Are there any alpha ketone phenethylamines with activity? I noticed modafinil and phenylpiracetam have this group (I know SARs don't work conveniently like that), and was curious if it had any certain role in binding to receptors


----------



## clubcard

an alpha methyl on an amine is an amide. Not basic.


----------



## LucidSDreamr

clubcard said:


> an alpha methyl on an amine is an amide. Not basic.



no, its still an amine, like alpha methylation of phenethylamine giving amphetamine. alpha carbonyl on an amine would be an amide


----------



## Hodor

aspiringdrugdesign said:


> What's that polymer looking thing with an opioid on it? Is that a delivery system?



That "polymer thing" is a carbon nanotube, an extremely rigid carbon-based nanostructure. You've probably heard about this stuff already, and how it is supposed to be the wonder material of the future that we'll use to make anything from ultra-lightweight vehicles to computer circuitry to giant tethers for space elevators. I think LucidSDreamr was making a joke about wanting to inject his hydromorphone straight into the receptor


----------



## LucidSDreamr

^main lining is for pussies. main-receptoring is gonna be all the rage in the future


----------



## Hodor

LucidSDreamr said:


> ^main lining is for pussies. main-receptoring is gonna be all the rage in the future



Why stop at hydromorphone though? _Reversible_ agonism? Pfffsh 8). If you truly want to get #redpilled (redneedled?), try CHLOROXYMORPHAMINE. This is oxymorphone with the 6-Oxo group replaced by a bis-chloroethylamine group, better known as _"nitrogen mustard"_, a type of military-grade blistering agent and cytotoxic chemotherapy drug. In other words, you're *irreversibly* gluing that opioid into the receptor through *chemical warfare*.


----------



## JacksinPA

I can't find any reference to methyl (1,2-diphenylethyl)carbamate. Is this a known molecule or something you are just interested in?


----------



## JacksinPA

Good luck with having anything to do with highly toxic nitrogen mustards.


----------



## JacksinPA

Potent CB1 agonist. Interesting open structure without connecting rings - terpenoid coupled to an aromatic.


----------



## JacksinPA




----------



## Dresden

SAM:  4-methylamphetamine
BILLY:  4-methylmethamphetamine
SAMANTHA:  4-methylethamphetamine

Ok, so this series is pretty much too strongly intoxicating to play around with, except for *maybe* SAMANTHA, the N-ethyl one.  (N-ethylamphetamines tend to be more forgiving).  Getting FUBAR does have its time and place, however.  So if you're gonna go that route, tread lightly and be forewarned.  Less toxic alternatives include JERRY (N-propylamphetamine) and EVELYN (N-ethylamphetamine), both great for non-stop stim/sleep cycles.  As far as all night dance parties go, though, there is no substitute for TONY (non-Darzen condensed MDMA).

* * *

An Addendum:

As far as I can tell, I was not in the Garden of Eden, did not eat from the Tree of Knowledge of Good and Evil, and know about as much about original sin (namely, zero) as does your pet goat, for example.  Human beings' constant judging of each other (and me) is beyond me.  I may be bizarre, but I am not evil.  See Frederick Nietzsche ("Beyond Good and Evil") and Prometheus (historical figure) for further reading.  

* * * 

Back on topic,

VISHNU's (meth) manifestations include but are not limited to SATAN/YAMA (4-nitro-meth) and KRISHNA (mescaline).  When he is in his meth form, which is usually, VISHNU can be defeated by EVELYN (eth), because 'ethyl tricks methyl.'  And, by homologous chemical/logical extension, JERRY (N-propylamphetamine) can defeat EVELYN (N-ethylamphetamine).  Everything in paragraph can be conjured up from over the counter almond oil btw, except for mescaline.  The haoma gets weaker with every new chemical age, just as the great ages get worse with time, and eventually the process repeats. 

This process [the ending of time?]--which as of late has been unfurling before our very eyes--doesn't seem to have any real beginning or end, and I would say we are right in the middle of it.

In related news, MTV is playing music videos again.


----------



## JacksinPA

This is the structure of the new antiviral drug being launched this year in Japan & hopefully next year in the U.S. One dose of this drug kills the flu virus by inhibiting an enzyme that it needs to replicate. The current medication for flu, Tamiflu, you need to take over 5 days.

The compound shown is a prodrug. The red part of the structure (a carbonate mixed ester) gets clipped off by an enzyme once the molecule gets inside the cells.


----------



## LucidSDreamr

That looks like a tca and some sort of old generation antiosychitic ...crazy looking drug


----------



## JacksinPA

Yes it is. I had to download a 425-page U.S. Patent Application & go through 700 or so structures to confirm this one. Interesting molecule . It inhibits the enzyme endonuclease that the flu virus needs to multiply. Shionogi has licensed this to the big Swiss pharma company Roche to market outside Japan & Taiwan. Since their Tamiflu has gone generic they need this new flu drug to make up for the loss in profits. I'll bet this one will be expensive for that one dose. Ten caps of generic Tamiflu cost me over $100, so you can expect this one to be much more than that. And most Medicare Plan D drug insurance programs don't pay for most expensive new drugs.

The cost to manufacture this stuff is going to be high as it is multi-step chiral chemistry.

The chiral separation part is interesting. The molecule has 2 chiral atoms so there would result a mixture of diasteriomers that could be separated readily via recrystalization.

I had only found a grainy image of this molecule in a pay site & had to go through all of those structures to find the correct one. The empirical formula agrees with the one in the Wikipedia article: https://en.wikipedia.org/wiki/Baloxavir_marboxil


----------



## aspiringdrugdesign

JacksinPA said:


> Potent CB1 agonist. Interesting open structure without connecting rings - terpenoid coupled to an aromatic.



In the cyclohexanone group at the top left, what are those dashed lines? Is that part of skeletal diagrams?


----------



## JacksinPA

The dashed lines are C-C bonds with C atoms at the center & ends of the 2 lines in the center. The synthesis involves coupling the alkynyl resorcinol (right half of molecule) with the bicyclic terpene *nopinone*. See attached structure of* nopinone*. In this drawing the bonds are solid lines. Just compare the 2. The drawing of AM1703 is just a different way of drawing a crowded molecule. The full nomenclature for *nopinone *is* bicyclo[3.1.1]heptan-2-one, 6,6-dimethyl-. *It is found in the aroma of certain flowers & is used in perfumery.





Here is another way of looking at this bicyclic structure:


----------



## adder

> aspiringdrugdesign said:
> 
> 
> 
> In the cyclohexanone group at the top left, what are those dashed lines? Is that part of skeletal diagrams?
Click to expand...


The dashed lines here symbolize that the bonds are below the plane of the drawing, however, one should never use dashed lines to represent bonds below the plane, such use is very unfortunate as in some cases it might create ambiguity as to what was meant by the author. Dashed lines are used to represent weak interactions due to electrostatic attraction such as hydrogen bonds, so using them to represent stereobonds is a bad idea. Honestly speaking, it amazes me why there may still be any debate on how to represent stereobonds and you run into structures drawn like this. Bonds below the plane are correctly represented by a hashed wedged bond starting from an atom in the plane of the drawing at the narrow end of the wedge, just like bonds over the plane are represented by a solid wedged bond (although for some reason for hashed bonds some advocated to use them the other way around, that is starting from an atom in the plane at the wide end; it will make sense of course if you apply appropriate logic, but it looks very ugly in my opinion when placed on the same atom on which a solid wedged bond is placed as well, it looks kind of ugly to me no matter what, but more importantly it lacks consistency). Compare structures below and decide for yourself what makes the most sense and what is the most elegant:


----------



## LucidSDreamr

adder said:


> The dashed lines here symbolize that the bonds are below the plane of the drawing, however, one should never use dashed lines to represent bonds below the plane, such use is very unfortunate as in some cases it might create ambiguity as to what was meant by the author. Dashed lines are used to represent weak interactions due to electrostatic attraction such as hydrogen bonds, so using them to represent stereobonds is a bad idea. Honestly speaking, it amazes me why there may still be any debate on how to represent stereobonds and you run into structures drawn like this. Bonds below the plane are correctly represented by a hashed wedged bond starting from an atom in the plane of the drawing at the narrow end of the wedge, just like bonds over the plane are represented by a solid wedged bond (although for some reason for hashed bonds some advocated to use them the other way around, that is starting from an atom in the plane at the wide end; it will make sense of course if you apply appropriate logic, but it looks very ugly in my opinion when placed on the same atom on which a solid wedged bond is placed as well, it looks kind of ugly to me no matter what, but more importantly it lacks consistency). Compare structures below and decide for yourself what makes the most sense and what is the most elegant:



i feel like the "most correct way" is less correct than the one in the blue box. And i always see it like the blue box, never really seen it like the green.  The green box (by drawing stereochemistry on the alcohol) implies that the other three bonds are running all on the same plane, which isn't the case


----------



## adder

The blue box certainly looks nicer to the eye and is all right to be used of course. But the green box doesn't imply that the other three bonds are running all on the same plane just as all the plain bonds representing the cyclohexane ring alone don't imply that the structure is flat. Drawing a solid wedged bond between C3 and OH is enough to define what the stereochemistry at C3 is and that's what the solid wedge is here for, using a hashed wedged bond between C3 and ethyl is not necessary. The blue box does not represent what the molecule looks like in 3D either after all.


----------



## aspiringdrugdesign

Thanks for the explanation guys, I had only ever seen the wedge/hash bonds to represent that concept before.






Knowing that thiophene can possibly act as a bioisostere to benzene, would this be of any practicality? Would it be much more difficult to synthesize?


----------



## LucidSDreamr

adder said:


> The blue box certainly looks nicer to the eye and is all right to be used of course. But the green box doesn't imply that the other three bonds are running all on the same plane just as all the plain bonds representing the cyclohexane ring alone don't imply that the structure is flat. Drawing a solid wedged bond between C3 and OH is enough to define what the stereochemistry at C3 is and that's what the solid wedge is here for, using a hashed wedged bond between C3 and ethyl is not necessary. The blue box does not represent what the molecule looks like in 3D either after all.



the cyclohexane isn't all on the same plane, but every single two bonds coming from each carbon (3 points) are all on the same plane, this breaks down on the green drawing. I 've been doing chemistry for about 11 years and never seen it like that until now.


----------



## aspiringdrugdesign

Genetics has been inspiring me --

Caffeine is a xanthine. Xanthosine triphosphate is a thing. Adenosine triphosphate is a thing, and caffeine is an adenosine antagonist -- giving it some of its stimulant effects. Would the body have any use for a caffeine analog of xanthosine triphosphate? I'm assuming that the three methyl groups are gonna muck this up, but here is a few pictures of my ideas: tautomers and ethyl/methyl bridge versions. I wasn't sure if the ribose would form an ethyl bridge or a methyl bridge because of caffeine's structure. 

My bad on the messy structures, the ribose triphosphate was a little tricky to draw 























Also, what would this be called? Caffeinosine triphosphate sounds a little goofy


----------



## adder

LucidSDreamr said:


> the cyclohexane isn't all on the same plane, but every single two bonds coming from each carbon (3 points) are all on the same plane, this breaks down on the green drawing. I 've been doing chemistry for about 11 years and never seen it like that until now.



GRAPHICAL REPRESENTATION OF STEREOCHEMICAL CONFIGURATION

OK, so I checked it with IUPAC recommendations to be fair. The paragraph on tetrahedral configuration starts on p. 1910 in the linked document if anyone is interested. First of all, based on IUPAC recommendations the original green box structure in my previous post is actually rather incorrect because there is a pair of plain bonds separated by 180 degrees, while if the green box style is to be used (i.e. only one stereobond), each pair of plain bonds should be separated by less than 180 degrees and ideally by exactly 120 degrees, except for specific cases where drawing a pair of plain bonds at 180 degrees is unavoidable (see p. 1913 in the linked document).

Both the green box and the blue box styles are correct though, however depending on the situation one may be preferred over another. If the blue box style is used, it is recommended that the bisects of plain bonds and stereobonds are collinear (top structure in the blue box), although it is not mandatory. In this particular case of this cyclohexanone analogue that I've given the blue box style should be preferred based on IUPAC recommendations (and for aesthetic purposes too, I agree), the green box style is correct too but is preferred for chiral atoms in fused and bridged systems.

I have redone the image and added the original green box structure into the red box, although I'm not sure if treating it in the same way as the other three depictions in the red box is the right thing to do. Reading the structure drawn this way should not be ambiguous to any chemist and it doesn't bring in any inconsistency like using dashed lines does for instance, on the other hand for aesthetic purposes it should be avoided.


----------



## JacksinPA

Probably but we can't get into talk of synthesis schemes here. But the name of the bicyclic heterocycle is* 4H-thieno[3,2-b]pyrrole*.






You might also consider the following isomers:


----------



## JacksinPA

I'm curious as to the possible bioactivity of these & related amphetamine analogs:






The sulfur compound is known but I could not find anything on the oxygen. In any event, nothing on bioactivity for either.


----------



## Pomzazed

JacksinPA said:


> I'm curious as to the possible bioactivity of these & related amphetamine analogs:
> 
> 
> 
> 
> 
> 
> The sulfur compound is known but I could not find anything on the oxygen. In any event, nothing on bioactivity for either.


 Bcos it is unstable and breaks to a phenol, an acetaldehyde and an ammonia


----------



## sekio

Yes, that is what is known as a hemiaminal


----------



## aspiringdrugdesign

Why doesn't cathinone form imine polymers if they have ketones and primary amines? Is there something about the bulkiness preventing imine formation?


----------



## Hodor

aspiringdrugdesign said:


> Why doesn't cathinone form imine polymers if they have ketones and primary amines? Is there something about the bulkiness preventing imine formation?



AFAIK, cathinone does condense/dimerize to 3,6-Dimethyl-2,5-Diphenylpyrazine, which is one of the reasons that khat needs to be eaten fresh (the other reason being the reduction of cathinone to the significantly less psychoactive cathine).

While the elimination of water should shift the equilibrium towards the condensation reaction, using the right methods the plant can apparently be dried without destroying most of the cathinone.


----------



## aspiringdrugdesign

Dresden said:


> This will SHONUF snuff out _Treponema pallidum_ in the brain (neurosyphilis).  For IV use.  The current treatment is only 50 to 60% curative.  And the RPR blood test is only 65% accurate (nearly worthless).  The N-(2-phenyl-1-methylethyl) residue will awaken the dormant, non-antigen displaying pleiomorphic spirochetes, with hope.  I be your Guinea Pig.  If not that, try plain carbomethoxylated penicillin G.  Is Tusckeegee in the House?  Fuck, yea.  [So So Def Records].
> 
> So which is it?  Do ya'll want more talk / explanations or less?  Less, I gather.



I want more talk/explanations, less neurotic/psychotic ramblings, reposts, and pre-existing molecules. 

What is this molecule supposed to be, a penicillin amphetamine hybrid? Would it work, or would the amphetamine substituent lower activity?

 Perhaps I'm being a blunt dick with what I just said, but this is a better post than the last few of yours.



Hodor said:


> AFAIK, cathinone does condense/dimerize to 3,6-Dimethyl-2,5-Diphenylpyrazine, which is one of the reasons that khat needs to be eaten fresh (the other reason being the reduction of cathinone to the significantly less psychoactive cathine).
> 
> While the elimination of water should shift the equilibrium towards the condensation reaction, using the right methods the plant can apparently be dried without destroying most of the cathinone.



Ah, that's actually a neat looking molecule. I wonder if it has any pharmacological significance? 






This is the molecule you're referring to, right?


----------



## roi

4-Fluoroisobutyrfentanyl/Remifentanil hybrid. Should increase Remifentanils duration by quite a lot, while also reducing its potency by ~2/3.


----------



## blueberries

A quick mashup between psilocin and 5-MeO; I call it Partyhatamine!






And another; Batwing 2C-B






Mescoxetamine


----------



## Pomzazed

The first and second are impossible due to instability, i dont think it can even be formed in thr first place.

First one breaks aromaticity forming reactive epoxide,  second one has very strained angle of bonds to the point of impossible.

Third one looks fine, tho


----------



## Solipsis

^ Quite probably active? https://en.wikipedia.org/wiki/Methamnetamine

Also for that matter, can't find anything on this.. i wonder if it is "just an appetite suppressant":






_1-phenyl-2-pyrrolidin-1-ylpropane_

The pyrrolidine group bears some comparison to something like a diethylamine, for the stimulant amphetamine type compounds it could be a pretty okay stim but those types of amine functions don't work so well for psychedelic PEAs.


----------



## roi

^Probably a weaker Prolintane?


----------



## Pomzazed

The methoxybenzopyridine, looks much alike methoxyindole to me.... eh


----------



## sekio

Several of Dresden's posts have been redirected to the new Name A Molecule Thread. For those who want to come up with silly names for drugs that's where they can post that now.


----------



## aspiringdrugdesign

Loosely based on methylphenidate and modafinil, not entirely similar however. Thoughts?


----------



## Pomzazed

Why thiophene oxide? Isnt that the toxic part? 
For the lower two molecules, i guess adding di-alkyl to N, will make it morelike of Lefetamine?


----------



## Dresden

Solipsis,






Would Make A Way Better 'Appetite Suppresant.'

roi,

Yes, Probably So.


----------



## doxylamine

You?re just trolling this thread at this point now, Dresden.


----------



## Dresden

Greenlighter Alert.


----------



## sekio

At least there's logic behind N-pyrrolidinocathinone being active.

Dresden's more "creative" entries have a home on his blog page now.


----------



## aspiringdrugdesign

Pomzazed said:


> Why thiophene oxide? Isnt that the toxic part?
> For the lower two molecules, i guess adding di-alkyl to N, will make it morelike of Lefetamine?



Ah, wasn't aware thiophene oxide is toxic! Does it get metabolized into something nasty? What if it's two oxygens instead? That's how modafinil is, but I'm not sure if the thiophene ring would change anything.


----------



## Pomzazed

The S=O (sulfoxide) nor S(=O)2 (sulfone) arent particulary toxic

Sometimes they can act as bioisostere of a carbonyl group, where sulfoxide is somewhat more “polarized” (has more characteristic of being S(+)—O(-) moreso than the carbonyl.

The thing i mentioned is that the thiophene is often considered (not always) hepatotoxic, whereas the toxic metabolite is the thiophene-S-oxide itself and not the thiophene.

Unless there is a particular fast pathway of elimination or site of metabolism that leads to easier excretion, thiophene is often oxidized to (either) thiophene-S-oxide, which is a reactive diene to participate in diels-alder reaction, or thiophene epoxide, which is a reactive electrophile.


----------



## Pomzazed

I see some saccharin...
Ps. Bleh! Stereocenters! Im too lazy to redraw image (its done on mobile phone, so ...)
Just assume we put in the “correct” stereoisomers then!   

Metamnesacrin 





Flubutosacrin 





Bimecanilosacin


----------



## Hodor

sekio said:


> At least there's logic behind N-pyrrolidinocathinone being active.



It is indeed active, having been sold as an RC for several years now, under the name a-PPP (alpha-PyrrolidinoPropioPhenone). It is significantly less potent and long-lasting than its infamous higher homologues a-PVP and a-PHP though, and thus never really caught on.


----------



## Pomzazed

Hmm... how should i name this..


----------



## sekio

That looks almost like resveratrol or pinosilvin, what is it supposed to do?


----------



## Pomzazed

first one is a hydrolysable prodrug of methoxy-amnepthamine
second one is a hydrolysable prodrug of a 4F-pentylcathinone
third is a hydrolysable prodrug of THC analog (replacing OH with NH2 retains equipotent activity, one methylcyclohexylethyl is for hydrophobic bulk pocket, another is a "tail"

fourth is similar to third, but the hydrophobic bulk has extra OH there (like HU-243) and a pi-stack from that benzene, other tail has phenylnitrile where the cannabinoid "tail" like a EWG there
(eg. a bromo or cyano analog of THC at the tail-end increase CB1 activity), although the lost of etheric O and adjacent dimethyl reduces activity

sth like this:


----------



## aspiringdrugdesign

I like the hydrolysis prodrug ideas Pomzazed! That's pretty cool. They hydrolyze to carboxylic acids or amides, right? 






THC analog with possible opioid activity unless my reasoning is faulty.

Has this been done before?


----------



## Pomzazed

Be worried if it will be opioid more than if it will be a cannabinoid then...
The cannabinoid "tail" position can tolerate much more change, size and functional-group wise!
And well yes basic groups have been tried there, like hydrazide in 83,84 or tertiary amine in 85,88


----------



## aspiringdrugdesign

Oo, that's a little exciting to see 88. I wonder if that cyclization is what gives it its affinity, or the tertiary amine in that position. Too bad they didn't make a version of 85 without the amide carbonyl.

Is there any info on the opioid affinities of those groups?


----------



## Pomzazed

I am not keen about opioids SARs, not much into it. Better wait for opinion from people who are in the field for more correct answer.

For things i can answer:
_I wonder if that cyclization is what gives it its affinity, or the tertiary amine in that position_

Cyclic or not, doesnt matter much, and

No, you just need a hydrophobic bulk along the tail length (the 1' position can be an etheric O without loss in affinity)
If the tail length is 1-3 atoms in length, it will bind but will be an antagonist
4+ atoms are agonists, >8 decreasing affinity and >10 is devoid of activity.

Electron withdrawing group (via SIGMA bond) at the tail end increase affinity
(eg. compare -CH2Br with plain -CH3)
at here N and O acts fine as withdrawing group in this manner, looking at high EN value, and not acting as donating group like via PI bond

Making it more polar, eg. 81, is ionizable at physiological pH, reduces affinity, but still able to bind
I believe an N there will make in to ammonium in bodypH, so it reduces aff. but since it is also a strong sigma- EWG so we get quite some aff. back too.


----------



## llaredda

to what degree of accuracy can you do this?  generally, im great with my numbers, however, i cant picture a molecule or how where to set the orbit of the electron and shit.  could always lookup a generic pic, but that pic didnt come from someone drawing it like you do... i have to guess.. you get your shit.  if you were able to by chance, picture and draw dexamp, levamp, and temazepam, it would likely help me understand a little better why it works so well, and how to maximize beneficial effects and minimize the crap.   i am artistically challenged so to speak  . need the artsy smart type to draw their interpretation, itl help me make sense of my medicines  .  edit .  divalproex sodium (valproic acid/epival) im iffy on that one


----------



## llaredda

am i wrong if i say i saw RLS releif AND some type of ADHD relief? i tend to be good at math, but when i was in school, i didnt make a point to learn my chemistry, so ive got some learning to do...  basically to me, that almost looks like a mix of an amphetamine style drug, and an opoid style drug.  if i am painting the wrong picture, please tell me, because a deeper understanding of the chemistry can be ultimetely beneficial


----------



## aspiringdrugdesign

Pomzazed, is there an upper limit to how much electronegativity at the end increases the affinity? Could you have multiple EWGs and have them mostly stack in effect?


----------



## Pomzazed

llaredda said:


> picture a molecule or how where to set the orbit of the electron and shit.


I think of them like picture with some hotspot for specific things arranged in 3D space, where "free pockets" are limited in space by various size. No, not accurate like a computer simulated model but can give a rough picture.
Secondly and sadly i cannot imagine why specific drug works so well, living things are much more complicated than "Oh, this molecules fits to this site best!". My imagination meets an end at macromolecule scale or polymers.

If you are mathman (respect you, i admit i hate calculations but i like the beauty of math), I can simplify what I think in this image. You'd get it instantly.




Just the distance d is not measured in SI nor angstrom unit in my head. It is the size of the "lego block" (eg. standard lego block is CH2 with certain size, some blocks are larger than other)

in actual i thought of more types of "nodes" than hydrophobic or philic, like H donor or acceptor, or some part prefers aromatic, or some part which prefers certain shape or size.
hardest thing to imagine is when the molecules wiggle (which they do), my brain runs out of ram to simulate after the system got large enough


----------



## Pomzazed

aspiringdrugdesign said:


> Pomzazed, is there an upper limit to how much electronegativity at the end increases the affinity? Could you have multiple EWGs and have them mostly stack in effect?


Interesting question, and i don't know the answer on that. I guess it can relate back to how much electronegative the tail is.
Multiple halogens, like -CF3 tail end works, and EWG in position not at the tail end also works eg -CH(NO2)-, or -O- (where it is EWG via sigma bond), or -CHF-, but is not that good unless it is 4+ or more C atoms away from the benzene ring.

I guess your perfluorinated-tail...er... "*Teflonabinoids*"  may also work*, but the CF2CF2CF2CF3 isnt that much more electronegative than CF2CF3
(*if the fluorous phase effect doesnt yet kick in, as perfluorocarbon tends to dissolve only in itself and forms separate 'teflon' phase, away from both aqueous and oil layer)


----------



## aspiringdrugdesign

Seems like it has limiting returns then 






Got a CF3 group and a sulfide instead of an ether (meant to make those wedge bonds protons, not methyls)


----------



## Hodor

llaredda said:


> am i wrong if i say i saw RLS releif AND some type of ADHD relief? i tend to be good at math, but when i was in school, i didnt make a point to learn my chemistry, so ive got some learning to do...  basically to me, that almost looks like a mix of an amphetamine style drug, and an opoid style drug.



Which picture were you referring to?


----------



## Volsam

Its been awhile since the last post and I like reading this thread when I eat!... 

So today I was reading about 2C-B-Ind and hypothesized a few molecules in my mind. Given the fact that 2C-B-Ind was rather weak as a psychedelic, I though changing the 4 position to propyl might change that to a more favorable effects/side-effects ratio.






Also, would a benzofuran analog of it be active at all?






And what about these guys? :D










Then I also thought of 2C-D's difurans analogs (obviously inspired by a crazy weird 2C-B-Fly), do you guys think that unsaturated version of that difuran can be made and what difference would it possibly have with saturated one?











Also, this weirdo - 
	

	
	
		
		

		
		
	


	




 Would it be even possible to make it and what effects do you think it would have?


----------



## aspiringdrugdesign

Why the 4-propyl? 

You put a tetrahydrofuran instead of a furan (aromaticity) but it'd probably have some serotonin activity as there'd be hydrogen bonding and a tryptamine structure  However, the methylamine branch instead of ethylamine branch would be problematic as it'd look more like gramine than tryptamine, which is toxic! 

To see how your 2C-D analogs might be different depending on saturation, you might want to look into the differences between 2C-B-FLY and bromo dragon-FLY, although there's an alpha methyl difference between those two as well. I'm not sure if there's a 2C-B-FLY analog that has unsaturated wings other than bromo-dragonFLY. 

I like your ideas!


----------



## cj187

That's an interesting idea turning the indane into a dihydrobenzofuran. Here's an analog of TMA-6 inspired by that idea:





Here's an even more constrained analog:





This one's a little goofy looking but it can be considered a constrained analog of DOM and 5-MeO-6-APB:





Here's the indane version so it's more symmetrical:





Another indane 2C-G-3 derivative:





Mescalysergide:





I was  just messing around when I made that one, but then I came up with these, which I  think actually have some potential. They are similar to the NDEPA series, but with an extra ring analogous to the lysergamide d-ring.








And now, a hybrid of 2C-TFM-2-dragonfly-5-butterfly-NBOMe and LSZ. Guaranteed to be the most potent psychedelic ever


----------



## Volsam

aspiringdrugdesign said:


> Why the 4-propyl?


Just really enjoy 2C-P so I thought propyl substitution will provide very good lipophilicity and it is heavier than Chlorine (35.4 g/mol) but lighter than Bromine (79.9 g/mol). Propyl alkyl chain being at approx 45 g/mol.



aspiringdrugdesign said:


> You put a tetrahydrofuran instead of a furan (aromaticity) but it'd probably have some serotonin activity as there'd be hydrogen bonding and a tryptamine structure However, the methylamine branch instead of ethylamine branch would be problematic as it'd look more like gramine than tryptamine, which is toxic!


Isn't it awesome how it is all made in nature! One carbon less in a chain that connects an dimethylamine with an indole and instead of godly DMT you get toxic Gramine! 



aspiringdrugdesign said:


> I like your ideas!


 Thank you much, I never liked (or rather never wanted to understand) chemistry (although always liked biology and physics) until I started trying drugs...8)


*cj187*, I really like your indane structure, I'd try it just because it looks so deliciously good and symmetrical! 
The goofy amphetamine version is probably going to be a neat empathogen but its my wild guess...

I wonder if your Mescalysergide would show activity, looks good!..
NDEPA variations also intriguing! (thanks for the link btw!) 

The last one is a pure craziness but I get the humor - put all most potent known psychs in one! 8(



Drawing drugs is fun, for those wanting to try for the heck of it, there is emolecules.com - I love doodling there! :D


----------



## Jabberwocky

Psychotridine is one crazy looking molecule: 

Psychotridine: https://en.wikipedia.org/wiki/Psychotridine

Would opening those rings and methylating those amines spice things up a bit?


----------



## sekio

I thought you were joking about that structure. But it's a real thing. Wow.

Bonus points to anyone who can propose a 1 step synthesis


----------



## sekio

Are the methylene analogues of barbiturates active?


----------



## cj187

Guys, I just discovered the ultimate psychedelic! It contains the structures of both DMT and MDMA:




Okay, so maybe it won't actually make you trip. But it will give you a boner!


----------



## Anniev215

Hey there guys so my dog was trying to complete the H Manufacturing process but is having trouble with the tar process and he's got everything to make the conversion with acetic anhydride and acetic acid glacial but can't make the conversion complete and doesn't know or can't find info on how to do it as he has the opium and the correct chemicals to make the process a good one for personal use still having trouble though you can't figure it out anybody can help with the molecule diagram and possibly the end process or process from A to B


----------



## sekio

If you can't figure out how to convert morphine to heroin you shouldn't be playing with big boy chemicals.


----------



## Pomzazed

sekio said:


> Are the methylene analogues of barbiturates active?



Diallylbarbiturate is active: see *Allobarbital*, although i don't like terminal alkenes, they look insidious


----------



## sekio

I know that much, barbiturates can play pretty fast and loose with the substituents, everything from methyl to isohexyl to phenyl is allowed. I was more interested in replacing the ureide group in barbiturates with either oxygens or methylenes.













Glutethimide shares a similar structure:


----------



## Pomzazed

sekio, i don't think the anhydride between [carbonic acid or carbamic acid] and malonic acid are stable to room temperature,
in the first case, i am not even sure if it can exists in dry ice cooled bath (-78C) without decomposition.

Third one looks VERY similar to glutethimide in regarding of shape and volume tho!


----------



## Pomzazed

OK, I'm playing your game.
What about these?


----------



## Solipsis

Can I get E but in a hydroxy instead of the methoxy.. or with a methoxy on the adjacent carbon? 

When I look at barbs I think: too bad, you could probably make em way more explosive.. (if this invites discussion on a topic which is inappropriate for the forum you can disregard this and I can delete this)

I have always found cyanuric acid a brilliant structure.. The tautomerism also applies to barbs. Not to mention cyanuric being essentially the compact perfect cyclic peptide haha.. The challenge is to switch from a super stable structure to an explosive or psychoactive one in the blink of an eye..

And also to form really sexy crystal lattices perhaps?


----------



## Pomzazed

Solipsis said:


> Can I get E but in a hydroxy instead of the methoxy.. or with a methoxy on the adjacent carbon?


Why? I am curious about this. Could you elaborate your idea on why it should be that.

btw, D overlays nicely with 1-pentyl-3-(4'-methoxynapthoyl)indole and F although has 2 weird spiro, can be overlayed similary to ethyl-phenethylbarb


----------



## JacksinPA

sekio said:


> Are the methylene analogues of barbiturates active?



I believe that one or both of those deleted nitrogens would be needed to interact with a receptor, possibly via hydrogen bonding.


----------



## JacksinPA

I would think by now medicinal chemists would have made all the possible variations on the barbituric acid nucleus & the different benzodiazepines as well. But you never know. Valium made Roche rich but they missed Xanax which made Upjohn rich.


----------



## JacksinPA

I've gotten interested in the potent opioid peptides found in the tropical poison dart frogs, particularly *dermorphin* which Wikipedia says has been used to dope race horses, so someone was or is making this synthetically, probably by Merrifield solid-phase. Wikipedia:* Dermorphin is about 30–40 times more potent than morphine but theoretically may be less likely to produce drug tolerance and addiction (due to its high potency).**[*4] The amino acid sequence of heptapeptide dermorphin is H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2, so the only exotic component is the D-Alanine. See https://en.wikipedia.org/wiki/Solid-phase_synthesis. Interesting article on this peptide: https://www.paulickreport.com/news/ray-s-paddock/chasing-the-frog-keeping-up-with-slippery-cheaters/
Dermorphin is described in the literature as very potent & long-lasting, probably due to the D-Ala preventing its rapid enzymatic breakdown in the body. This is an IV drug but there are probably other routes of administration.
Hexapeptides are also active opioids. Activity is related to enzymatic stability (D-amino acid substitutions). One is H-Tyr-d-Ala-Phe-Gly-Tyr-Pro-OH, so the terminal serine in dermorphin can be eliminated.
I read some time ago about guys playing with fentanyl analogs. One guy would play while the other guy had Narcan (naloxone) handy if he should appear to OD. Because of its potency, correct dosing with this stuff would be tricky.


----------



## JacksinPA

Opioid receptor binding correlation:


----------



## JacksinPA

Tracing the binding correlations between dermorphin & morphine was interesting as it indicates that the main opioid pharmacophore is fixed on the first tyrosine residue of these opioid peptides. Those who want to dream up interesting molecules with potential biological activity might want to use tyrosine as a good starting point.







This graphic was generated using ChemDraw 17 Professional.


----------



## Pomzazed

Thats very interesting correlation!


----------



## JacksinPA

Yes it is. If you look at the amino acid sequences of all of your psychoactive peptides, they all start with tyrosine. It was interesting to find out why. It was also interesting to find out that these peptides can be a short as 4-5 residues, all starting with Tyr, like Tyr-Gly-Gly-Phe, etc. That puts them within range of a well-trained & well-equipped experimentalist, as most of these amino acids are sold in health food & vitamin stores.

You could design all kinds of potentially active molecules starting from tyrosine.

The big problem I see with the very potent ones like dermorphin is dosing & safety. One would need a very accurate balance capable of measuring at least tenths of a milligram.


----------



## JacksinPA

An interesting difference between the dermorphin & morphine molecules is the amine function. In dermorphin, it is a primary amine. In morphine, it is a tertiary amine. The amine group in tyrosine would make another point on which to build structural variations. Since at least one of the N-H bonds is responsible for hydrogen bonding with the receptor, converting it to a secondary amine may work. The substituent involved would be a methyl or higher alkyl group.

Another interesting modification would be to esterify the phenol function in tyrosine which would make it more lipid soluble & better able to cross the blood-brain barrier. Or it could be converted into an ether.


----------



## JacksinPA

The structural relationship between the active opioid alkaloid in kratom & morphine is not immediately apparent, but as shown in the attached graphic I can establish 6 points of correlation between mitragynine & morphine, the same number of correlation points I observed between dermorphin & morphine. It is not surprising that the FDA came to the same  conclusion.






Graphic created using ChemDraw 17 Professional.


----------



## JacksinPA

Here is the 6 point binding correlation for the opioid tramadol against morphine. The dotted line between the phenyl rings could not be drawn due to it being too close to another.

I don't see the usefulness of the hydroxyl group on the cyclohexane ring or the O-methyl group of tramadol. In fact, the major metabolite of tramadol is *d**esmetramadol* *which lacks the O-methyl group & is a more potent opioid.
*


----------



## JacksinPA

*Tapentadol*

This is a quick-acting, long-acting opoid that also inhibits the reuptake of norepinephrine. It is also an interesting molecule from the POV of having 2 chiral centers, which creates a mixture of diasteriomers than can be separated by recrystallization. The (R,R) isomer is the commercial product & also the weaker analgesic. The DEA listed it as Schedule II, in the same category as morphine & fentanyl. I assume that the other (S,S) diasteriomers are more active though the Grunenthal process patent makes only the (R,R) diasteriomer & makes no claims about its others (R,S, S,R, S,S). See https://www.sciencedirect.com/science/article/pii/S1110093113000239


----------



## JacksinPA

PZM21 is a novel opioid that is structurally quite different from the previous examples. But the indicated receptor binding correlations show that it binds to opioid receptors & has an activity level similar to morphine.

Note that the structure in red on the left end of PZM21 is structurally close to that of tyrosine.


----------



## JacksinPA

Anyone have experience with L-theanine? Available in health food stores & online. One reviewer on Amazon said it made her hypomanic (bipolar). Affects glutamate. I'm leery of trying things like this unless I absolutely have to because sometimes the results can be unpleasant for a long time after.


----------



## aspiringdrugdesign

It relieves caffeine body load, I haven't really noticed any other effects beyond that. I only bought it once, but I've seen other anecdotal reports of anti-anxiety relief.


----------



## JacksinPA

Thanks. It might help with melatonin for sleep if I have to go in that direction. But I have some type of bipolar & that negative report from a former user on Amazon concerns me. A supplement like this that can screw with an NT like glutamate could have nasty effects long after you stop taking it.

On the topic of sleep, I've used Dramamine with varying results. The first time I tried it was just before a night flight on a commuter airplane in bad weather, to prevent motion sickness. Damned if I didn't wake up until the plane had landed on its destination! Things like that catch my attention.

 It is closely related to *diphenhydramine* HCl, or *Benadryl*. It is primarily a H1-antagonist, but also possesses an antimuscarinic effect.






I had read the Benadryl, which is the active ingredient in most OTC sleep pills, has an idiosyncratic effect. IOW, it works for some but not others. But in the mixture sold as Dramamine it knocked me right out. But Benadryl by itself has no effect on me.

The purine compound is 8-chlorotheophylline, which is supposed to act as a stimulant to keep you from falling asleep.


----------



## Volsam

L-Theanine is a bit weird to me too - if I go over 100-150mg a day, it presents itself as tight neck and sore muscles. More than 300mg will cause weird not very pleasant hypomania. Lower dosage (100mg and less) seem to work as advertised (calming effect) for me. Been taking it few times a week for at least 4 years with no apparent side effects.

*JacksinPA*, I very much appreciate your recent contributions with drawing out the correlations between opioid acting drugs and underlining the Tyrosine structure in them! It made me think...8) 
The longer I look at molecules of different psychoactives, the more I see how they are all like keys with differing groves on them, but structural similarity is amazing! :D

Look at Galantamine and how similar it is to Codeine! But look at their pharmacological profiles: Codeine is opioid receptor agonist that eventually gets converted to Morphine by our body. Galantamine primarily differs in that the amine is located one chain closer to the phenyl ring. And its pharmacology becomes an ACh inhibitor! I wonder what would happen to it if we "move" that amine a bit further and remove that methyl exposing the oxygen, as in with Morphine, would that modified Galantamine acquire opioid activity then?..






------------------------------------------------------------------------------------------------------
Also, yesterday I've stumbled upon Opium Lettuce plant (Lactuca virosa) and it's main active alkaloids are Lactucin and Lactucopicrin. They are mainly adenosine receptor agonists and the Lactucopicrin is also ACh inhibitor. 




Going to perform some extraction on the plant and see how the effects are. Automatically, I think of it as an "anti-caffeine" stuff! :D


----------



## Bagseed

ad the modified galantamine, the morphine rule states that there should be 2 carbons between the amine and the tertiary carbon, no? since the structure is close to the morphinans, maybe this should be considered.


----------



## JacksinPA

Thanks for the kind words.

Your proposed modification to galantamine would involve a lot of difficult chemistry. Known opioid effects can be gotten from the molecules I recently figured.

Regarding opioids, I have a paging receiver on which I hear all the EMS calls for this suburban Phila county. I heard at least 3-4 OD calls yesterday & that was from only listening for 4-5 hours. It is truly an epidemic.

I'm not familiar with the _Lactuca _but would be interested in hearing the results of your study_. _As they lack nitrogen atoms, neither one is an alkaloid_._


----------



## JacksinPA

Buspirone is a generic non-depressant anxiolytic. From the Wikipedia article:

*Pharmacodynamics[edit]*


SiteKi (nM)SpeciesRef*5-HT1A**3.98–214*
*21 (median)**Human*[35]
[34]5-HT1B>100,000Rat[36]5-HT1D22,000–42,700Human[37][38]*5-HT2A**138*
759–1,300*Human*
Rat[39]
[39][36]*5-HT2B**214**Human*[39]*5-HT2C**490*
1,100–6,026*Human*
Rat/pig[39]
[39][36]5-HT3>10,000Rat[40][41]5-HT4>10,000Rat[41]*5-HT6**398**Mouse*[42]*5-HT7**375–381**Rat*[43][44]α11,000Rat[36]α26,000Rat[45] *α2A**7.3 (1-PP)**Human*[36]β8,800Rat[36]D133,000Rat[36]*D2**484*
*240**Human*
*Rat*[46]
[36]*D3**98**Human*[46]*D4**29**Human*[46]mACh38,000Rat[36]GABAA
(BDZ)>100,000Rat[36]Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.
Buspirone acts as an agonist of the serotonin 5-HT1A receptor with high affinity.[4][36] It is a preferential full agonist of presynaptic 5-HT1Areceptors, which are inhibitory autoreceptors, and a partial agonist of postsynaptic 5-HT1A receptors.[4] In accordance, an animal study found that buspirone dose-dependently decreases serotonin levels in specific brain areas while increasing dopamine and norepinephrine levels.[4] It is thought that the main effects of buspirone are mediated via its interaction with the 5-HT1A receptor.[4] Some of its effects may be mediated via oxytocin release secondary to 5-HT1A receptor agonism.[47][48][_non-primary source needed_] Buspirone also has lower affinity for the serotonin 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7 receptors.[34]
In addition to binding to serotonin receptors, buspirone is an antagonist of the dopamine D2 receptor with weak affinity.[4][36] It preferentially blocks inhibitory presynaptic D2 autoreceptors, and antagonizes postsynaptic D2 receptors only at higher doses.[4] In accordance, buspirone has been found to increase dopaminergic neurotransmission in the nigrostriatal pathway at low doses, whereas at higher doses, postsynaptic D2 receptors are blocked and antidopaminergic effects such as hypoactivity and reduced stereotypy, though notably not catalepsy, are observed in animals.[4]Buspirone has also been found to bind with much higher affinity to the dopamine D3 and D4 receptors, where it is similarly an antagonist.[46]
A major metabolite of buspirone, 1-(2-pyrimidinyl)piperazine (1-PP), occurs at higher circulating levels than buspirone itself, and is known to act as a potent α2-adrenergic receptor antagonist.[45][49][50] It may be responsible for the increased noradrenergic and dopaminergic activity observed with buspirone in animals.[49][51] In addition, 1-PP may play an important role in the antidepressant effects of buspirone.[51] Buspirone also has very weak and probably clinically unimportant affinity for the α1-adrenergic receptor.[36][52] However, buspirone has been reported to have shown "significant and selective intrinsic efficacy" at the α1-adrenergic receptor expressed in a "tissue- and species-dependent manner".[52]
Unlike benzodiazepines, buspirone does not interact with the GABAA receptor complex


----------



## JacksinPA

A pre-WWII German discovery:


----------



## starlyte2

Buckmethylpropan


----------



## JacksinPA

Possibly one of the simplest opioids is fentanyl. Its chemical & structural simplicity spurred a lot of interest in so-called 'designer drugs' that would get around laws banning specific compounds. Now these molecules & variations are covered under laws banning analogs.

Fentanyl is 50-100 times more potent than morphine and up to 50 times more potent than heroin.


----------



## JacksinPA

Recalling the recent discussion of the key role tyrosine (and its decarboxylated form tyramine) have in naturally occurring opioids, I looked for the derivative of fentanyl that would have a phenolic hydroxyl group in what I've labeled as the 4' position on the phenethyl group. This would give an additional receptor binding point which could influence its activity. It seems odd that this molecule has been possibly overlooked. I can't afford to look for it in Chemical Abstracts online. Anyone?

A post in 2015 by sekio stated that '4'-hydroxy fentanyl has an IC50 of 86 nM' which makes it significantly more potent than fentanyl itself, which is not surprising.


----------



## JacksinPA

AH-7921 was discovered in the U.K. in the 1970s. But I am having a hard time trying to draw an opioid receptor correlation for this molecule that would explain it being 90% as potent as morphine. See https://en.wikipedia.org/wiki/AH-7921. The 3,4-dichlorobenzamide group is obviously essential to its activity but I fail to see exactly how it would interact with a receptor.

Upjohn took the AH-7921 structure & optimized it to result in U-47700. U-47700 is apparently a RC or black market item as it was found in Prince's toxicology report.

 Any guesses? These molecules act on the_ kappa_ opioid receptor.


----------



## JacksinPA

Upjohn had a major program running for years to optimize these opioid_ kappa_ agonist molecules. This page illustrates 2 of the later developments. For one thing, it was found that a methylene group spacer was useful & that the 3,4-dichloro substitution was not necessary for enhanced activity.

Wikipedia: *U-50488* is a drug which acts as a highly selective κ-opioidagonist, but without any μ-opioidantagonist effects.[1] It has analgesic, diuretic and antitussive effects,[2] and reverses the memory impairment produced by anticholinergic drugs.[3] U-50488 was one of the first selective kappa agonists invented and research on its derivatives has led to the development of a large family of related compounds.[4][5]

*U-69,593 is a drug which acts as a potent and selective κ1-opioid receptor agonist.[1][2][3] In animal studies it has been shown to produce antinociception,[1][4][5] anti-inflammation,[6] anxiolysis (at low doses),[7][8][9] respiratory depression,[5] and diuresis,[10] while having little effect on gastrointestinal motility.

The 3,4-dichloro-substituted derivative of U-69,593 is called** spiradoline. **Spiradoline (U-62066) is a drug which acts as a highly selective κ-opioid agonist.[1] It has analgesic,[2] diuretic[3] and antitussive effects,[4] and produces subjective effects in animals similar to those of ketazocine and alazocine.[5] The main effect in humans is sedation, along with analgesic and diuretic effects, but significant side effects such as dysphoria and hallucinations have stopped it from being used clinically.[6] Kappa-agonists have been shown to react negatively with the mu receptor[citation needed], instead of having an assumed synergy since they are both opioid receptors, such as with the mu (μ) receptors and delta (δ) receptors (which both mediate pain-relief, euphoria and overall potency of opioid effects).

Hallucinations are one thing but dysphoria is a state to stay away from: *dys?pho?ri?adisˈf?rēə/
_noun _*PSYCHIATRY*




*a state of unease or generalized dissatisfaction with life.*
*==============================================================*


----------



## JacksinPA

Methadone. See https://en.wikipedia.org/wiki/Methadone. From Wikipedia:

*Mechanism of action[edit]*

Levomethadone (the _R_ enantiomer) is a μ-opioid receptor agonist with higher intrinsic activity than morphine, but lower affinity.[44] Dextromethadone (the _S_ enantiomer) does not affect opioid receptors but binds to the glutamatergic NMDA (_N_-methyl-D-aspartate) receptor, and acts as an antagonist against glutamate. Methadone has been shown to reduce neuropathic pain in rat models, primarily through NMDA receptor antagonism. Glutamate is the primary excitatory neurotransmitter in the central nervous system. NMDA receptors have a very important role in modulating long-term excitation and memory formation. NMDA antagonists such as dextromethorphan (DXM), ketamine (a dissociative anaesthetic), tiletamine (a veterinary anaesthetic) and ibogaine (from the African tree _Tabernanthe iboga_) are being studied for their role in decreasing the development of tolerance to opioids and as possible for eliminating addiction/tolerance/withdrawal, possibly by disrupting memory circuitry. Acting as an NMDA antagonist may be one mechanism by which methadone decreases craving for opioids and tolerance, and has been proposed as a possible mechanism for its distinguished efficacy regarding the treatment of neuropathic pain. The dextrorotary form (dextromethadone), which acts as an NMDA receptor antagonist and is devoid of opioid activity, has been shown to produce analgesia in experimental models of chronic pain. Methadone also acted as a potent, noncompetitive α3β4neuronal nicotinic acetylcholine receptor antagonist in rat receptors, expressed in human embryonic kidney cell lines.[45]


----------



## Pomzazed

Any known derivatives of N-*benzoyl*piperazine? *(NOT benzyl)* which has pharmacological effects?


----------



## JacksinPA

Yes. Just do a Google search for that name. You get 4 hits but they are all pay-per-article. A couple are for glycine transporters. See
https://en.wikipedia.org/wiki/Glycine_transporter. See also https://www.nature.com/articles/nrd3893.


----------



## Pomzazed

JacksinPA said:


> Yes. Just do a Google search for that name. You get 4 hits but they are all pay-per-article. A couple are for glycine transporters. See
> https://en.wikipedia.org/wiki/Glycine_transporter. See also https://www.nature.com/articles/nrd3893.


Thanks! and sigh the paywall again, though we can 'evade' that but i try not to use that often.

So GlyT acts both as inhibitory (via GlyR binding) and excitatory (by being NMDA agonist)? That's quite strange profile (new to me)
I see similar structure of those being used to "sedate" too, aka N-benzoyl-N'-cycloalkylpiperazines
However, despite being dissimilar, the described effect are very similar to N-benzoylphthalimide, N-benzylphthalimide and N-benzoylsaccharine...
If ignoring the basicity of the "far, non-amide N" and assumes them as only H-bond donor right away, it kinda overlays well with the O in latter case. (in 3D)


----------



## JacksinPA

A 'reduced' analog of methadone. This is a known compound, so apparently someone has already looked at this molecule. See https://pubchem.ncbi.nlm.nih.gov/compound/204510. Another name for this compound is given as *AC1L4CPY* from ABI Chem in Germany ([/FONT][/COLOR]http://www.abichem.com/). A cursory Google search turned up no additional data.








The meta-hydroxy derivative of *AC1L4CPY* should have more activity as it has an additional receptor binding point. I didn't search for this molecule.








The m-hydroxy derivative is also a known compound but I so far have found very little information about it. See 
http://isomerdesign.com/PiHKAL/explore.php?domain=pk&id=10526


----------



## JacksinPA

I took the structure of 4'-hydroxyfentanyl & applied the same minimilization technique I had use to 'reduce' methadone & arrived at* 4-(2-(piperidin-1-yl)ethyl)phenol*, which is another known compound that had apparently been submitted to the EPA as part of a TSCA application for a new compound (https://comptox.epa.gov/dashboard/dsstoxdb/results?search=DTXSID20293932) It would also be of interest to do an online CA search to find out who has an interest in this compound.

It would be of interest to find out if this very simple molecule has the hoped for biological activity. That would also be the case for the simpler compound without the phenol group (minimilized fentanyl).


----------



## JacksinPA

This approach may not be too promising. Further simplifying the molecule as shown gives the known alkaloid *hordenine*, which is toxic. See https://en.wikipedia.org/wiki/Hordenine


----------



## DotChem

Take Strawberry ketone here: the compound that gives strawberry its smell and  typical flavor. So-called weight loss compound (no evidence but ppl  still buy into the hype google it).. anyway here is its structure:






Now add amino alfa to the ketone (very easy to do) you get this:







analog  of the amino acid Tyrosine.  Tyrosine is strictly required in all endogenous endorphins peptides for opioid activity. here is Tyrosine structure: 
	

	
	
		
		

		
		
	


	




 So this compound is same as Tyrosine but with the Tyrosine COOH replaced by COCH3. Now this molecule is potent  pure mu agonist but also a NDRI so may be similar effect but more potent than desmethyltramadol + it might smell and taste like earthly fruity freshly cut strawberries.. Yummmy! %)! lots of similar ketones do but that's another story!

notice how it is now also a cathinone analog similar to methedrone or ethodrone or similar cathinones like methedrone here:





but with the CO switched from the phenyl side to the alfa-alkyl side and the OMe replaced by OH.

Now if you were to replace the primary amine with a pyrrolidine, you now get MDPV type analogs with the CO moved to the alkyl side:






Will it smell and taste like strawberries?.. who knows?.. lemme know if anybody has come across one of these.. cheers
EDIT: inspired by PT


----------



## JacksinPA

Now add amino alfa to the ketone (very easy to do) you get this:

I don't agree. You will have to protect/deprotect that phenol group before you can add that amino function so it becomes a multi-step problem.


----------



## Midnight Sun

In the video currently circulating of the raid of a large and popular RC vendor, visible for a moment is a bag of lilolidine.

Never heard of it before & doesn't seem to have any use outside of being a precursor.  Wonder what they were going to use it for.  






just a fantasy.  probably not even active.  still wonder what the lilolidine was going to be used for.


----------



## JacksinPA

Lilolidine is a raw material for anti-cancer drugs. See https://pubchem.ncbi.nlm.nih.gov/compound/Lilolidine#section=Patents

On questions such as the one you asked, Google is an excellent research tool.


----------



## DotChem

JacksinPA said:


> Now add amino alfa to the ketone (very easy to do) you get this:
> 
> I don't agree. You will have to protect/deprotect that phenol group before you can add that amino function so it becomes a multi-step problem.


not really! depend how you go about doing it.. (here is one easy way with a phenolic ketone No need to protect the phenol !..but no synthesis talk on BL tho. (@mod: remove if inappropriate)


----------



## JacksinPA

Interesting method but I don't see how you avoid brominating the terminal methyl group instead of your desired position. You might get an uneven mixture which might be hard to separate. End of synthesis talk.


----------



## Pomzazed

What is the function of Phenolic OH in morphine?
Hydrogen bond donator, or acceptor? I guess the former, since codeine is much weaker.
Or is there another binding mode of that OH?


----------



## JacksinPA

Pomzazed said:


> What is the function of Phenolic OH in morphine?
> Hydrogen bond donator, or acceptor? I guess the former, since codeine is much weaker.
> Or is there another binding mode of that OH?



I would guess both. Try Googling that question.


----------



## JacksinPA

https://pubs.acs.org/doi/abs/10.1021/jm00189a007?journalCode=jmcmar. It's only the first page of the article but people have been looking at the role that the phenolic hydroxyl plays with receptor binding. Check out the article's abstract.


----------



## Dresden

Hey, send me a sample.  I'll be your Guinea Pig.  I still think raspberry ketone is the way to go, though.


----------



## DotChem

ketamine long lost cousin: FRl15427




developed in france japan as safer ketamine analog (no bladder fuckup).. this is about 10x more potent than ketamine as NMDAr antagonist well tolerated substituted fully w/pcp in rodent.. doesnt look like any disso one can think of. MXE??


Or this one pretty interesting; a spiroindanyl isoindole .. this compound is about 1/3 PCP and fully substitute with tcp in rats.. (ref..).  





I wonder if they wont be safer that ketamine MXE.etc  I mean no muscarinic cholinergic of arycyclohexylamines since apparently this is what cause bladder fuckup of ketamines and the like. cheaper and way easier to make too.. safer antidepressant for sure..


----------



## sekio

> doesnt look like any disso one can think of



sort of reminds me of a ring opened analog of mk801... either way it would be Really Cool to see human trials of this as an rc,...


----------



## DotChem

^ good eyes!!.. I didnt notice .indeed it looks like MK801 with ring open. it is ~10x less potent than mk801 which is good cause mk801 is insanely potent with unbelievably long half-life (days?? ) but yeah I think it would be REALLY COOL new disso rc the unsubstituted (i mean no MeO) is about 1.5xpcp tho..half-life is anybody guess but probably similar to pcpc..


----------



## sekio

A lot of posts have been moved to the Name A Molecule thread. It didn't go anywhere, just got unstickied.


----------



## JacksinPA

Rather fanciful structures that combine both pharmacophores of morphine but avoids the fused ring system of that alkaloid. They appear to be difficult molecules to approach synthetically. The 6-methyl should have been drawn as being in a chiral center.


----------



## JacksinPA

*Known morphine analog*

Interestingly, as far as the EPA is concerned, the racemic form of this aminoindene is a known compound (CAS 78950-87-5).


----------



## Dresden

RUN DMC

Inspired by Ambien (zolpidem).


----------



## JacksinPA

*Another morphine analog preserving both pharmacophores*

Further reducing the fanciful structures in order to obtain morphine analogs with simpler structures, I came up with this:


----------



## Dresden

Nice.  I bet this one is superific:





IAN BEAVIS ADAMS MACGREGOR


----------



## Bagseed

here we go again...


----------



## DotChem

little known Cannabis molecules:

Cannabisativine (isolated from roots bark of sativa not the buds!):




Looks (remotely) like anandamide (endogenous cannabinoid receptor ligand) could be CB agonist or antagonist.. anybody knows anything about this compound?? 
Here is Anandamide :


----------



## JacksinPA

I doubt that macrocyclic compound would have any endocannabinoid-like activity as it lacks any double bonds, which are necessary for activity. I posted structures here of simpler compounds that would have activity, including one that has been isolated from an evergreen shrub's seeds. Interestingly, those seeds are a brisk selling item on eBay.

I haven't studied the SAR for these but the key portions are the multiple double bonds, which both act to fold the chains to mate with the receptor & to act in binding. The terminal end can be either an amide or either a 2-gylyceryl ester or ether.


----------



## Dresden

Bagseed, 

Don't troll me.


----------



## JacksinPA

*Alpha-Linolenic Acid for your cardiac health*

In a break from the usual posts in this forum I'd like to talk about a recent discovery of mine that is actually good for you: *omega-3 fatty acids *& in partiuular *alpha-linolenic acid.*

Lipids are fats produced in the body & that circulate in the blood stream. These, in general, occur as 2 types: lipoproteins that carry cholesterol & triglycerides, which are similar to natural animal fats in that they consist of glycerol esterified by 3 molecules of fatty acids. Both *Low-Density Lipoprotein (LDL)* & *triglycerides*, if present at high levels, can bind to the walls of arteries and result in the formation of atherosclerotic plaque. IOW, hardening of the arteries. This is a bad thing as these plaques build up they can lead to heart attacks & strokes.

Big pharma is introducing a number of products intended to lower high triglyceride levels. These are in the form of 1 gram enteric capsules filled with highly purified omega-3 fatty acids or their ethyl esters. Omega-3 acids are thought to be effective in lowering triglyceride levels. But these products are in the form of big capsules that I have difficulty swallowing & they are expensive, as all new drug products tend to be.

I am concerned about both LDL & triflycerides. I take Lipitor, a so-called* statin, *a* sterol biosynthesis inhibitor* to keep my LDL levels in the right range. So I grew concerned about managing my triglycerides & started reading some articles on the net.

I found that walnuts contain high levels of an omega-3 fatty acid called *alpha-**linolenic acid*. In fact, 1 ounce of walnut meat contains 2.5 grams of it. So I am now taking an ounce a day of tasty walnuts. Even my doctor thought that this was a good idea. And an inexpensive as well as tasty solution to my triglyceride problem.


----------



## Dresden

I take 145 mg of






TRICOR  (fenofibrate)

every AM for high blood triglycerides.


----------



## DotChem

JacksinPA said:


> I doubt that macrocyclic compound would have any endocannabinoid-like activity...


you right, it might not .. altho I was thinking the macrocycle might mimic the pseudo-carbocycle of anandamide: the double bonds of anandamide and related arachidonic merely restrict the molecule into a pseudocyclic conformation .. but who knows?....  was just curious about these sativa alkaloids like these others:

Cannabisin A:





Cannabisin B:





or Grossamide:






may or may not have cannabinoid psychoactivity.. .. may be opioids.. but who knows?? (I couldnt find any biological data on those)


JacksinPA said:


> ..I posted structures here of simpler compounds that would have activity, including one that has been isolated from an evergreen shrub's seeds. Interestingly, those seeds are a brisk selling item on eBay...


could you repost structures again when you have the chance??.. are they alkaloids or fatty acids...


----------



## JacksinPA

Dresden said:


> I take 145 mg of
> 
> 
> 
> 
> 
> 
> TRICOR  (fenofibrate)
> 
> every AM for high blood triglycerides.



I looked at the fibrates as one option along with niacin (nicotinic acid) & the omega-3 fatty acids. The expense as well as the side effects with both the fibrates & niacin did not turn me on. When I found the natural source for the linolenic acid it was an easy choice. My doctor liked the omega-3 choice & did not suggest either a fibrate or niacin. This was yesterday when I had my annual Medicare physical so she took her time with me. Even though she is a DO & not an MD, she's very sharp & I value her opinions.

While my LDL & triglycerides are normal, I recently had an echocardiogram to compare against one I had taken 4 years ago & there were enough negative differences in plaque build-up in my ascending aorta for my doctor to suggest I see a cardiologist. I drink more than I should (vodka at ice temp, Russian style) & ethanol is one of the factors that drives triglyceride production. So my choice of adding linolenic acid was defensive. The cardiologist (2 months to get an appointment!) may have other thoughts. I'm planning to get my blood tested for lipids before I see him so we both know what we're talking about.


----------



## JacksinPA

DotChem said:


> you right, it might not .. altho I was thinking the macrocycle might mimic the pseudo-carbocycle of anandamide: the double bonds of anandamide and related arachidonic merely restrict the molecule into a pseudocyclic conformation .. but who knows?....  was just curious about these sativa alkaloids like these others:
> 
> Cannabisin A:
> 
> 
> 
> 
> 
> Cannabisin B:
> 
> 
> 
> 
> 
> or Grossamide:
> 
> 
> 
> 
> 
> 
> may or may not have cannabinoid psychoactivity.. .. may be opioids.. but who knows?? (I couldnt find any biological data on those)
> 
> could you repost structures again when you have the chance??.. are they alkaloids or fatty acids...



There are only 2 species in the plant family Cannabinaceae:_ Cannabis_ (marijuana, hemp) & _Humulus_ (hops). There are a lot of interesting secondary metabolites in hops that you might want to take a look at. Who knows what you're ingesting when you have a beer?

FYI I am using ChemDraw 17 Professional to draw structures & the free image posting app PostImage. The ChemDraw is a hoot as it is a lot of fun & very easy to use once you get the hang of it. The downside is that it costs something like $1,500 for the whole ChemOffice bundle from Perkin-Elmer but I got my copy free for participating in one of their new release beta-test.


----------



## JacksinPA

Which structures do you want me to repost? They are all still here.


----------



## DotChem

Oh never mind.. I thought there were different structures.. thx


----------



## Nagelfar

JacksinPA said:


> Rather fanciful structures that combine both pharmacophores of morphine but avoids the fused ring system of that alkaloid. They appear to be difficult molecules to approach synthetically. The 6-methyl should have been drawn as being in a chiral center.
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> 
> Interestingly, as far as the EPA is concerned, the racemic form of this aminoindene is a known compound (CAS [FONT=&]78950-87-5).
> 
> [/FONT]
> 
> 
> 
> 
> Further reducing the fanciful structures in order to obtain morphine analogs with simpler structures, I came up with this:



These are great empirical studies from a purely abstract starting/standpoint. This thread needs more of the above style and ambition.

(then again, it may just be the fantasy of the compound in question in my present state)

reminds me of the benzomorphan class, like Dezocine:


----------



## JacksinPA

Thanks for the reply. Interesting that you should bring up dezocine, as the bonding pattern between the phenolic atomatic ring & the nitrogen atom is different from the examples I have presented in prior posts. It's also interesting that the nitrogen atom in dezocine is primary as compared to the tertiary atom in morphine. These differences may help to explain its mixed agonist/antagonist activity. 

There appears to be more possibilities for dreaming up biologically active opioid molecules than I had  thought if this alternate bonding scheme is adopted, though my principal focus has been on pure agonists modeled after morphine.

I had not intended to do a thorough analytical survey of the morphine analogs. Most of my books on drugs, such as Lednicer's survey, are still hidden in boxes that remain unpacked since I moved nearly 4 years ago! Just as well, as I don't have the shelf space for them since we downsized. The internet & Google have replaced the need for most of my books, luckily.

Here is the Wikipedia article on dezocine: https://en.wikipedia.org/wiki/Dezocine. It is no longer sold or used outside of China.


----------



## C12H16N2O-OH-OH-YE

*read my SN* 

OP:   I just went ahead and changed my legal name as well , since (instead of wrighting danger fantastic I'd written the chemical formula out on the application already.. The OH-OH-YE was simply flashback and a turret happening simultaneously. I decided to keep it. It bonds we'll
Im glad to know I'm not alone!! &#55357;&#56836;


----------



## JacksinPA

C12H16N2O-OH-OH-YE said:


> *read my SN*
> 
> OP:   I just went ahead and changed my legal name as well , since (instead of wrighting danger fantastic I'd written the chemical formula out on the application already.. The OH-OH-YE was simply flashback and a turret happening simultaneously. I decided to keep it. It bonds we'll
> Im glad to know I'm not alone!! &#55357;&#56836;



You're in the wrong forum.


----------



## JacksinPA

Interesting recent article on the effect of a wide range of natural product molecules as GABA(A) receptor modulators.  Available full text as pdf download at:
http://www.mdpi.com/1420-3049/23/7/1512.


----------



## JacksinPA

https://en.wikipedia.org/wiki/Apigenin

Interesting molecule, available online & in health food stores. Possibly a true 'mellow yellow.' Likely acts as an antioxidant beside it's listed biological effects.






From the Wikipedia article:
Apigenin acts as a monoamine transporter activator, one of the few chemicals demonstrated to possess this property.[8] Apigenin is a weak ligand for central benzodiazepine receptors _in vitro and exerts anxiolytic and slight sedative effects in an animal model.[9] Apigenin shows second-orderpositive modulatory activity at GABAA receptors.[10][11] It has also effects on adenosine receptors[12] and is an acute antagonist at the NMDA receptors (IC50 = 10 μM).[11] In addition, like various other flavonoids, apigenin has been found to possess nanomolar affinity for the opioid receptors (Ke = 410 nM, 970 nM, and 410 nM for the μ-, δ-, and κ-opioid receptors, respectively), acting as a non-selective antagonist of all three opioid receptors.[13]

_*A note of caution from the same article:

In vitro studies have shown that apigenin may be toxic to red blood cells.[14]*


----------



## DotChem

^ Interesting.. Best source of apigenin tho is Passion Flower extract. Contains more apigenin than Chamomille + other more potent GABAergic flavonoids like vitexin  ie 8-(6-glycosyl)-apigenin .. the ultimate "yellow mellow" really.. 


> ...The medical utility of only a few species of _Passiflora_ has been scientifically studied.[22] In initial study in 2001 for treatment of generalized anxiety disorder, maypop extract performed as well as oxazepam but with fewer short-term side effects.[23] It was recommended to follow up with long-term studies to confirm these results....


As well as oxazepam? no wonder FDA tried to ban it.. anyway very interesting compounds..thanks for posting..
Here is vitexin structure:


----------



## JacksinPA

Hereis an interesting review of passion flower extract: https://www.webmd.com/vitamins/ai/ingredientmono-871/passionflower. Seems useful, for a number of things but according to them it was taken off the market in 1978. Here is the Wikipedia article on vitexin, though it doesn't give anything on biological activity: https://en.wikipedia.org/wiki/Vitexin. It's the flavone glucoside if apegenin & would be expected to have similar effects.


----------



## JacksinPA

Meptazinol, a very simple opioid analgesic. Mixed agonist/antagonist activity. I screwed up when I drew the receptor binding correlation. There is only a 2-carbon bridge between the phenol group & the tertiary amine in morphine. I'll post a new analog of this that may have pure agonist activity.


----------



## JacksinPA

GABA-A receptor agonists:






These compounds produce sedative, anxiolytic, anticonvulsant & muscle relaxant effects. Muscimol & its relatives produce sedative, hypnotic & hallucinogenic effects.


----------



## Pomzazed

^ in the correlation above; carbonyl C in GABA should be dotted into carboximino C in muscimol, not at N. They are isostere.

Isoguvacine is not toxic as a gaba agonist, but by other mechanism. (Being michael acceptor to unknown amino group target) causing cancer.

Isonipecotic acid main action to raise gaba isnt acting as direct agonist, but as GATI.


----------



## JacksinPA

Here's a summary breakdown of the phytochemicals found in Passion Flower:

*Constituents:*Alkaloids; harmine, harman, harmol, harmaline, harmalol, and Passiflorin. 

Flavonoids: apigeninand various glycosides, homoorientin, isovitexin,kaempferol, luteolin, orientin, quercitin, rutin, saponaretin, saponarin and vitexen. 

*Chemical Composition:*Alkaloids,*Apigenin*,Carbohydrates,Coumarins,Flavonoids,Fructose,Glucose,Gum, 

 *Harmaline,Harmalol,Harman,Harmine*,Maltol,Plant alcohols,Orientin,Raffinose, 
 Saponaretin,Saponarin,Scopoletin,Stigmasterol,Sitosterol,Sterols,Sucrose,Umbelliferone,Vitexin. 

*Phytochemicals:*

 Chemical analysis on *Passionflower*  indicates it contains three main groups of active chemicals: alkaloids, glycosides, and flavonoids. Interestingly, when the glycosides and flavonoids are isolated and tested individually they have demonstrated the opposite effects for which the plant is commonly used for. Only when the two groups of chemicals are combined as a whole herb, do researchers observe* the plant's sedative effect*. Passionflower also contains naturally occurring serotonin as well as a chemical called *maltol which has documented sedative effects* (and which might explain the naturally calming properties of passionflower). A group of harmane alkaloids in passionflower have demonstrated antispasmodic activity and the ability to lower blood pressure. In addition, a flavonoid named *chrysin has demonstrated significant antianxiety activity. *
 The main plant chemicals in passionflower include: alkaloids, alpha-alanine, apigenin, aribine, chrysin, citric acid, coumarin, cyclopassifloic acids A-D, cyclopassiflosides I-VI, diethyl malonate, edulan I, edulan II, flavonoids, glutamine, gynocardin, harmane, harmaline, harmalol, harmine, harmol, homoorientin, isoorientin, isoschaftoside, isovitexin, kaempferol, loturine, lucenin-2, lutenin-2, luteolin, n-nonacosane, orientin, passicol, passiflorine, passifloric acid, pectin, phenolic acids, phenylalanine, proline, prunasin, quercetin, raffinose, sambunigrin, saponarin, saponaretin, saponarine, schaftoside, scopoletin, serotonin, sitosterol, and stigmasterol. 

 There is some controversy over the exact composition of P. incarnata. Approximately 2.5 percent appears to be flavonoids such as vitexin, orientin, homo-orientin, saponarin, schaftoside, and a few others as glucosides, together with free flavonoids including apigenin, luteolin, quercetin, and kaempferol. 

 In Europe, passionflower is required to contain not less than 0.8 percent total flavonoids, calculated as vitexin. 
 *The harman alkaloids that have been identified by some chemists are disputed by others.* Umbelliferone, scopoletin, and maltol have been reported. 
 An antifungal, antimicrobial compound dubbed passicol is found in fresh plant matter but dissipates quickly from the dried herb or aqueous extract. 
======================================================
Harmaline is psychoactive: https://en.wikipedia.org/wiki/Harmaline
Harmine inhibits the enzyme MAO-A: https://en.wikipedia.org/wiki/Harmine
Harman (Harmane) is another MAO inhibitor & acts at the benzodiazepine receptor
Harmalol is a scheduled poison. See https://en.wikipedia.org/wiki/Harmalol


----------



## roi

Fluclobenzorex. Fluzx? Kinda surprising that there haven't been any (?) NBCl RCs, given that Clobenzorex is a known pharmaceutical and orally active and stuff.


----------



## DotChem

^ prodrug of amphetamine?. like Captagon? aka phenethylline ie Chocolate(theophylline) conjugated to amphetamine aka ISIS amphetamine) .. interesting



JacksinPA said:


> Meptazinol, a very simple opioid analgesic.



kind of not too active tho..mixed agonist-antagonist half codeine ??!!  




Pomzazed said:


> ^..Isoguvacine is not toxic as a gaba agonist, but by other mechanism. (Being michael acceptor to unknown amino group target) causing cancer...


Not so much by reaction with amino groups in proteins (most amino groups of proteins are charged at physiological pH so not so reactive.. But on the other hand, thiols of proteins cysteine residues are extremely reactive towards michael acceptors like those.. they'll react pretty much indiscriminately with SH to give covalent adducts and wreak HAVOC.. cancer is one.. liver necrosis .. hypoxia and brain death..etc pretty nasty compounds..  





JacksinPA said:


> Here's a summary breakdown of the phytochemicals found in Passion Flower:
> 
> ..In Europe, passionflower is required to contain not less than 0.8 percent total flavonoids, calculated as vitexin.
> *The harman alkaloids that have been identified by some chemists are disputed by others.* Umbelliferone, scopoletin, and maltol have been reported.
> An antifungal, antimicrobial compound dubbed passicol is found in fresh plant matter but dissipates quickly from the dried herb or aqueous extract.
> ======================================================
> Harmaline is psychoactive: https://en.wikipedia.org/wiki/Harmaline
> Harmine inhibits the enzyme MAO-A: https://en.wikipedia.org/wiki/Harmine
> Harman (Harmane) is another MAO inhibitor & acts at the benzodiazepine receptor
> Harmalol is a scheduled poison. See https://en.wikipedia.org/wiki/Harmalol



Good to know passion flower extracts contains harman alkaloids besides flavonoids.. That explains why they're as good as benzo as anxiolytics.. Lots of harmans are BZ receptors modulators: Harmine is believed to be endogenous benzodiazepine receptor ligand (agonist).. but there's lot of controversy with harman alkaloids.


----------



## JacksinPA

As noted, there is disagreement among scientists about the harmane alkaloids being present.


----------



## aspiringdrugdesign

DotChem said:


> little known Cannabis molecules:
> 
> Cannabisativine (isolated from roots bark of sativa not the buds!):
> 
> 
> 
> 
> Looks (remotely) like anandamide (endogenous cannabinoid receptor ligand) could be CB agonist or antagonist.. anybody knows anything about this compound??
> Here is Anandamide :



A 13 member cyclic ring, well I never


----------



## aspiringdrugdesign

DotChem, would it be a prodrug of amphetamine or would it have pi stacking similar to NBOMe's n-benzyl functions?


----------



## Dresden

2CG3

Got a marvelous review in PiHKAL; has it surfaced ever?


----------



## Pomzazed

@Dotchem,
Ah yes, i forgot about the thiol. So yes those are much more of michael reactants.

@aspiringdrugdesign,
What’s wrong with 13-membered macrocyclics apart from the hard synthesis?


----------



## aspiringdrugdesign

@Pomzazed,

There's nothing wrong with it, I just feel like they're not a common sight especially when it comes to medicines and drugs. Wouldn't it be slightly unstable and prone to breaking open at the amide?


----------



## DotChem

aspiringdrugdesign said:


> DotChem, would it be a prodrug of  amphetamine or would it have pi stacking similar to NBOMe's n-benzyl  functions?


which structure? the one mentioned by @roi: yeah I think so: it might  get metabolized (first pass by the liver) into 4-FA and  ortho-chlorobenzaldehyde (and further to o-Chlorobenzoic acid) so it is really a  prodrug of 4-Fluoroamphetamine (4-FA).  Similar to phenethylline (gets  metabolized to amphetamine and theophylline or caffeine) or  lysdexamphetamine (metabolized to dextro-AMPH and Lysine).. I dont see  no advantages of AMPH prodrugs over plain d-AMPH beside going around  legal issues and the law..

The 13-member macrocycle I mentioned  was extracted from cannabis sativa strain roots.  Was wondering if it  may have any psychoactivity at all..but who knows?.. yeah the synthesis  will be tricky (may be high dilution techniques may help).. but then  again, since it can be extracted from cannabis..cheaper than synthesis..    here is one route (AMAZINGLY complex.. a PhD student thesis maybe):  Total Synthesis of Cannabisativine .. have a good day


----------



## JacksinPA

This would be a difficult & expensive synthesis. The key intermediate would be the fused ring benzaldehyde which would involve multiple reaction steps & purifications. Possible but improbable.


----------



## S.J.B.

roi said:


> Fluclobenzorex. Fluzx? Kinda surprising that there haven't been any (?) NBCl RCs, given that Clobenzorex is a known pharmaceutical and orally active and stuff.



The _ortho_-chlorobenzyl group is an interesting choice.  It would likely be somewhat slower to metabolize to the amphetamine than if a simple _N_-benzyl group were present.  If one were trying to make a phenethylamine prodrug of this type with the intention of having the prodrug cleaved as quickly possible, I would go for an _ortho_- or _para_-methoxy benzyl.  Perhaps this is why the 25I series tends to be fairly ineffective when taken orally:  they are rapidly transformed into their 2C-x equivalents, drugs that are active at much larger doses.


----------



## roi

I tried tens of tested 25I-NBOMe doses orally (capsuled, no accidental absorption), slowly working up to 25mg, with no effects at all.

The amphetamine-NBCl is apparently sold as 30mg, so the conversion doesn't seem to be that bad there.


----------



## Pomzazed

aspiringdrugdesign said:


> @Pomzazed,
> 
> There's nothing wrong with it, I just feel like they're not a common sight especially when it comes to medicines and drugs. *Wouldn't it be slightly unstable and prone to breaking open at the amide*?



No.

There is very few ring strain energy in 13-membered cycles, even lower than a 5 or 7 membered ring! It is large enough to "act much alike a straight chain" already

See number on the table in this wiki link and follow ref[4] if you are interested:
https://en.wikipedia.org/wiki/Ring_strain

The only hard part is to make it out; they just don't like to cyclize in large cycles due to the many loss of dS due to the loss in degree of freedom from a loss of "conformational modes" the ring-atom-members could have been
(just a hint: dG = dH - TdS)


----------



## Limpet_Chicken

I wouldn't even compare meptazinol to 0.5~ codeine. Only thing remotely interesting about it IMO is that its selective IIRC for the MOR1 isoform.

Tried it, and you couldn't pay me to take it again, felt like it was ripping me a whole new set of arseholes. Due to the free phenol, perhaps. I recall years ago, preparing the benzoyl and the propionyl ester, can't remember which of them it was that got tried, but general thinking was along the lines of being inspired by aspirin, to reduce potential GI side effects, seemed to fly, in that respect, but it was an exercise in turd-polishing to be quite honest. Both of them got made, one of them went down the bog, well, chucked both of them IIRC, but one of them was  tested in-vivo and found to be as pointless and unrewarding as the parent compound, minus the awful GI effects.


----------



## JacksinPA

Dresden said:


> I take 145 mg of
> 
> 
> 
> 
> 
> 
> TRICOR  (fenofibrate)
> 
> every AM for high blood triglycerides.



I'd be careful taking this long term, especially if you take other things that affect your liver: alcohol, statins, azole antifungals. See The side effects of fibrates include *nausea, stomach upset, and sometimes diarrhea. Fibrates can irritate (inflame) the liver. The liver irritation usually is mild and reversible, but it occasionally can be severe enough to require stopping the drug. Fibrates can cause gallstones when used for several years.*


----------



## JacksinPA

I don't agree. I don't have my original source for that receptor correlation but I did find this:

*https://www.sciencedirect.com/topics/neuroscience/muscimol
*
Muscimol is a conformationally restricted analog of GABA in which a *hydroxyisoxazole moiety replaces the carboxyl group of GABA*. *The 3-hydroxyisoxazole is recognized as a carboxyl group equivalent by GABA**A and GABAC** receptors* but not by GABABreceptors. The neuronal GABA uptake system recognizes the 3-hydroxyisoxazole moiety, in that muscimol is a weak inhibitor of GABA uptake but is neither an inhibitor of nor a substrate for GABA aminotransferase, indicating that this enzyme does not interact with the 3-hydroxyisoxazole moiety.


----------



## JacksinPA

Meptazinol isomer - pure agonist? Known compound but could find no info on biological activity. I would think this stuff would act as a pure opioid agonist. But a study I read says that the isomers of meptazinol have equal activity (structures not identified). Ortho, meta, para hydroxy forms?


----------



## Pomzazed

JacksinPA said:


> I don't agree. I don't have my original source for that receptor correlation but I did find this:
> 
> *https://www.sciencedirect.com/topics/neuroscience/muscimol
> *
> Muscimol is a conformationally restricted analog of GABA in which a *hydroxyisoxazole moiety replaces the carboxyl group of GABA*. *The 3-hydroxyisoxazole is recognized as a carboxyl group equivalent by GABA**A and GABAC** receptors* but not by GABABreceptors. The neuronal GABA uptake system recognizes the 3-hydroxyisoxazole moiety, in that muscimol is a weak inhibitor of GABA uptake but is neither an inhibitor of nor a substrate for GABA aminotransferase, indicating that this enzyme does not interact with the 3-hydroxyisoxazole moiety.



I didnt argue you on that point, i mean the dotted line should point to the carbon not nitrogen, this is the same as what the reference mentioned.
Lemme draw picture:


----------



## JacksinPA

Another fanciful attempt to mimic the opioid agonist properties of morphine in a simpler molecule not involving fused ring systems. Not a simple molecule & would require some tinkering to optimize effect. Known compound but found no biological data.


----------



## JacksinPA

I see your point & it looks valid.


----------



## Dresden

gamma-Hydroxy-Muscimol (GHM)

A penny por sus pensees?


----------



## sekio

hmm, logic sez it might be a ghb-type drug... that's a goodun... and no silly name? has dresden's account been hacked or something?? </s>

but more likely some sort of GABAB stuff happenin...


----------



## JacksinPA

At first glance you are missing the aminomethyl function found in muscimol, which mimics the gamma-amino function in GABA. And I would guess regarding stability that the hydroxymethyl group in your suggestion might want to tautomerize to the aldehyde at certain pH ranges, which wouldn't be active. Nice idea, though.


----------



## JacksinPA

Interesting acetylenic analog of trans-4-aminocrotonic acid. Interesting that it did not turn up in a Google search though I think it would be an interesting biological tool as well as moderately challenging synthetically.

I screwed this structure & nomenclature before. It is a known compound but the only uses are as pharma raw materials. No bio data found.


----------



## JacksinPA

Anyone have an experience using ACD/ChemSketch? It appears that I'm going to be losing my ChemDraw 17 on September 19.


----------



## sekio

Just, uh, cough torrent ChemBioDraw and keygen it.


----------



## Bagseed

chemsketch sucks bigtime ime


----------



## JacksinPA

I don't understand your response. ChemBioDraw is just another Perkin-Elmer product. I don't know how much it costs but I doubt it's free for all. I'm lost about torrent as I've never run into it before. Can ypu PM me? Thanks!


----------



## JacksinPA

Bagseed said:


> chemsketch sucks bigtime ime



Why do you say that? Difficult to earn how to use, etc?


----------



## JacksinPA

ACD/ChemSketch has 4.5 star reviews on CNet (19 reviewers). Their 'how to use' tutorial video looks very straight-forward: https://www.selectscience.net/Selec...o-use-acd-chemsketch-video-guide?videoID=4285 And at FREE, it beats ChemDraw's $2300 price tag by a lot. (That's a rough price based on my having previously owned ChemDraw 11.0, giving me a 20% discount over their $2945 list for ChemDraw 17).


----------



## Pomzazed

Chemsketch is the best free one if you cannot afford chemdraw or obtain it behind a curtain.
It has most of the functionality you would want to use.

However it will feel quite sluggish to (not the performance tho); until you get use to which button do what and where they are.

@JacksinPA
While u still have access to chemdraw, try using its Chem3D program, and use the overlay function.
You will like it very much if you like comparison with the dotted lines like what are posted.
(Draw two molecules, press CtrlE to open model explorer, select target atom, R click the choose overlay, set some 2-3 overlay points, continue to minimize and overlay, can also measure distance differneces after)


----------



## JacksinPA

Another analog of morphine:






The stereochemistry at the amine may be off. Even though simpler in structure & not involving any fused ring systems, this would not be a simple synthesis project. Not found in Google search.


----------



## S.J.B.

JacksinPA said:


> Another analog of morphine:



The 2-aminotetralins are known psychoactive compounds, although I don't know of any that are mu opioid agonists.  See: 2-AT (and the compounds listed under "Chemical derivatives" on this page).


----------



## JacksinPA

S.J.B. said:


> The 2-aminotetralins are known psychoactive compounds, although I don't know of any that are mu opioid agonists.  See: 2-AT (and the compounds listed under "Chemical derivatives" on this page).



Thanks for the 'heads up' on this class, which I had ignored until now. Here is a reference: https://www.revolvy.com/page/2%2DAminotetralin. Some of these are stimulants. Lots of liks on various substituents in this class.


----------



## sekio

JacksinPA, have you heard of the "morphine rule"? It's a rough SAR predictor for opioid-type activity. Some of these compounds you are drawing do not follow it (no quaternary carbons).







> Morphine, a potent and addictive analgesic (“painkiller”), and related molecules share a characteristic set of four features (connected in this order) called the morphine rule:
> 1) a (possibly substituted) phenyl ring
> 2) an sp3 hybridized (quaternary) carbon atom
> 3) a CH2-CH2 sequence
> 4) an sp3 hybridized nitrogen atom (tertiary amine)


note the underlines are my corrections.


so maybe:


----------



## JacksinPA

Thanks for the input, which I am aware of. Feel free to add methyl groups wherever you want to my structures. I am not interested in cluttering up my sketches with all the possible methylated forms. Anyone looking to do creative work based ion my drawings would either have the  sense to optimize those structures or waste a lot of time & $$$ in the lab.

As with the 2-aminotetralin strictures, some interesting non-opioid activities derive from simply dissecting the morphine structure into simpler analogs.


----------



## JacksinPA

JacksinPA said:


> Another analog of morphine:
> 
> 
> 
> 
> 
> 
> The stereochemistry at the amine may be off. Even though simpler in structure & not involving any fused ring systems, this would not be a simple synthesis project. Not found in Google search.



While _R_ is the correct stereochemistry for potent dopaminergic activity in this series of 2-ATs, I found very little on the 6-hydroxy compound. There is a lot of interest in 6,7-ADTN: 

*A broad spectrum dopamine receptor agonist.  Demonstrates a marked selectivity for the human dopamine D3 receptor. 6,7-ADTN and psychostimulants such as cocaine and amphetamine reduce excitatory synaptic transmission in the nucleus accumbens by activating presynaptic dopamine receptors. 

*A number of multi-step syntheses of 6,7-ADTN have been published, all low-yielding. The *R *stereochemistry has to be at least 97%.


----------



## JacksinPA

A very interesting 2-AT is *MDAT*, the methylene ether derivative of 6,7-ADTN. From the Wikipedia aricle:

*6,7-Methylenedioxy-2-aminotetralin (MDAT) is a drug developed in the 1990s by a team at Purdue University led by David E. Nichols.[1] It appears to act as a serotonin releasing agent based on rodent drug discrimination assays comparing it to MDMA, in which it fully substitutes for, and additionally lacks any kind of serotonergic neurotoxicity.[1] Hence, MDAT is considered likely to be a non-neurotoxic, putative entactogen in humans.

*https://en.wikipedia.org/wiki/Empathogen–entactogen







I found nothing on the stereochemistry of the amine group. & I don't have access to the J Med Chem article where it was made & tested. Has this ever been encountered as a RC?


----------



## sekio

> Has this ever been encountered as a RC?



If memory serves, this was advertised for sale at around the same time people were hawking MDAI, 5-IAI, and the other indane/tetralins. But it's worth taking that with a grain of salt; especially if the synthesis is more complex than a 2- or 3-step "bucket" recipe - complicated synthesis plus pre-existing stocks of similar drugs that aren't selling well adds up to a grand total of... every unscrupulous vendor under the sun selling lots of shit drugs like 4-methoxymethcathinone as whatever the pill-popping public requests, be it "mephedrone", "benzo fury", "bath salts", "E", "pills"...



> I don't have access to the J Med Chem article where it was made & tested.



In this day and age, _EVERYONE_ has access to such things, just find the DOI (Digital Object Identifier) and plug it into Sci-Hub or Library Genesis (Libgen), like so: https://sci-hub.tw/10.1021/jm00164a037 ... and you get a PDF for downloading or reading, free of charge.


----------



## JacksinPA

> In this day and age, _EVERYONE_ has access to such things, just find the DOI (Digital Object Identifier) and plug it into Sci-Hub or Library Genesis (Libgen), like so: https://sci-hub.tw/10.1021/jm00164a037 ... and you get a PDF for downloading or reading, free of charge.



I live by the axiom that a day passing without learning something new is a day wasted. These tools were new to me, so thanks for the info. Libgen wouldn't work for me but *Sci-Hub* produced a pdf of the Nichols paper. See https://sci-hub.tw/10.1021/jm00164a037. This result amazed me knowing the strict copyright requirements of the ACS. In scanning this paper it appears that the MDAT used in the rat discrimination studies was racemic, which would eliminate the steps involved in resolving it in order to get a chiral active drug molecule. I'm curious to see if studies were done to study the relative activities of the _R_ & _S_ forms of MDAT give the strict chiral requirements in the related 6,7-ADTN. A Google search for 'chiral or _R_ or _S_ MDAT' produced no results.

Reading the experimental details in this paper is a reminder that Nichols (since retired I think) was working with a team of M.S. & Ph.D.-level graduate students & that the equipment, methods & chemicals used would be exactly like the ones they would be using when they went to work as research chemists for Merck or Pfizer. Paar shakers for catalytic hydrogenation, NMRs & Kugelrohr apparatus for high-vacuum short path distillation would usually not be found in the typical home lab. And anyone contemplating volume production would need a well-equipped pilot plant with lots of accessories.


----------



## Pomzazed

NMR in home lab? Wow!


----------



## JacksinPA

And a lot more beside. The primary purpose of the NMR is to verify the identity of each product as it is isolated. IR is still also widely used for this purpose.


----------



## JacksinPA

JacksinPA said:


> And a lot more beside. The primary purpose of the NMR is to verify the identity of each product as it is isolated. IR is still also widely used for this purpose.



I'm sure there are contract labs who will provide an NMR from a small sample but I'd think they would not be cheap. And besides that the operator might be studied enough to use the spectrum of your sample to deduce the structure. So unless you were in with them somehow or representing a big company, the ID of your sample might come to the attention of either the DEA or a blackmailer who would want some of your stash. Crap like that can & does happen.


----------



## S.J.B.

Pomzazed said:


> NMR in home lab? Wow!



You can get benchtop NMR instruments nowadays, but they definitely aren't cheap.



JacksinPA said:


> I'm sure there are contract labs who will provide an NMR from a small sample but I'd think they would not be cheap. And besides that the operator might be studied enough to use the spectrum of your sample to deduce the structure. So unless you were in with them somehow or representing a big company, the ID of your sample might come to the attention of either the DEA or a blackmailer who would want some of your stash. Crap like that can & does happen.



Universities around here with NMR facilities allow NMR time to be purchased by external researchers: the prices are reasonable, and I think you would be able to run the sample yourself.  That said, if you aren't affiliated to a known company, the facility manager might be wary and check out what you were analyzing...


----------



## Pomzazed

Benchtop NMR is not that useful for this kind of research. At 60 MHz and requiring high concentration.
Also it doesnt decouple C, then that is seen is alot of island peak and broad overlapping main peak.

Mostly useful with small uncomplicate things with mw like < 350, without many groups.
Useful for routine checkup type of work.

Trust me, i tried these many brands,...
Thats why i said wow nmr in home lab...


----------



## DotChem

2-methyl-THBC aka "Russian Olive" 






> 1, 2, 3, 4-Tetrahydro-2-methyl-b-carboline is found in fruits of Elaeagnus angustifolia. _*Elaeagnus angustifolia*_, commonly called *Russian olive*,[1] *silver berry*,[2] *oleaster*,[2] *Persian olive*,[2] or *wild olive*,[2] or commonly referred to as  _senjhor_ or _sinjhor_ in Pakistan, _sinjid_ in Afghanistan , Iydə in Azerbaijan, _senjed_ in Iran and _p'shat (փշատ)_ in Armenia,  is a species of _Elaeagnus_, native to western and central Asia, Afghanistan, from southern Russia and Kazakhstan to Turkey, Iran and parts of Pakistan. It is now also widely established in North America as an introduced species.  ..
> 
> In Iran, the dried powder of the fruit is used mixed with milk for  rheumatoid arthritis and joint pains. It is also one of the seven items  which are used in _Haft Seen_ or the seven 'S's which is a traditional table setting of Nowruz, the traditional Persian spring celebration.. wiki



looks like a restricted DMT




 where one of the methyl of DMT is connected to the indole ring.. wonder it has any DMT-like activity (different from harmane and harmaline betacarbolines)


----------



## JacksinPA

This stuff is available in bulk (5-10 kgs) plus LTL ocean freight from sources such as Alibaba in China. Unless you are skilled in this sort of transaction, I'd be leery. (Been watching Season 2 of _*The Wire*_ which is set on the Baltimore docks).

The fruit material contains a complex mixture of flavonoids, sterolds, anthocyananins, alkaloids, etc. See 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5108988/ Extracting the alkaloid (basic)  fraction might be as simple as putting it into a blender with hydrochloric acid, filtering off the solids, then letting the acid evaporate. You're still going to wind up with a mixture of compounds with uncertain biological properties. I couldn't find anything on psychoactivity. Seems like a lot of effort & expense to obtain a questionable final result.

BTW, what do you use to draw your structures?


----------



## DotChem

Extraction is probably not the best way to go for this specific  compound. Easily accessible from tryptamine via straighforward easy  Pictet Spengler rx or by methylation of pinoline eg in formic acid (will  give the 5-methoxylated congener tho).  It is way much cheaper to  synthesize and you avoid bunch of other alkaloids, flavonoids..etc than  extraction from fruits.  the question really is if it might have same  psyhoactivity as DMT: it is just its ring restricted isomer, isn't it?  and very close to Pinoline:




Pinoline  (presumably syntheszed in the pineal gland of humans! just like DMT  presumably!!) is rather interesting molecule: it has potent neurogenesis  activity, like 5HT2a agonist psyhedelics LSD, NBOM.etc.  even at trace  concentration! 



> Mario de la Fuente et al. 2015 "Neurogenic  Potential Assessment and Pharmacological Characterization of  6-Methoxy-1,2,3,4-tetrahydro-β-carboline (Pinoline) and  Melatonin–Pinoline Hybrids" http://pubs.acs.org/doi/abs/10.1021/acschemneuro.5b00041


which makes me think it might have DMT-like psychoactivity.  I couldnt find anyhthing on that specific compound either..    


As  for chem drawing, I use ChemAxon MarvinSketch.  It is way better than  ChemDraw or ChemSketch.  Has way more features. You can actually use it in ChemDraw mode or  ChemSketch if you like besides other options.  The free version has tons of  features besides simple 2D drawing such as conformation analysis,  superimpose and compare 2 or more molecules conformations in 3D, predict  parameters like pKa, cLogP, water solubility.etc.  Or scan database (pubchem, surechem.etc) for 3D similarity to your structure..The paying version is even more powerful allowing molecule  docking in proteins..etc but even the free version is pretty  powerful if you don't mind annoying "subscribe to the full version " popup every time you fire the software.. check'em out:  https://chemaxon.com/products/marvin


----------



## JacksinPA

Thanks for the (hopefully) helpful info on chem drawing. I love ChemDraw but life goes on.

I see a number of problems with your suggested approach: where & how are you going to get yourself 100-500 gr of tryptamine? When I worked for a big chemical company getting samples from other companies was not a problem. Tryptamine does not appear on the DEA Orange List (dea watch list). It is available from multiple Chinese sources, one of whom even accepts PayPal! (http://www.globalsources.com/si/AS/Shanghai-City/6008846763756/pdtl/Tryptamine/1057243520.htm). It might be easier to go from that straight to DMT though I don't want to get involved with synthesis methods here.

Caution: I'd request a small sample first & check the M.P. Some years ago a lot of people got ill from contaminated tryptophan that came from the Orient. These GNC-type health food stores may not be high on the QC scale.

Another idea based on tryptophan is to find a way (enzymatic or thermal?) to decarboxylate it to tryptamine. Here's a start: https://erowid.org/archive/rhodium/chemistry/tryptophan.html


----------



## DotChem

JacksinPA said:


> ..It might be easier to go from that straight  to DMT though I don't want to get involved with synthesis methods  here...



yeah no synthesis discussion of specific compound is allowed on BL  but for general info and sake of the safety of kitchen-chemists who might  consider attempting to get dmt from tryptamine: commonly used methods of  amines methylation by reductive methylation say in formic acid doesnt  work in the case of tryptamine: the intermediate almost always cyclizes to give a  betacarboline (you can't avoid that ..). it's almost always the major  product & hard to separate from an intractable mixture of n-methyltrypatamine, nn-dimethyltryptamine, n-methylcarbolines, starting tryptamine..etc So lest you used direct methylation with nasty toxic cancer-causing  chemicals like MeI, dimethylsulfate..etc... anyhow not wanting to  discuss any chemistry but just so anybody trying to attempt that in  his/her kitchen at home and reading this be warned.



JacksinPA said:


> ..Another idea based on tryptophan is to find a way (enzymatic or  thermal?) to decarboxylate it to tryptamine. Here's a start: https://erowid.org/archive/rhodium/c...ryptophan.html.



There are easier and milder methods that use microwave oven to decarboxylate alfa aminoacids..  shorter times (minutes not days!) and higher yields


----------



## JacksinPA

I've been giving the N-methylation of tryptamine some thought. Alkylation with methyl iodide will give the quaternaty ammonium salt but I found a reference where the quaternary methyl can be selectively removed by treatment with sodium borohydride in polar solvents. The reference is #2 in Organic Preparations & Procedures vol 12, 19809, no. 6 but it's available only via a pay wall. Pre DOI? The reference doesn't give the author's names. Don't have the original reference (#2). There are additional references here: https://www.tandfonline.com/doi/abs/10.1080/00397917408064096?src=recsys. NaBH4 is available in small amounts on eBay but not on Amazon.
Journal*Organic Preparations and Procedures International *

*The New Journal for Organic Synthesis*


*Volume 12, 1980 - Issue 6*

Another Dow publication states that the NaBH4 only works with cyclic compounds involving quaternary carbons.


----------



## JacksinPA

Interesting paper on dealkylating quatenary ammonium salts using ethanolamines: https://www.thevespiary.org/rhodium/Rhodium/Vespiary/talk/index.php/topic,3255.0.html


----------



## JacksinPA

JacksinPA said:


> Interesting paper on dealkylating quatenary ammonium salts using ethanolamines: https://www.thevespiary.org/rhodium/Rhodium/Vespiary/talk/index.php/topic,3255.0.html



Ethanolamines are inexpensive but have their own unique properties: MEA smells like ammonia, DEA is carcinogenic, and TEA may be both carcinogenic & an allergen. It is also on the banned compound list for its potential to be a starting material for nitrogen mustard war agents.


----------



## JacksinPA

JacksinPA said:


> Ethanolamines are inexpensive but have their own unique properties: MEA smells like ammonia, DEA is carcinogenic, and TEA may be both carcinogenic & an allergen. It is also on the banned compound list for its potential to be a starting material for nitrogen mustard war agents.



Piperidine (b.p. 106 deg C.) might serve as an alternative to the ethanolamines. Unfortunately it is not available from either eBay or Amazon.

Also unfortunately, it is said to have an animal-type odor.


----------



## Pomzazed

Jacksin check your PM


----------



## JacksinPA

I just did but there was nothing new. BTW, I saved that article. Thanks!


----------



## JacksinPA

Since oral administration of DMT works best with a MAOI, I started looking for either simple RCs or naturally occurring compounds. I found tis interesting abstract:

https://www.ncbi.nlm.nih.gov/pubmed/3821373


Life Sci. 1987 Mar 16;40(11):1075-82.
*Quinoline and quninaldine as naturally occurring inhibitors specific for type A monoamine oxidase.*

Naoi M, Nagatsu T.
*Abstract*

Type A monoamine oxidase (MAO-A) in human placental mitochondria was competitively inhibited by naturally occurring substances, quinoline and quinaldine, using kynuramine as substrate. Quinoline had a higher affinity for MAO than kynuramine. MAO-A in human brain synaptosomal mitochondria was also competitively inhibited by quinoline, while type B MAO (MAO-B) was reversibly and non-competitively inhibited by quinoline. Quinoline inhibited MAO-A much more potently than MAO-B. Of several compounds structurally similar to quinoline, isoquinoline noncompetitively inhibited MAO-A and -B activity.

Isoquinoline is available from Amazon. It's description as far as flavor goes leaves a lot to be desired.

MAOI-A attacks serotonin, a structural analog of DMT.

https://www.livestrong.com/article/82970-common-herbs-mao-inhibitor-activity/

Common herbs that contain alkaloids that inhibit MAOI-A include Syrian Rue (_Peganum harmala_) which grows extensively in the Western U.S. and is not regulated. See 
https://www.zamnesia.com/content/312-the-effects-of-syrian-rue


----------



## sekio

Quinoline (and isoquinoline for that matter) are aromatic hydrocarbons, generally Not Good Stuff to expose yourself to in more-than-trace amounts. They are certainly not very "druglike"...

Also, isoquinoline is not the same as quinoline


----------



## JacksinPA

I noted the unpleasant nature of isoquinoline & quinoline also. I certainly would take a pass on ingesting any aromatic no matter what it tasted like.

Isoquinoline is sold by Amazon but quinoline is not. Sorry if I wasn't clear about their not being identical. Just an interesting note about their availability & biological activity.


----------



## DotChem

JacksinPA said:


> Interesting paper on dealkylating quatenary ammonium salts using ethanolamines:





JacksinPA said:


> https://www.thevespiary.org/rhodium/Rhodium/Vespiary/talk/index.php/topic,3255.0.html



I missed that lasted posts. very interesting indeed.  It looks like it is the best route to go  .. but I wonder why nobody has looked at starting with dirt cheap indole-3-acetic acid and dimethylamine. IAA is a plant hormones used in agriculture.. as cheap as table salt, or almost! google it ).  you can see how easy it would be to get to dmt.. but then again no synthesis talk on BL.. so back to ring restricted pinoline-type DMT analogs: It turns out they're actually Monoamine relasers (more serotonergic than DA/NE so possibly emptathogen like mdma!! kind of surprising but interesting considering that pinoline is an endogenous molecule (could it be the natural empathy-stimulating molecule in humans.. who knows?. Some of the betacarbolines congeners are too polar to cross the blood brain barriers but some are incredibly potent serotonin releaser like the 5-hydroxy-THBC (Ki less 5 nM!! ) according to this paper (a bit old but worth to study.. 


> Tetrahydro-beta-carbolines and corresponding tryptamines: In vitro inhibition of serotonin, dopamine and noradrenaline uptake in rat brain synaptosomes.





> Acta Pharmacol Toxicol (Copenh). 1980 Apr;46(4):299-307.​


----------



## JacksinPA

The route from IAA to DMT would likely involve reduction with LAH, which is no cup of tea & a good way to start a fire withe volatile ethers involved & the need for strictly anhydrous conditions. Drug labs are usually uncovered by the police after the FD has finished up putting out your house fire. In my experience, the PD always responds to FD calls.


----------



## JacksinPA

Syrian Rue itself (whole plant) does not seem to be available but the seeds are from a number of online sellers. There is one if these folks who sells the extracted harmane alkaloids, which are potent MAOI-A inhibitors. A lot less work & a lot prettier (but more expensive) to let him do the extraction/isolation. Pix in his listings look like bona fide stuff (fine yellow powders) & the number of sales listed indicate that he has had a lot of satisfied customers.





A note of caution about using & abusing these ethnochemicals:

Peganum harmala, commonly called "Syrian rue," is native to countries around the Mediterranean sea and western United States. Known for its sedative effects when consumed by farm animals, its seeds have stimulant and hallucinogenic effects at low doses (3-4 g when eaten) in humans. Its active ingredients harmaline and harmine have monoamine oxidase inhibitor properties. A 41-year-old female prepared a hot drink by boiling approximately 100 g of P. harmala seeds in water (10-20 times the recommended dose for "calming one's nerves"). Upon presentation to the emergency department, she was unconscious and had hypertension, tachycardia, and tachypnea. Hepatic and renal function markers were grossly elevated. After intubation, she improved with supportive care over the course of five days. Her level of consciousness, renal and hepatic markers gradually returned to normal. Poisoning with high doses of Peganum harmala can be life-threatening, although patients usually recover with supportive therapy alone.
_(PDF) Syrian rue tea: A recipe for disaster_. Available from: https://www.researchgate.net/publication/23268202_Syrian_rue_tea_A_recipe_for_disaster [accessed Sep 03 2018].


----------



## DotChem

JacksinPA said:


> The route from IAA to DMT would likely involve reduction with LAH, which is no cup of tea & a good way to start a fire withe volatile ethers involved & the need for strictly anhydrous conditions. Drug labs are usually uncovered by the police after the FD has finished up putting out your house fire. In my experience, the PD always responds to FD calls.


Actually you wouldnt really need LAH for that: NaBH4+cat LiCl would do just fine (actual reducing agent is LiBH4, if you can get your hand on it, but you don't need to, cat LiCl with nabh4 would work fine).. not the best of yield but easy to separate pure final product+ you wont blwo up the neighborhood!!..Yea man! no synthesis talk allowed on BL but for the sake of safety since you mentioned LAH in case somebody reading your post got the idea.  Of course, LAH is the best for this purpose but in a lab setting not for kitchen chemists.. isn't it what they use for rocket fuel in space shuttle??  (That shit once ignites in my face when I forgot to close the lid for a few minutes.. lucky I was wearing goggles !!! ​


----------



## DotChem

JacksinPA said:


> Syrian Rue itself (whole plant) does not seem to be available but the seeds are from a number of online sellers. There is one if these folks who sells the extracted harmane alkaloids, which are potent MAOI-A inhibitors. A lot less work & a lot prettier (but more expensive) to let him do the extraction/isolation. Pix in his listings look like bona fide stuff (fine yellow powders) & the number of sales listed indicate that he has had a lot of satisfied customers.


​


JacksinPA said:


> A note of caution about using & abusing these ethnochemicals:
> 
> Peganum harmala, commonly called "Syrian rue," is native to countries around the Mediterranean sea and western United States. Known for its sedative effects when consumed by farm animals, its seeds have stimulant and hallucinogenic effects at low doses (3-4 g when eaten) in humans. Its active ingredients harmaline and harmine have monoamine oxidase inhibitor properties. A 41-year-old female prepared a hot drink by boiling approximately 100 g of P. harmala seeds in water (10-20 times the recommended dose for "calming one's nerves"). Upon presentation to the emergency department, she was unconscious and had hypertension, tachycardia, and tachypnea. Hepatic and renal function markers were grossly elevated. After intubation, she improved with supportive care over the course of five days. Her level of consciousness, renal and hepatic markers gradually returned to normal. Poisoning with high doses of Peganum harmala can be life-threatening, although patients usually recover with supportive therapy alone.​_(PDF) Syrian rue tea: A recipe for disaster_. Available from: ​https://www.researchgate.net/publication/23268202_Syrian_rue_tea_A_recipe_for_disaster [accessed Sep 03 2018].​




Unlike the Carbolines such as Harmine and the dihydrocarbolines (like Harmaline and Harmalol) that are MAO inhibitors, the tetrahydrocarbolines (THBCs) like tetrahydroharmine or pinoline are not.  Pinoline is about 1000x less as MAO inhibitor than the monounsaturated and fully oxidized carbolines (will dig out refs on that later). 

On the other hand, iirc unlike the THBCs, carbolines and dihydrocarbolines are not monoamines releaser/reuptake inhibitor ??? correct me if I am wrong tho. I cant find any study on that. Almost all focus on their MAO activity They look similar (chemical structure wise) but they have distinct pharmacology.  I would think THBCs would be more like DMT but apparently they're also somehow like MDMA I mean in terms of serotonergic/da/net releasing ratios.. So possibly they'll be like a DMT/MDMA combination in effect.. but who knows? .. oh BTW, as I mentioned they're robustly neurogenic like LSD, DOM or noribogaine .. I mean pinoline but not harmaline or harmine.

edit: that woman who OD'ed on Syrian rue harmala was actually lucky. She probably was not taking any other medication (and/or foods like cheese) containing groups (amines) that are detoxify by MAO. If she's eaten cheese (containing Tyramine) MAO inhibition might shoot up concentration of its brain tyramine and all sort of amines. Cheese might get her pretty high, I mean psychotic high because of the tyramine.  But could be brain dead or worse.. ​


----------



## Limpet_Chicken

Jacksin-if LibGen is blocked for you,try connecting through TOR. LibGen is blocked in the UK by court orders aimed at ISPs, bunch of bastards.

But you can just connect via TORbrowser and if its still blocked, then you only need to switch a new TOR circuit for the site, until the exit node isn't one located in the UK


----------



## JacksinPA

DotChem said:


> Unlike the Carbolines such as Harmine and the dihydrocarbolines (like Harmaline and Harmalol) that are MAO inhibitors, the tetrahydrocarbolines (THBCs) like tetrahydroharmine or pinoline are not.  Pinoline is about 1000x less as MAO inhibitor than the monounsaturated and fully oxidized carbolines (will dig out refs on that later).
> 
> On the other hand, iirc unlike the THBCs, carbolines and dihydrocarbolines are not monoamines releaser/reuptake inhibitor ??? correct me if I am wrong tho. I cant find any study on that. Almost all focus on their MAO activity They look similar (chemical structure wise) but they have distinct pharmacology.  I would think THBCs would be more like DMT but apparently they're also somehow like MDMA I mean in terms of serotonergic/da/net releasing ratios.. So possibly they'll be like a DMT/MDMA combination in effect.. but who knows? .. oh BTW, as I mentioned they're robustly neurogenic like LSD, DOM or noribogaine .. I mean pinoline but not harmaline or harmine.
> 
> edit: that woman who OD'ed on Syrian rue harmala was actually lucky. She probably was not taking any other medication (and/or foods like cheese) containing groups (amines) that are detoxify by MAO. If she's eaten cheese (containing Tyramine) MAO inhibition might shoot up concentration of its brain tyramine and all sort of amines. Cheese might get her pretty high, I mean psychotic high because of the tyramine.  But could be brain dead or worse.. ​



I've been in emergency rooms a number of times & they don't make for 'fun' evenings.


----------



## JacksinPA

Limpet_Chicken said:


> Jacksin-if LibGen is blocked for you,try connecting through TOR. LibGen is blocked in the UK by court orders aimed at ISPs, bunch of bastards.
> 
> But you can just connect via TORbrowser and if its still blocked, then you only need to switch a new TOR circuit for the site, until the exit node isn't one located in the UK



Sci-Hub worked the first time for me & I was amazed to get free access to full-image ACS journal articles that they would normally charge you $35 for. They put a lot of money into their journals & are very jealous of their copyrights. As more & more libraries go digital, the value of their storehouse of articles only increases.

As far as Lib-Gen goes, I have neither the time nor inclination to develop a second method for getting what I can already get via Sci-Hub.


----------



## blueberries

Ok; this is pretty damn basic but you never know..LSD has a fairly similar structure to DMT too

https://imgur.com/a/lseaWsN


----------



## JacksinPA

blueberries said:


> Ok; this is pretty damn basic but you never know..LSD has a fairly similar structure to DMT too
> 
> https://imgur.com/a/lseaWsN



Correct, as can be  seen in the attached graphic:


----------



## JacksinPA




----------



## DotChem

The NN-dipropyl analog of above compound is a dopaminergic antagonist trialed in phase I as antipsychotic and then discontinued.. probably the volunteers were hallucinating!! .. looks like the one you drew


----------



## blueXtX

Indazole and napthyl analogs of ETH-LAD and LSD.


----------



## Pomzazed

Shhh... dont believe me...!


----------



## JacksinPA

A couple of interesting isoxazole analogs:


----------



## S.J.B.

JacksinPA said:


> A couple of interesting isoxazole analogs:



Are there any known tryptamine or phenethylamine analogues active at 5-HT2A that contain a basic nitrogen in the aromatic portion?


----------



## JacksinPA

You left methyl groups on the nitrogens, not n-propyl.


----------



## JacksinPA

There are 4 isomers of pyrrolopyridines but I didn't see any that had hallucinogenic effects. As far as the 
	

	
	
		
		

		
		
	


	




pyridyl analogs of phenethylamines, check PIKHAL. For the tryptamines, check TIKHAL.


----------



## Dresden

Pyridinyl amps not in PiHKAL.

Not only can the DMT overlay skeleton be found in LSD, but the methamphetamine (2-methylamino-1-phenylpropane) one as well.


----------



## JacksinPA

Dresden said:


> Pyridinyl amps not in PiHKAL.
> 
> Not only can the DMT overlay skeleton be found in LSD, but the methamphetamine (2-methylamino-1-phenylpropane) one as well.



Good points. Thanks for checking PIKHAL.

I met Alec Shulgin at an ACS convention in Anaheim, CA years ago. Nice guy. Wish I had had more time to spend with him.


----------



## Lachdanan

MDx-like entactogenic activity with a phthalan base ring structure? Toxicity risks?

APBs ->  aminopropyl-phthalans (5APP, 6APP)


----------



## Bagseed

well I guess you need the electronegative substitution (oxygen) on the benzene ring, dunno if a carbon on there will work. but I am by no means a pharmacologist...


----------



## Limpet_Chicken

Can anyone give any info as to both acute and longterm toxicity of pthalimide? (unrelated to the above, it just reminded me)

Because of the instability of primary amine cathinones, its possible to employ a pro-drug strategy, namely preparing the pthalimidopropiophenone homolog to the cathinone, the pthalimide getting cleaved off in the acidic environment of the stomach, thus causing the  otherwise unstable as hell psychedelic cathinone analogs to be released into an environment which ensures they are dilute in solution and ergo, less likely to meet up with another molecule of the psychedelic cathinone and dimerize to pyrazine crap.

I'd very much like to know  how safe this  is, not interested for simple stimulant and thus heavy use, but for occasional use in facilitating research of cathinone  analogs of psychedelic phen/phets.


----------



## sekio

I thought I recalled seeing phthalimides as prodrugs for cathinones at some point or other, but presumably they are poor prodrugs as amides/imides are tougher nuts to crack than esters...


----------



## Limpet_Chicken

Yeah, that was where I got the idea from, I recall something about pthalimidopropiophenone being used orally as a stimulant in, IIRC, israel.

I think it was israel, anyway, I definitely recall something about it being done.

Just want to know about the potential toxicity of pthalimide, since if is highly toxic obviously my research will have to go in other directions.
But it'd be very good to explore more beta-ketophenthylamines and psychedelic cathinones without that damnable instability. In the case of cathinones, the alpha-methyl group provides some additional stability doesn't it? how much greater is the stability of a given beta-ketophenethylamine vs it's alpha-methyl homologue?

Psychedelic cathinones have interested me for a while, as has  potentially lengthening the chain, see if the corresponding pyrovalerones etc. are effective as  psychedelics.


----------



## Neopunk

Why do you want to know about the toxicity of phthalimide, when by cleavage of the prodrug not phthalimide, but phthalic acid is obtained? The first one however is quite non-toxic. Once I performed a Gabriel-synthesis and remember it not even having H&P-statements :D
Of course that doesn't mean it's safe in long-term use. But really, you rather have to look at phthalic acid, which seems to be irritating to skin, eyes and airways.
My guess would be that the use of a phthalimido-protecting group shoulnd't be too problematic if used occasionally.


----------



## cj187

Would it be feasible to make an ester prodrug that has OH groups to increase water solubility?


----------



## Bagseed

Are the salts of 4-AcO-DPT not water soluble?


----------



## Lachdanan

Bagseed said:


> well I guess you need the electronegative substitution (oxygen) on the benzene ring, dunno if a carbon on there will work.



3-Methoxy-4-methylamphetamine is definitely entactogenic.


----------



## sekio

> Would it be feasible to make an ester prodrug that has OH groups to increase water solubility?



Nature beat you to it... it's the phosphoric acid ester known as psilocybin.


----------



## Bagseed

not the same thing, as the PO ester has an acidic hydrogen which can protonate the basic nitrogen to give a zwitterion. the proposed structure with all the alcohols won't do the same, but I think you are aware of that.


----------



## BPD help plz

Pomzazed said:


> Wee! Great!
> So now the random molecule wont spread around all over the topics!
> 
> Let me start this (supposedly fun?) topic by this one:
> (Please vote a name for it!)


I Bow Before You Oh Masterful one!!


----------



## BPD help plz

Hi, errr...I'm a newbee here...first day and all....i have lots of 'practical' knowledge over the years, sadly the chemistry side of things i failed to ever pay attention to therefore alas my first time try of making methcathinone went totally wrong.....i'm kinda at a loss of how to 'blog' post...but mucho impressed at your structure knowledge, is it ok if i hang on your coat tails a bit?


----------



## Pomzazed

Be no worries, you know every people is clueless before then learn something!
Just take it step by step and not just hop to the fancy stuffs without understanding the basics of what is going on.

One big difference between “cooker” and “chemist” is that cooker only follow the recipes blindlessly with no understanding what the molecules is behaving inside the reaction, while the chemist have knowledge and can “see” what, how, when, why and where things happens.

This topic is meant to be fun, most things are designed out of some basis but they arent tested out so never make them and try. That will be extremely dangerous. Some of them are just for mental masturbation like my MDBuckyball you quoted!


----------



## BPD help plz

I wish my Science teacher had been remotely interesting then i may have actually gone done the chemistry path as i recall 'asking santa' for a chemistry set......a MASSIVE chemistry set (for kids but i bet you couldn't get them now a-days)...and santa....(with my Dad's help)...got me said chemistry set.....it , as i recall, was equipped with the works, test tubes, chemicals of all sorts ...over 1000 different 'experiments'.....think i did about 1 with Dad on Xmas day before it went into storage before moving house then never saw it again.....but by then....i had started Science and my teacher was as interesting as watching paint dry....actually, no, i think i learnt more watching paint dry


----------



## Pomzazed

As of current state, there are enough online resource that can be used for self learning comparing to old days.

Trust me, learning in most school, univ is just as boring as what you described.
Chem has much more, just not skip to learn only the “cool” things only.

You dont even need an interactive media to be fluent in chemistry, just a scan of a good textbook will do
Some are not too hard to understand thoroughly. You just need to know where to download them (for free)
It is ok if textbooks are of old age, you just need to update your knowledge when you find a more recent source.

I can speak of this by first hand experience, now being a chemist myself, i learn univ-grade chem since like 14-15yo
By just sifting thru the “offline” library in school, univ. And, more importantly, being as chemistry obsession since a child, 
I still do find how chem is taught in school super boring, and in univ just....er...okay-level.

Query me in pm if you still want sth specific to learn  Let’s not flood this thread with personal re-re-reply


----------



## JacksinPA

The license period on my copy of ChemOffice 17 expired. Even though I own the earlier 11 version, that's for 32-bit machines & won't work in my Dell 64-bit Windows 7 desktop.

Perkin-Elmer wants over $2900 for ChemOffice 17. Even with the 20% discount they will give me for owning the earlier version, that's still $2500 or so for a program I only use occasionally.

I searched eBay for ChemOffice & found a guy in Spain selling ChemOffice 16 which is Windows 7 compatible. New, with download & license key. Listing #232946706683. For under $5. Three left. My experience with both versions 11 & 17 showed that they were basically the same structure drawing version of ChemDraw. I bought one. He has 3 left. Great value for $5!


----------



## Dresden

"Has anybody tried making dieneyl cyclohexane amphetamine analogues?"

I think they would have a tendency to aromatize to benzene.  Saw this question on a earlier page; didn't realize it was ancient.  Sorry to be erratic.


----------



## JacksinPA

JacksinPA said:


> The license period on my copy of ChemOffice 17 expired. Even though I own the earlier 11 version, that's for 32-bit machines & won't work in my Dell 64-bit Windows 7 desktop.
> 
> Perkin-Elmer wants over $2900 for ChemOffice 17. Even with the 20% discount they will give me for owning the earlier version, that's still $2500 or so for a program I only use occasionally.
> 
> I searched eBay for ChemOffice & found a guy in Spain selling ChemOffice 16 which is Windows 7 compatible. New, with download & license key. Listing #232946706683. For under $5. Three left. My experience with both versions 11 & 17 showed that they were basically the same structure drawing version of ChemDraw. I bought one. He has 3 left. Great value for $5!



I finally received the download link + password to get into my ChemDraw Professional 16.0. I've been studying a group of structurally related perfume chemicals called irones. Here are the structures. The mixture is extremely expensive due to having to harvest & extract from flower bulbs, then let age for 2 years or so for enzymatic air oxidation. This method makes it too expensive for use in commercial perfumes. I've  been running a patent search on synthetic approaches to manufacturing these at lower costs:






This is just a test of my new ChemDraw Professional 16.0 & it has all the functionality of my earlier 32-bit ChemDraw 11 & later 64-bit ChemDraw 17. The structures were generated by the program from the alphabetical names. Pretty neat! Saves the time needed to draw the structures manually.


----------



## JacksinPA

Mitragynine & the more potent opioid 7-hydroxymitragynine from KRATOM:


----------



## Pomzazed

Jack, do u want all 3 isomer of irones, can they be as mixtures or only one isomer is desired in pure form?


----------



## JacksinPA

I just stared downloading pdfs of the articles & patents on the irones this weekend so I haven't had time to get into them all. But it seems that one of the problems with making a good perfume-quality mixture is the ratio on the 3 isomers which is not going to be in the exact ratio of 1:1:1 due to both the structural dissimilarity of the isomers or their precursors & the structural specificity of the oxidizing enzymes(s). In Nature, where your letting the precursors extracted from *Iris* flower bulbs oxidize naturally, there is no problem getting an acceptable product but it is very expensive. Doing all 3 isomers in the lab & then mixing them to get an acceptable blend is the real challenge. Pure isomers are blended to get the final product. Because the final mixture is so expensive, a lot of work has been done on this by the big perfume companies.

It's a big relief to finally get ChemDraw back. They apparently only gave me a 6-month extension on ver. 17 in response to my helping with their beta-test.


----------



## JacksinPA

KROKODIL (Desomorphine)

This is a wide-spread opioid of abuse usually made via a 2-step reduction starting from codeine. It is structurally similar to morphine but lacks morphine's allylic alcohol function in what I have labeled as the 'C' ring.


----------



## Pomzazed

Crocodile is far from desomorphine, while it is still main actives inside it.
The phosphorus and iodine compounds are not removedm thus very corrosive and make dead tissues, rotten flesh, falling off organs and degraded bones in users.


----------



## JacksinPA

*WO2009/106982 Pfizer 2009 CB-1 Receptor Agonists*












I haven't gotten into this 289-page patent application yet but it is obvious that some serious medicinal chemistry effort went into designing these indazole compounds. The amide side chains are either esters or amides & have either alpha-isopropyl or -tert-butyl substituents. But the basic pharmacophore is 1-(4-fluorobenzyl)indazole in both.

Pfizer's work on synthetic cannabimimetics goes back over 40 years (1970s). These structures are new to me.


----------



## JacksinPA

Another 2009 Pfizer patent describes a series of benzimidazolone compounds with activity at CB1/CB2 but the exact mode of activity is not clear. Example 169 (pictured below) seems to be the most active based on the biological data given.


----------



## JacksinPA

It is a street drug & is prepared using some very nasty & corrosive reagents that may not be adequately removed before use. So I agree that desomorphine & KROKODIL may not be the same thing. Desomorphine in pure form is a long way from KROKODIL.


----------



## Pomzazed

CB. Receptor can accept vast array of molecule,
Align them using your chem 3D with these
- anandamide
- thc
- jwh-018 or similar
- fubinaca or similar

Put the tail together fixed at one spot, put the carbonamide of anandamide, phenolic OH of thc, and carbonyl of jwh and fubintogether,
and lock the bulk hydrophobic group together - the ene of anandamide, terpene of thc, naphthalene of jwh and aminoacid residue of fubi.

You can see the shape and requirement right there afterward, CB is quite a whore recepter (not pun, this is real word)


----------



## JacksinPA

Cyclopropylfentanyl:


----------



## JacksinPA

Following the recent discussions on the manufacture of DMT from the amino acid tryptophan, here are some thoughts on potential psychoactive derivatives. No synthetic details included.

See https://i.postimg.cc/y8LrMDzQ/DMT-derivatives.jpg All of these compounds are said to be psychoactive. 5-Bromo-N,N-dimethyltryptamine is reported to have sedative activity. See https://www.ncbi.nlm.nih.gov/pubmed/18217716


----------



## Dresden

5-bromo-DMT is found in certain underwater ocean sponges, ostensibly as an underwater weapon, and is likely psychoactive in its own right.

5-MeO-DMT can be had from milking the venom of giant leaping toads.

DMT:

Indole acetic acid (a common plant hormone) --> indole ethyl alcohol --> indole ethyl bromide --> DMT

I call this synthetic sequence THE BUTTERFLY RXN.


----------



## JacksinPA

Dresden said:


> 5-bromo-DMT is found in certain underwater ocean sponges, ostensibly as an underwater weapon, and is likely psychoactive in its own right.
> 
> 5-MeO-DMT can be had from milking the venom of giant leaping toads.
> 
> DMT:
> 
> Indole acetic acid (a common plant hormone) --> indole ethyl alcohol --> indole ethyl bromide --> DMT
> 
> I call this synthetic sequence THE BUTTERFLY RXN.



The frog is an endangered species & hiking around the Sonoran Desert looking to capture one might cause you to acquire some stainless steel handcuffs from all the ICE in that area. Then how do you get them home & keep them alive? I understand they make a lot of noise.

I have no idea where & how you can find those sponges. Right ID = OK, bad ID = dead or very sick.

We've discussed starting from locally available tryptophan to make DMT. Could be a lot less expensive than IAA. And that reduction you propose involves some dangerous & hard-to-get reagents. And you can't get HBr at your local Walmart.


----------



## Dresden

I have known of people who kept pet toads and milked them.

PBr3, actually.

But anyway, by all means, whatever reaction floats your boat.  To me it's nothing.


----------



## JacksinPA

Walmart doesn't stock PBr3 either. It's a very hazardous material that is a) difficult to obtain and b) require expertise in handling in specialized glassware with effective ventilation. To buy anything from Sigma-Aldrich you have to prove your a_ bona fide_ company. And I'm sure they report sales of certain materials to the DEA. Much easier to start with tryptophan from GNC.


----------



## sekio

Making HBr is not that daunting, food grade H3PO4 plus sodium bromide (pool supply store), mix & distill. Just don't do it in a spider-man coffee mug.

5-XYZ-tryptamines can also be easily made from 5-sub-indole a la Shulgin with oxalyl chloride intermediate. Assuming you have the lithal to do IAA->indole-ethanol.


----------



## JacksinPA

sekio said:


> Making HBr is not that daunting, food grade H3PO4 plus sodium bromide (pool supply store), mix & distill. Just don't do it in a spider-man coffee mug.
> 
> 5-XYZ-tryptamines can also be easily made from 5-sub-indole a la Shulgin with oxalyl chloride intermediate. Assuming you have the lithal to do IAA->indole-ethanol.



Oxalyl chloride is even nastier that PBr3. I think you were referring to PBr3  in the above.


----------



## S.J.B.

Dresden said:


> ...indole ethyl alcohol --> indole ethyl bromide...



The best conditions for that displacement, if one is trying to avoid noxious things, would be the Appel variant that uses triphenylphosphine and tetrabromomethane.  It is not by any means atom-economic, but the reagents are crystalline solids and therefore much easier to deal with than bromine or phosphorus tribromide.  Still not Wal-Mart specials, of course.


----------



## sekio

There are better variants of the Appel reaction... do they teach this concept of "atom economy" these days? Try for instance triphenylphosphine plus methyl iodide/methyl bromide. That actually ate the inconel off a thermocouple in the heated liquid state, good clean fun.

The fact that all the reactants in an appel reaction are crystalline is actually bad for scaling as you tend to form huge amounts of TPPO sludge... "real men" would use mesyl/benzensulfonyl chloride (liquid) or tosyl chloride (solid) instead to form a group you can displace with e.g. dimethyl amine.

If the tosylate is not suitably reactive then do a quicky finkelstein. R-O-Ts plus KI 1.3eq in DMF (or DMF/acetone mixture, the literature will tell you that you want NaI in acetone but ignore it and trust uncle sekio), heat at 50-60c with stirring, when you find there's no more precipitated KOTs then work up by adding cold water/crushed ice (dissolves KOTs, excess KI, and DMF/acetone) and extracting with suitable nonpolar solvent (less dense than water, maybe MEK or IBK for polars? ether works fine for most iodides). Decolorize product with sodium sulfite or the like then dry the nonpolars and pop on a rotovap, bam, 80% yield every time

indol-3-yl-N,N-dimethylglyoxylamides are the intermediates used in TiHKAL for a lot of tryptamine synthesis. You don't need neat oxalyl chloride, the 2M solutions people sell for Swern rxns will work fine too. Oxalyl is smelly but has good atom economy due to low equivalent m.w.


----------



## Pomzazed

- Both oxalylchlorid and phosphortribromid arent evil at least to me. I handled nastier things before. (Say, gaseous phosgene)
- To make it even less atom economic (lol); but faster reaction and more complete in appel reaction, use hexabromoacetone or tribomoacetamide. This will occur at like 15C so no need reflux, more like needing an ice bath and it goes to completion in like 30 seconds, filter the phosphinoxid out as usual.


----------



## S.J.B.

sekio said:


> There are better variants of the Appel reaction... do they teach this concept of "atom economy" these days? Try for instance triphenylphosphine plus methyl iodide/methyl bromide.



It is taught as something to strive for but in reality it's very much secondary to cost (and a number of other factors - toxicity, supply stability, etc.).

I wouldn't use tetrabromomethane personally, just suggesting it for those prioritizing the minimization of noxious vapours.  I like to use triphenylphosphine and bromine, and have always found it to work very well.



> The fact that all the reactants in an appel reaction are crystalline is actually bad for scaling as you tend to form huge amounts of TPPO sludge...



Usually the mixture can be poured into pentane or another suitable hydrocarbon solvent, to crash out the triphenylphosphine oxide, and then filtered.  Perhaps not ideal once past a certain scale.



> "real men" would use mesyl/benzensulfonyl chloride (liquid) or tosyl chloride (solid) instead to form a group you can displace with e.g. dimethyl amine.



Mesylate formation from alcohols is definitely more pleasant than installing a bromide, especially with mesyl anhydride (solid).


----------



## JacksinPA

Volsam said:


> *JacksinPA*, I very much appreciate your recent contributions with drawing out the correlations between opioid acting drugs and underlining the Tyrosine structure in them! It made me think...8)
> The longer I look at molecules of different psychoactives, the more I see how they are all like keys with differing groves on them, but structural similarity is amazing! :D
> 
> :D



I post here to keep my mind & my time useful. It's also to hopefully get people thinking about structure-activity relationships as well as choosing viable synthetic routes to get to new or existing molecules. Right  now I'm back searching this thread to find my posts on converting tryptophan into DMT while avoiding the need for difficult or hazardous reagents.


----------



## JacksinPA

*DMT from tryptophan - summary

Here is a general recap of my recent posts over  months on converting store-bought L-tryptophan into DMT without the use of any hazardous or difficult-to-obtain reagents.

The classic approach to methylating that amine is to use methyl iodide. As a thought, *methyl bromide* is a commercial (and highly toxic) insecticide/fumigant & might be more readily available in cylinders from commercial sources that might not ask too many questions.

A gas at room temperature, **methyl bromide readily penetrates skin, cloth, and other protective materials such as rubber and leather. It is nonflammable and toxic at low concentrations. Methyl bromide is odorless and odor provides no warning of hazardous concentrations.*


----------



## Dresden

KrZ from the Hive successfully synthesized DMT from tryptophan years ago.  

S/he decarboxylated tryptophan by refluxing it in turpentine, a high boiling solvent, and then reduced the resulting tryptamine with 2 molar equivalents of formaldehyde with sodium cyanoborohydride in methanol IIRC.


----------



## JacksinPA

Dresden said:


> KrZ from the Hive successfully synthesized DMT from tryptophan years ago.
> 
> S/he decarboxylated tryptophan by refluxing it in turpentine, a high boiling solvent, and then reduced the resulting tryptamine with 2 molar equivalents of formaldehyde with sodium cyanoborohydride in methanol IIRC.



Turpentine is a good high-boiling solvent but there are obvious flammability & ventilation issues, as well as the difficulties involved with recovering the tryptamine. Partition with an aqueous weak acid like acetic might be less trouble than trying to distill the turpentine.

 The hard part is that reducing agent which is not commonly available.

There are a number of reagents such as ethanolamines that are known to work in my demethylation scheme.


----------



## Dresden

NaBH4 in pyridine will also work.


----------



## JacksinPA

Dresden said:


> NaBH4 in pyridine will also work.



You can get NaBH4 on Amazon, as well as pyridine.


----------



## Dresden

Some people reading this can probably get them.  You don't have to get sassy.


----------



## JacksinPA

Dresden said:


> Some people reading this can probably get them.  You don't have to get sassy.



I was trying to be helpful. Too bad you took it the wrong way. It was not my intent to be 'sassy.'


----------



## JacksinPA

Forget my suggestion of using CH3Br for the methylation. It is a banned substance (toxic + greenhouse gas), a gas & very toxic. No odor & it goes through rubber gloves. Much better option is CH3I, which is a liquid & can be made by a number of methods in the lab. Much less toxic as well.


----------



## JacksinPA

CH3I works well in 'exhaustive methylation' of primary amines:


----------



## JacksinPA

Dresden said:


> KrZ from the Hive successfully synthesized DMT from tryptophan years ago.
> 
> S/he decarboxylated tryptophan by refluxing it in turpentine, a high boiling solvent, and then reduced the resulting tryptamine with 2 molar equivalents of formaldehyde with sodium cyanoborohydride in methanol IIRC.



According to references on Google, mineral oil (which is odorless) boils at 310 deg. C while turpentine (odor) boils in the range of 149-180 deg C. Since rate of reaction varies with temperature, my choice from a safety POV would be mineral oil. Heating mantle, Variac,  temp probe, mag stirrer, reflux condenser.

As can be seen, turpentine does not come close to the melting point of L-tryptophan, but that might not be an absolute requirement.

Melting points:

L-tryptophan - 289 deg C.
Tryptamine - 113-116 deg C.


----------



## S.J.B.

JacksinPA said:


> According to references on Google, mineral oil (which is odorless) boils at 310 deg. C while turpentine (odor) boils in the range of 149-180 deg C. Since rate of reaction varies with temperature, my choice from a safety POV would be mineral oil. Heating mantle, Variac,  temp probe, mag stirrer, reflux condenser.



I've never heard of someone using mineral oil as a solvent, and I certainly would not attempt to reflux it at over 300 C.  If the reaction goes at the boiling point of turpentine there is no reason to try and raise the temperature higher.  It will likely just lead to greater decomposition.


----------



## JacksinPA

Thanks. My interest would be at or slightly about the m.p. of the Trp, not at the b.p. of mineral oil. Turpentine will not get up to the m.p. of Trp while mineral oil will. Despite the earlier report using turpentine, I'm skeptical that the reaction would go below the m.p.

New approaches begin with people trying things that others have not tried. I see nothing wrong with mineral oil & it does not have the odor & flammability of turpentine, which is a mixture of pinenes. Pinenes are one of the reason that soft wood forests make such intense fires. Weak bases such as tryptamine in this case can be extracted out of the oil using aqueous white acetic acid (vinegar). Upon evaporation the solid product would be tryptamine acetate.

So we've gotten half way through the proposed synthesis scheme using only products available at the local shopping mall. That sort of innocent simplicity makes it more interesting to me.


----------



## Dresden

I am simply reporting what KrZ used.
KrZ was no amateur and is legit AF.
An exhaustive methylation of tryptamine procedure can be found in TiHKAL by Shulgin.


----------



## JacksinPA

Thanks. I will check that out. Still hard to believe that they used smelly turpenitine as the reaction medium. Would not be my first choice for the reasons I've already stated..


----------



## Pomzazed

Mineral oil doesnt really dissolve anything, being mostly simple unbranched alkanes.
Also, decarboxylation seems to be somewhat accompanied by ketone (idk mechanism) catalytically, which i think is present in a small amount in turpentine (less than a percent) but enough to facilitate the reaction.


----------



## sekio

Turpentine heated in the presence of air will make ketones, alpha pinen+oxygen -> verbenone, limonene->carvone/piperitone, carene->carenone etc.


----------



## Dresden

sekio,

This may be a stupid question, but does

Safrole + turpentine + O2 (g) --> PMK?


----------



## JacksinPA

Pomzazed said:


> Mineral oil doesnt really dissolve anything, being mostly simple unbranched alkanes.
> Also, decarboxylation seems to be somewhat accompanied by ketone (idk mechanism) catalytically, which i think is present in a small amount in turpentine (less than a percent) but enough to facilitate the reaction.



Mineral oil is intended to be a high boiling liquid reaction medium, not a solvent. The basic product is extracted out with white vinegar as the acetate salt.


----------



## JacksinPA

Dresden said:


> I am simply reporting what KrZ used.
> KrZ was no amateur and is legit AF.
> An exhaustive methylation of tryptamine procedure can be found in TiHKAL by Shulgin.



Thanks for providing the page/reaction number references (which turns out to be pp. 412-415 (T#6)):

The operation that intrigued me is his use of freshly made AgCl to partially accomplish the demethylation of the quat salt by precipitating the iodide followed by pyrolysis & isolation via the picrate salt. It seems to me that there are too many steps/reagents involved here & that a good industrial or experimental chemist could simplify this scheme significantly. For example, picric acid is hard to come buy as it is classified as an explosive. Making fresh AgCl sounds tedious. And pyrolysis of indole compounds may produce byproducts.


----------



## JacksinPA

*Hypaphorine

*A Google search for the exhaustive methylation of Trp came up with this interesting alkaloid. Pharmacologically it is of interest for promoting sleep:

Lenticin or hypaphorine is a compound found in lentil extracts. It can also be detected in blood after an individual has consumed lentils and may therefore serve as a food biomarker. Lenticin is an indole alkaloid that is essentially an N-methylated form of tryptophan. It is known to be a sleep-inducing compound (PMID: 18571406). In plants it is an agonist of the plant hormone indole acetic acid.

https://pubchem.ncbi.nlm.nih.gov/compound/Hypaphorine#section=Pharmacology-and-Biochemistry

Ozawa M, Honda K, Nakai I, Kishida A, Ohsaki A:*Hypaphorine**,* an indole alkaloid from _*Erythrina velutina*_, induced sleep on normal mice. *Bioorg Med Chem Lett. 2008 Jul 15;18(14):3992-4.* doi: 10.1016/j.bmcl.2008.06.002. Epub 2008 Jun 6.


----------



## JacksinPA

sekio said:


> Turpentine heated in the presence of air will make ketones, alpha pinen+oxygen -> verbenone, limonene->carvone/piperitone, carene->carenone etc.



Wouldn't be my first choice as a reaction medium. At the very least you'd have to run the reaction under dry nitrogen or similar inert gas.


----------



## JacksinPA

JacksinPA said:


> *DMT from tryptophan - summary
> 
> Here is a general recap of my recent posts over  months on converting store-bought L-tryptophan into DMT without the use of any hazardous or difficult-to-obtain reagents.
> 
> The classic approach to methylating that amine is to use methyl iodide. As a thought, *methyl bromide* is a commercial (and highly toxic) insecticide/fumigant & might be more readily available in cylinders from commercial sources that might not ask too many questions.
> 
> A gas at room temperature, **methyl bromide readily penetrates skin, cloth, and other protective materials such as rubber and leather. It is nonflammable and toxic at low concentrations. Methyl bromide is odorless and odor provides no warning of hazardous concentrations.*



*Reference on the decarboxylation of Trp: The procedure involved the heating of tryptophan (1) in a relatively small amount of tetralin with catalytic amount of carbonyl compounds (2) as shown in the table until the evolution of carbon dioxide was ceased. Tryptamine (3) thus formed was cleanly distilled from the reaction mixture and a single crystallization yielded a pure product in good yield.

The highest yield for the most available carbonyl compounds  (MEK) is about 85%. Note that the ketone is used in 'catalytic' amounts.

Purification of tryptamine via distillation involves very low pressure & possible kugelrohr-type short-path bulb-to-bulb distillation. B.p. :*137 ?C (279 ?F) (0.15 mmHg)
https://erowid.org/archive/rhodium/chemistry/tryptamine.takano.html

An alternative purification method not involving high vacuum:* 'A good way to purify tryptamine without having to resort to distillation under strong vacuum is to dissolve the crude tryptamine hydrochloride in water, adjust the pH to between 7.6 and 8.2 and extract the solution with chloroform. The pH is then adjusted to 14 with NaOH and the pure tryptamine is filtered off with suction and air dried. *https://erowid.org/archive/rhodium/chemistry/tryptophan.html


----------



## JacksinPA

https://www.sciencedirect.com/science/article/pii/S0040402001852674

*The reactions of thiolate ions derived from thiophenol and homocysteine with substituted quaternary ammonium salts result in alkyl transfer from nitrogen to sulfur.

*Thiolate ions are known to scavenge alkyl groups from quaternary ammonium salts. Using cheap & readily available sodium mercaptobenzothiazole, I propose the following sequence:







A possible alternative thiolate is *sodium thiophenoxide* from a number of sources in the Orient, possibly obtainable as samples.


----------



## S.J.B.

JacksinPA said:


> Wouldn't be my first choice as a reaction medium. At the very least you'd have to run the reaction under dry nitrogen or similar inert gas.



It's likely that the oxygenated products being formed from turpentine in air at high temperature are (a) aiding in solubilizing the tryptophan and (b) acting as catalysts for the decarboxylation.


----------



## JacksinPA

Could be but I'd have enough other things to concern myself with in this project without worrying turpentine-induced side products.

Check out my very recent post on using a commercially available thiolate to deiodomethylate the Trp derivative. I think it might work.


----------



## S.J.B.

JacksinPA said:


> Check out my very recent post on using a commercially available thiolate to deiodomethylate the Trp derivative. I think it might work.



Yep, I imagine so.


----------



## JacksinPA

A note about thiol compounds. One of the suggested thiolates is sodium thiophenoxide, which is converted to (methylthio)benzene in this reaction. These sulfur compounds are very smelly & are the same class of mercaptans used as odorants in natural gas, LNG & propane. Unless you live out in Kansas or Montana & the nearest neighbor is 15 miles away, expect a visit from the FD if someone nearby catches a whiff of this stuff. I'm not familiar with the sodium mercaptobenzothiazole or its ethyl ether derivative, but these are likely smelly also. Here is an MSDS for a 50% solution: https://www.columbuschemical.com/MSDS/SDS/Sodium Mercaptobenzothiazole 0032.pdf. Sounds like pretty nasty stuff requiring special handling, including adequate ventilation (fume hood), rubber gloves, full face mask respirator, etc.

The end product, 2-(methylthio)benzimidazole, is also hazardous: *Contact with water liberates toxic, extremely flammable gas. Water-reactive.* It us also likely to be very smelly, so disposal could be a problem. So this chemistry must be done in non-aqueous media.. Precipitation of the NaI should help drive the reaction toward completion.

How to separate the DMT base from the 2-(methylthio)benzimidazole while avoiding water is the current question. Passing the crude reaction mixture through a column bed of acidic ion exchange resin seems to be one approach, then washing the bed with a non-aqueous solvent before eluting the DMT. Care must be taken to make sure the solvent system used is compatible with the ion exchange resin.


----------



## JacksinPA

*Metabolites from South Pacific sponge Hytrios sp.

Interesting paper on 5.6-dibrominated derivatives of DMT & hypaphorine. (*https://pdfs.semanticscholar.org/1005/095fd9bfc7074ffe78dcff010b738e502b46.pdf). These are reported to exhibit antibacterial activity. In marine secondary metabolites, bromine addition to molecules is linked to increasing toxicity. It is therefore very doubtful that the native compounds would show any significant psychoactivity. Interestingly, it may be possible to convert 5,6-dibromo-N,N-dimethyltryptamine to DMT via catalytic hydrogenation to remove the bromine atoms.


----------



## Dresden

Of course it's active.
Why do you think the sponge uses it?


----------



## JacksinPA

Brominated secondary metabolites in marine invertebrates are toxic defensive compounds designed to deter predators & ward off diseases. They are too toxic to be psychoactive in humans, I believe. But  they may have other activities, such as antidepressants & sedatives. See abstract below.


----------



## JacksinPA

https://www.ncbi.nlm.nih.gov/pubmed/18217716

J Nat Prod. 2008 Feb;71(2):186-9. doi: 10.1021/np070371u. Epub 2008 Jan 25.
*Secondary metabolites from three Florida sponges with antidepressant activity.*

Kochanowska AJ1, Rao KV, Childress S, El-Alfy A, Matsumoto RR, Kelly M, Stewart GS, Sufka KJ, Hamann MT.
*Author information*

*Abstract*

Brominated indole alkaloids are a common class of metabolites reported from sponges of the order Verongida. Herein we report the isolation, structure determination, and activity of metabolites from *three Florida sponges*, namely, Verongula rigida (order Verongida, family Aplysinidae), Smenospongia aurea, and S. cerebriformis (order Dictyoceratida, family Thorectidae). All three species were investigated chemically, revealing similarities in secondary metabolites. Brominated compounds, as well as sesquiterpene quinones and hydroquinones, were identified from both V. rigida and S. aurea despite their apparent taxonomic differences at the ordinal level. Similar metabolites found in these distinct sponge species of two different genera provide evidence for a microbial origin of the metabolites. Isolated compounds were evaluated in the Porsolt forced swim test (FST) and the chick anxiety-depression continuum model. Among the isolated compounds, *5,6-dibromo- N,N-dimethyltryptamine ( 1) exhibited significant antidepressant-like action in the rodent FST model*, *while 5-bromo- N,N-dimethyltryptamine ( 2) caused significant reduction of locomotor activity indicative of a potential sedative action. *The current study provides ample evidence that marine natural products with the diversity of brominated marine alkaloids will provide potential leads for antidepressant and anxiolytic drugs.


----------



## JacksinPA

[h=1]CONVENIENT DEALKYLATION OF QUATERNARY AMMONIUM SALTS[/h]
*The New Journal for Organic Synthesis* vol. 12 1980 no. 6





=================================================================
*NaBH4 in polar solvents looks workable for dealkylating the quaternary ammonium salt.*
Journal[h=1]Organic Preparations and Procedures International [/h][h=1]The New Journal for Organic Synthesis[/h]
[h=2]Volume 12, 1980 - Issue 6[/h]


----------



## Pomzazed

The active demethylating agent is a strong nucleophile thiolate anion. Any would do.
And to make it strong, use one that is primary thiol. Sodium hydroxide is strong enough to deprotonate it to active species.

Hate odour? Use larger nonvolatile one like a octadecanethiol or like.


----------



## JacksinPA

Pomzazed said:


> The active demethylating agent is a strong nucleophile thiolate anion. Any would do.
> And to make it strong, use one that is primary thiol. Sodium hydroxide is strong enough to deprotonate it to active species.
> 
> Hate odour? Use larger nonvolatile one like a octadecanethiol or like.



Thanks for the constructive input. The simplest is *Sodium methanethiolate, which reacts to form methanethiol, which smells exactly like s**t. That may not be a negative as it does not resemble the higher MW gas odorants. It could be scrubbed with NaOH solution & sent to the sewer where it would be in good company. The gas could be fed to a drum of aqueous caustic & later pumped to the septic drain. This would avoid the troublesome end product you get using sodium mercaptobenzothiole. Not a bad idea.*


----------



## Pomzazed

Still, once the pH decrease as when you drained it from your strongly basic trap into the sewer, the equation shifts back.
(Normal acid-base equation...) and it releases alot of volatile thiol, not good!

Imagine the odorants of these are nose-detectable in ppb range. Now you have moles of it....along sewage line.

Edit:
For more input, any demethylating agents you would find in literature works by SN2 mechanism, you will need a strong unhindered nucleophile for this, hydride is a good one as pee your above reference stated about LiAlH4 or selectride, however owing to the autoignition, flammability of these agent it is discourage to use in preparative scale, and limited to preparation for analysis, mostly.

On the second, primary thiol is very good nucleophile and will achieve similar dealkylation effect, so it gained more popularity of use despite the strong smell. The benzothiazole is one of the example to find a “less stench” thiol to perform such action, it is much better less smelly in comparison to like, methanethiol, but still.....bleh. That’s why i recommended the thiol that is large enough to be nonvolatile.
(Dont drain it tho, bacteria still able to digest them to H2S and lower stench thiol)

Another application of these demethylation thiol is, under stronger reaction, it is able to dealkylate aryl-alkyl-ether at >70% yield at correct conditions . (Say, codeine to morphine)


----------



## JacksinPA

Yes but it smells like normal sewage, not like a gas odorant which have higher MW. As it is a natural product, it could not be discriminated from the stuff normally in the sewer even with sophisticated test gear. And sodium methanethiolate is available as a convenient solid or solution


----------



## JacksinPA

Here is a revised scheme for converting N,N,N-trimethyltryptammonium iodide to DMT:


----------



## Dresden

Will this work?






+ turpentine + O2 (g) -->


----------



## sekio

No. MDP2P will turn to polymer in environs with excessive heat/O2.


----------



## JacksinPA

JacksinPA said:


> *DMT from tryptophan - summary
> 
> Here is a general recap of my recent posts over  months on converting store-bought L-tryptophan into DMT without the use of any hazardous or difficult-to-obtain reagents.
> 
> The classic approach to methylating that amine is to use methyl iodide. As a thought, *methyl bromide* is a commercial (and highly toxic) insecticide/fumigant & might be more readily available in cylinders from commercial sources that might not ask too many questions.
> 
> A gas at room temperature, **methyl bromide readily penetrates skin, cloth, and other protective materials such as rubber and leather. It is nonflammable and toxic at low concentrations. Methyl bromide is odorless and odor provides no warning of hazardous concentrations.*



*Methyl iodide is extremely toxic, much like its relative methyl bromide. In one report a worker handling MeI suffered from symptoms severe enough that they were thought to be from a stroke. (See https://jmedicalcasereports.biomedcentral.com/articles/10.1186/1752-1947-4-177).

'A 41 YR OLD CHEMIST DEVELOPED METHYL IODIDE INTOXICATION. CHARACTERISTICS OF METHYL IODIDE POISONING INCLUDE DELAY BETWEEN EXPOSURE & ONSET OF SYMPTOMS, EARLY SYSTEMIC TOXICITY WITH CONGESTIVE CHANGES IN LUNGS & OLIGURIC RENAL FAILURE, PROMINENT CEREBELLAR & PARKINSONIAN NEUROLOGIC SYMPTOMS AS WELL AS SEIZURES & COMA IN SEVERE CASES, & PSYCHIATRIC DISTURBANCES THAT LAST FROM MONTHS TO YEARS.' (See *https://monographs.iarc.fr/agents-classified-by-the-iarc/).

*In/ a fatal case of poisoning in a worker exposed to methyl iodide fumes during its manufacture: severe neurological symptoms preceded death; all organs showed congestion at autopsy.
**[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php p. V41 221 (1986)] 

Even though the preps on Youtube look simple, MeI is nothing to fool around with.*


----------



## JacksinPA

Dresden said:


> Will this work?
> 
> 
> 
> 
> 
> 
> + turpentine + O2 (g) -->



Oxidations of this sort usually involve DMF, CuCl2 & PdCl2. No turpentine.


----------



## Dresden

Don't forget


----------



## JacksinPA

What does p-benzoquinone have to do with it?


----------



## Dresden

Improves yield IIRC.


----------



## JacksinPA

This revised scheme seeks to get around the toxicity problems associated with MeI by using the simpler *Finkelstein Reaction* to generate *benzyl iodide* from benzyl chloride. My expectation is that reaction with the thiolate will selectively remove the benzyl group, leaving free DMT.






Benzyl methyl sulfide should not be too hard to handle as it is used as a food flavoring additive.


----------



## sekio

Benzyl halides are lachrymators and are actually nastier to work with than MeI - MeI is toxic sure, but not stinky.

Also, any low m.w. methylsulfide would be stink-o-rama, thioanisole is particularly egregious "Has a solvent type odor and an solvent type flavor" - thanks good scents.... I'd bet that benzyl methyl sulfide would have ppb odor threshold.


----------



## JacksinPA

I was warned in undergrad chemistry to avoid going into 2 graduate fields: sugar chemistry, because they are difficult to crystallize and sulfur chemistry, for obvious reasons.


----------



## Dresden

Tryptamine + 2 eq. formaldehyde + HgCl2 + Heavy Duty Reynold's Wrap Al foil + MeOH  -->  DMT ?


----------



## Pomzazed

No, because of https://en.wikipedia.org/wiki/Pictet–Spengler_reaction will dominate the reaction, and i doubt any DMT will be found in the product.


----------



## sekio

Dresden, you've never heard of Eschweiler-Clarke methylation? Makes the aluminum amalgam reaction look like the utter mess that it is.

2eq. Formic acid, 2eq. formaldehyde, tryptamine, heat it. Done.


----------



## JacksinPA

A relatively recent paper on selective monp- & dimethylation of primary amines.

'Amines can be methylated when treated with formaldehyde and zinc in aqueous medium. Selective mono- or dimethylation can be achieved by proper choice of pH, stoichiometry and reaction time. This method can also be applied for amino acids.'

https://www.sciencedirect.com/science/article/pii/S004040390701711X


----------



## Dresden

sekio,

No, I haven't.  I pretty much quit reading about chemical syntheses after The Hive.  (before that ended even)


----------



## Bagseed

sekio said:


> Dresden, you've never heard of Eschweiler-Clarke methylation? Makes the aluminum amalgam reaction look like the utter mess that it is.
> 
> 2eq. Formic acid, 2eq. formaldehyde, tryptamine, heat it. Done.


has anyone done that on tryptamine and reported on the yield? sounds to good to be true... no nasty alkyl halides involved.. formaldehyde and formic acid being easily available.


----------



## Pomzazed

I still doubt on tryptamine on why it wouldnt yield carbolines as product,  but I’ve done that many times on glutamic acid to make N,N-dimethylglutamic acid successfully. Fast and easy. (At times i was made it to make a CO2-strip cocatalyst in industrial product)
Only care to take is to effectively remove excess formaldehyde from crude.


----------



## JacksinPA

JacksinPA said:


> A relatively recent paper on selective monp- & dimethylation of primary amines.
> 
> 'Amines can be methylated when treated with formaldehyde and zinc in aqueous medium. Selective mono- or dimethylation can be achieved by proper choice of pH, stoichiometry and reaction time. This method can also be applied for amino acids.'
> 
> https://www.sciencedirect.com/science/article/pii/S004040390701711X



Another reference (full paper): https://www.thevespiary.org/rhodium...ous-formaldehyde-and-zinc81ca.pdf?topic=262.0


----------



## JacksinPA

Dresden said:


> Tryptamine + 2 eq. formaldehyde + HgCl2 + Heavy Duty Reynold's Wrap Al foil + MeOH  -->  DMT ?



Stay away from mercury salts or you may wind up 'Mad as a hatter.'


----------



## JacksinPA

A big foreign chemical company I worked for developed this chemistry as a method of producing meta-trifluomethylphenyl-2-propanone, the raw material for one component of the subsequently banned diet drug fenfluramine (Fen-Phen). I happened on a copy of the synthesis, which was no longer of interest to them. As both the starting aniline & isopropenyl acetate are commercial products, this might be a possible path to making DOM (aka STP).

DOM was developed by Alexander Shulgin after he left Dow Chemical's former agrochemical research facility in Walnut Creek, CA. See https://patents.google.com/patent/US4105695?oq=ininventor:shulgin

As a side note, 2,5-dimethoxyaniline is also commercially available. Brominating it in the 4-position seems pretty straightforward to get to the potent DOM analog DOB. See https://en.wikipedia.org/wiki/2,5-Dimethoxy-4-bromoamphetamine. I've worked with 2,5-dimethoxyaniline & it is a very reactive molecule. It tends to react with oxygen to form dark orange-yellow nigraniline-type dyes, probably at  the highly activated 4-position..


----------



## Gaffy

It's basically LSD, BK-MDMA, 4-Fluoro-phenylpiperazine and Ketamine all in one molecule.


----------



## JacksinPA

I have used Sci-Hub in the past to obtain pdf copies of ACS journals but my attempts to get a JOC article didn't work this AM. It is a way to make isopropenyl acetate without using ketene starting from allyl acetate, which should either be available commercially or easy enough to make.


----------



## S.J.B.

Alright, time to get the thread back on track, we're getting a little too far into synthesis discussion.


----------



## JacksinPA

*SECOND GENERATION DESIGNER BENZOS*:  Some are not like your mother's diazepam (Valium).

In 2012 new designer benzos began appearing in head shops & online RC suppliers: pyrazolam, flubromazepam & diclazepam (structures to follow in next post). As soon as these were scheduled, a second generation of these drugs began to appear (this post): clonazolam, deschloroetizolam, flubromazolam, & meclonazepam. I haven't had a chance to look into the pharmacology of all of these, but flubromazolam should be considered a very dangerous & potent drug: '*Flubromazolam is a novel synthetic depressant substance of the benzodiazepine class which produces anxiolytic, disinhibiting, sedative, muscle relaxant, and memory suppressing effects when administered. It is incredibly potent (active in the microgram range) with an unusually long 18 hour duration.'

*






These molecules appear to have been taken from the patent literature, as many thousands of benzos have been synthesized & tested since their discovery in the 1960s. Most never made it to market as many, like flubromazolam, were found to be either too potent or toxic for safe & effective use.


----------



## JacksinPA

As mentioned in the last post, here are the structures of the 3 benzos that were initially available earlier in this decade. As indicated by the 'Ro-5-' number for diclazepam, these were originally made by big pharma in the 1960s-70s, in this case Hoffman-La*Ro*che.






To indicate the potency of these molecules, diclazepam was said to be 10 times more potent than diazepam (Valium).


----------



## JacksinPA

While compiling this list of designer benzos, I overlooked *nifoxapam*. From WikiPedia:* Nifoxipam produces strong tranquillising and sleep-prolonging effects and has much lower toxicity compared to lormetazepam and flunitrazepam in mice.

*


----------



## Hodor

JacksinPA said:


> Most never made it to market as many, like flubromazolam, were found to be either too potent or toxic for safe & effective use.
> (...]
> To indicate the potency of these molecules, diclazepam was said to be 10 times more potent than diazepam (Valium).



10 times as potent as diazepam isn't a big deal. So is lorazepam.
Alprazolam is 20 times the potency of diazepam and 40 times the potency of temazepam, yet doctors are less reserved about prescribing xanax than they are about restoril. 

Heck, triazolam and brotizolam are pharm benzos that are considered twice as potent as alprazolam (and thus roughly as potent as clonazolam or flubromazolam).

Personally, I'd wager the main reason most of these designer benzos never saw the light of day was simply because getting a drug to market costs a lot of of money, and it didn't take too long for those markets to become saturated with benzos of different half-lives and effects profiles.

Don't get me wrong though: RC benzos, especially the strongly hypnotic ones, absolutely aren't something to fuck around with; I am just saying that the main issue here is people being able to easily acquire obscene quantities of these on the net, sometimes even as a pure powder.
There's a difference between some dude in Japan getting a script for 2x0.5 mg of etizolam per day from a legit psychiatrist for an anxiety disorder, and a guy in America ingesting 20 mg of etizolam solution, blacking out, and crashing their car in a stupor.


----------



## JacksinPA

Hodor said:


> 10 times as potent as diazepam isn't a big deal. So is lorazepam.
> Alprazolam is 20 times the potency of diazepam and 40 times the potency of temazepam, yet doctors are less reserved about prescribing xanax than they are about restoril.
> 
> Heck, triazolam and brotizolam are pharm benzos that are considered twice as potent as alprazolam (and thus roughly as potent as clonazolam or flubromazolam).
> 
> Personally, I'd wager the main reason most of these designer benzos never saw the light of day was simply because getting a drug to market costs a lot of of money, and it didn't take too long for those markets to become saturated with benzos of different half-lives and effects profiles.
> 
> Don't get me wrong though: RC benzos, especially the strongly hypnotic ones, absolutely aren't something to fuck around with; I am just saying that the main issue here is people being able to easily acquire obscene quantities of these on the net, sometimes even as a pure powder.
> There's a difference between some dude in Japan getting a script for 2x0.5 mg of etizolam per day from a legit psychiatrist for an anxiety disorder, and a guy in America ingesting 20 mg of etizolam solution, blacking out, and crashing their car in a stupor.



Interesting observations about triazolam & brotizolam. I'll have to check into those.

Tolerance to benzos acquired over both long & short periods of time is something that I'm veryinterested in. I took flurazepam for sleep for years, then a new doc switched me to temazepam, which did very little by comparison. A couple of years ago I askedmy then doc for a scrip for flurazepam. It was interesting that even 2 caps had no effect. I had obviously built up a strong tolerance to it.

During a recent endoscopy they were shoot a mix of fentanyl & midazolam into my IV line but I was conscious throughout the whole operation. This was only my third experience with fentanyl, which knocked me right out when I had cataract surgery. I've woken up under midazolam during a colonoscopy. It seems to be the GI docs favorite for that op. My last colonoscopy I had them use propofol, which worked like a charm, though I had to be entubated for oxygen during. So I think I've developed a tolerance for both midazolam & fentanyl after only brief exposures.

My favorite mystery benzo is alprazolam. I've been taking it for 40 years & have built up almost no tolerance, which is very interesting. My doctor wants me to taper off it but the withdrawal experiences at my age don't seem worth the bother if  drug works & I'm experiencing none of the published side effects.

Of course, fentanyl is an antinociceptive/narcotic unlike benzos which are more hypnotics. And fentanyl is much more potent than most prescribed benzos.


----------



## JacksinPA

Here is the chemistry of triazolam (Halcion) & brotizolam. Halcion is marketed by prescription in the U.S. while the other is sold as *Lendormin **in Europe &  Japan.*





Halcion: 'The recommended dose for most adults is 0.25 mg before retiring. A dose of 0.125 mg may be found to be sufficient for some patients (e.g., low body weight). A dose of 0.5 mg should be used only for exceptional patients who do not respond adequately to a trial of a lower dose since the risk of several adverse reactions increases with the size of the dose administered. A dose of 0.5 mg should not be exceeded.'

In my experience, this makes 0.125 mg of Halcion equal to roughly 2 mg of alprazolam, or about 16 times as potent.

Brotizolam: ' It is used in the short-term treatment of severe or debilitating insomnia. Brotizolam is an extremely potent drug and has shown anti-anxiety activity at doses as low as 0.08 to 0.1 milligrams, but the usual hypnotic dose of brotizolam is 0.125 to 0.25 milligrams,[7] and it is rapidly eliminated with an average half-life of 4.4 hours (range 3.6–7.9 hours).' That makes it, in my experience, about 8 times more potent than alprazolam ( 2mg dose).


----------



## Hodor

I'd say your math is way off, or you're seriously underestimating your own alprazolam tolerance.

I've said it before on other threads about alprazolam dosages, and I think this bears repeating here:
The fact that in the US, the 2mg "bar" has become the standard for a "single dose" of alprazolam, is kind of fucked up.
A bar should be enough to treat someone's anxiety over a whole day when divided into 4x0.5 mg doses. Heck, the average patient should probably try not to exceed 1 mg in total per day on average, since they're going to be experiencing diminishing returns with increased doses anyway. In some countries, 2mg xanax "bars" are even in a different Controlled Substance Schedule than the .25/.5/1mg "footballs", and thus virtually unseen except as counterfeit presses from the dark web.

As someone who was on alprazolam for years, and also tried triazolam once, I can tell you that a .25mg football of triazolam hit pretty much as hard as a .5mg football of alprazolam; there is no way that triazolam could be considered "16 times" the potency of alprazolam, unless you were mistakenly comparing daily doses (triazolam is used purely as a hypnotic, meaning it is only taken once per day at bedtime, while alprazolam can be dosed several times per day for around-the-clock anxiety relief).

Edit: That said, triazolam is different from alprazolam in that it is more selective for different subunits of the GABA receptor, so a dose that provides the same degree of anxiety relief is going to feel somewhat more sedating... but still, certainly not to the point where .125 mg of triazolam would feel as sedating as 2 mg of alprazolam.


----------



## JacksinPA

I was only giving approximate numbers based on published info as I have not have had experience with either drug,


----------



## Hodor

IMO none of the information in the literature supports the notion that triazolam is 8 or even 16 times as potent as alprazolam.

The standard dose of triazolam as a sleep aid is .125 to .25mg.
If it really was 16 times as potent as alprazolam, you'd think people using xanax as a sleep aid would be told to eat a whole bar or two at bedtime, which I'm pretty sure doesn't happen. At least not anymore.

People - especially in the US - used to be fairly careless about prescribing high doses of xanax because they thought it was more benign than some of the more sedating benzos... which it may very well be, just not to the point where it would be a good idea to script someone more than 2mg per day unless their anxiety is downright crippling and they already have a certain benzo tolerance. Of course triazolam, too, used to be overprescribed. The song "Halcyon" by the British trance duo Orbital and its music video are about the artists' mother and her addiction to triazolam (sold under the brand name "Halcion").

If a doctor were to prescribe xanax for insomnia today, they probably wouldn't start off their patient on more than .5 mg per day, just like they wouldn't start someone off on more than .25 mg of triazolam.


----------



## JacksinPA

Hodor said:


> IMO none of the information in the literature supports the notion that triazolam is 8 or even 16 times as potent as alprazolam.
> 
> The standard dose of triazolam as a sleep aid is .125 to .25mg.
> If it really was 16 times as potent as alprazolam, you'd think people using xanax as a sleep aid would be told to eat a whole bar or two at bedtime, which I'm pretty sure doesn't happen. At least not anymore.
> 
> People - especially in the US - used to be fairly careless about prescribing high doses of xanax because they thought it was more benign than some of the more sedating benzos... which it may very well be, just not to the point where it would be a good idea to script someone more than 2mg per day unless their anxiety is downright crippling and they already have a certain benzo tolerance. Of course triazolam, too, used to be overprescribed. The song "Halcyon" by the British trance duo Orbital and its music video are about the artists' mother and her addiction to triazolam (sold under the brand name "Halcion").
> 
> If a doctor were to prescribe xanax for insomnia today, they probably wouldn't start off their patient on more than .5 mg per day, just like they wouldn't start someone off on more than .25 mg of triazolam.



My original alprazolam scrip for was for panic attacks - 1 mg/day. A succession of doctors kept increasing it. I'm still amazed that there is no evidence of tolerance, I think most consider it to be fairly benign until you wind up in the hospital for mixing things like alcohol with it.

In my experience, 1 mg Xanax gives you 1 hour of deep sleep. Two mg = 2 hours.


----------



## JacksinPA

Here is the chemical structure of Xanax (alprazolam) Notice the similarities with respect to the earlier posted structures, especially with regard to the chlorine atom on the 2' position of the phenyl ring. Alprazolam differs from Halcion by the absence of this chlorine atom.


----------



## Hodor

JacksinPA said:


> My original alprazolam scrip for was for panic attacks - 1 mg/day. A succession of doctors kept increasing it. I'm still amazed that there is no evidence of tolerance, I think most consider it to be fairly benign until you wind up in the hospital for mixing things like alcohol with it.
> 
> In my experience, 1 mg Xanax gives you 1 hour of deep sleep. Two mg = 2 hours.



No evidence of tolerance?
Have you ever tried going off all benzos c/t for a week?

The fact that you woke up during your midazolam anaesthesia points to a significant degree of benzo tolerance (the benzodiazepines are all cross-tolerant with each other).

Also, you have to consider that benzodiazepines have non-linear dose-response curves, and people on benzos are notoriously limited in their ability to tell how strongly they are affected by the drug (what people are sometimes calling "delusions of sobriety") ...been there, done that, as they say.

At any rate, getting back to the benzo SAR's, I recently noted in a thread on clorazepate that it's interesting how the vast majority of benzos seem to have a chlorine substituent in the 7 position of the benzodiazepine ring (or the 8 position, if you go by the numbering scheme of the triazolobenzodiazepines), to the point where many of them don't even bother to put a "clo-" in their name:
Sure, there's chlordiazepoxide, clorazepate and clobazam proudly flying the flag, but on the other hand you've got diazepam, flurazepam, estazolam, midazolam, alprazolam, triazolam, tetrazepam, oxazepam, prazepam, temazepam, nordazepam, adinazolam and many others seemingly trying to hide their humble chlorine-substituted origins 

I wonder if substituting alkyl groups would be possible in this position. Etizolam is a triazolo-thienodiazepine which has an ethyl group on its benzothiophene ring, although I wonder if this substitution would work on a normal benzodiazepine lacking the electronegative sulfur atom in the thiophene ring. Etizolam is, after all, pretty damn potent due to the presence of the triazole ring, but still signficantly less potent than its closest chlorine-substituted triazolobenzodiazepine analogues.


----------



## Pomzazed

Has weird substituting group been tried as BZP analogues?
i am guessing EWG pseudohalogen would work, since other strongly EWG like a nitro work.

By this i also include one that substituted diredtly onto the ring, eg. Pyridinyl instead of Phenyl.


----------



## Hodor

Pomzazed said:


> By this i also include one that substituted diredtly onto the ring, eg. Pyridinyl instead of Phenyl.



There is a pyridodiazepine called zapizolam, which I don't think was ever sold as a legit pharmaceutical, but was apparently banned in Sweden some time ago, so presumably it was made available as an RC at some point. No idea about the effects though.
https://en.wikipedia.org/wiki/Zapizolam

Zolazepam, on the other hand, is known to be approximately 3 times as potent as diazepam, and is commonly used as an animal tranquilizer in conjunction with the dissociative tiletamine under the brand name "telazol".
Here, the diazepine ring is fused to a dimethylpyrazole ring without any additional EWG's on it. It is water-soluble but will still rapidly penetrate the blood-brain-barrier, which are obviously desirable qualities for a substance intended to rapidly knock out animals upon IM administration.
https://en.wikipedia.org/wiki/Zolazepam


----------



## JacksinPA

Hodor said:


> No evidence of tolerance?



Perhaps some in that I'm taking 4 mg/night as compared to 40 years ago I was taking flurazepam for sleep, not Xanax. The danger here is that flurazepam is supposed to be long-lasting while Xanax is only 1-2 hours. Getting up to go pee while hung on flurazepam sounds dangerous to me. Falls in the bathroom get you EMS rides to trauma hospitals which in my area are nearly an hour's drive away. I fell down a short flight of stairs into the garage while on Ambien & it compression fractured several of my lumbar vertebrae which means I'm now 2.5 inches shorter.



> Have you ever tried going off all benzos c/t for a week?



No, nor would I try that. I go to sleep usually with no benzo in my system, but that only lasts 1-2 hours, when I have to get up to pee. It's then I need 2 mg to get back to sleep. With no benzo I would be a zombie trying to deal with 1-3 hours of sleep/night, which is very unpleasant. And insomnia is one of the effects of benzo withdrawal. I also suffer from nocturnal polyuria. Humans produce more urine at night & by urodynamic measurement 4 years ago my bladder capacity is only about 100 cc, so I'm up at least twice at night to pee & wake up with a partially full bladder.



> The fact that you woke up during your midazolam anaesthesia points to a significant degree of benzo tolerance (the benzodiazepines are all cross-tolerant with each other).



It's interesting that I also apparently developed tolerance to non-benzo fentanyl on the third experience. No wonder people OD on this popular stuff.

Propofol is my anesthetic of choice now. Rapid onset, quick recovery, no hangover. But you need a full-time anesthesiologist to give you oxygen & monitor your vital signs.


----------



## JacksinPA

I'd be interested in evaluating an azido (Nsub3) group in place of the main ring system chlorine. I've seen nitro. Another EWG that is of interest to me is CFsub3. I'm sure they've all been made & evaluated. Too potent or toxic?

Azido is electron donating, which is why it doesn't appear. Here is a table of EWGs:

Magnitude of the EWG effect

Substituent Name Structure Strong: Triflyl-SO2CF3, trihalides-CF3, -CCl3 cyano groups-C≡N, sulfonates-SO3H, nitro group-NO2, ammonium-NH3+, ammonium (quaternary amine)-NR3+. Moderate: aldehyde-CHO, ketones-COR, carboxylic acid-COOH, acyl chloride-COCl, esters (benzoate)-COOR, amide-CONH2 *Weak: halides-F, -Cl, -Br, -I*


----------



## JacksinPA

*Zolazepam*[1] (*Flupyrazapon*) is a pyrazolodiazepinone derivative structurally related to the benzodiazepine drugs, which is used as an anaestheticfor a wide range of animals in veterinary medicine. Zolazepam is usually administered in combination with other drugs such as the NMDAantagonist tiletamine or the α2 adrenergic receptor agonist xylazine, depending on what purpose it is being used for. It is around four times the potency of diazepam (0.32 mg/kg versus 1.2 mg/kg in animal models) but it is both water-soluble and un-ionized at physiological pH meaning that its onset is very fast.[2]
Zolazepam was developed by Horace A. de Wald and Donald E. Butler for Parke-Davis[3] and was the result of a very detailed analysis of the benzodiazepine structure (U.S. Patent 3,558,605 filed in 1969).
Zolazepam, in combination with tiletamine, has been used in the tranquilization of wild animals, such as gorillas and polar bears, and has been found to be superior to ketamine because of reduced side-effects.[4][5] A 1:1 mixture of zolazepam and tiletamine is sold under the name *Telazol*.
========================================================
The interesting thing here is that I know Don Butler & called on him at the Pfizer facility in Holland, MI. He's a good friend but I haven't talked to him in years. He also invented the process for making Lipitor (atorvastatin) for controlling cholesterol biosynthesis.


----------



## JacksinPA

Anyone had any first-hand experience with this?


----------



## JacksinPA

Or this? Described as an entactogen. See https://en.wikipedia.org/wiki/5-MAPB


----------



## Hodor

JacksinPA said:


> I'd be interested in evaluating an azido (Nsub3) group in place of the main ring system chlorine. I've seen nitro. Another EWG that is of interest to me is CFsub3. I'm sure they've all been made & evaluated. Too potent or toxic?



Organic azides do not tend to be the most stable compounds, to the point where inorganic azide salts and low-molecular weight organic azides tend to be shock-sensitive explosives.... not to mention azide salts as well as several organic azides being fairly toxic.

Trifluoromethyl groups shouldn't pose any such problem. I know of trifluoromethyl analogues of nordazepam (triflunordazepam) and clobazam (triflubazam), but these never saw market adoption, probably because you'd only see a modest increase in potency at best, while requiring a harder to obtain precursor.

Interestingly, benzos containing a trifluoro_ethyl_ group on the 1-nitrogen atom did see pharmaceutical use. One of these is halazepam (N-fluoroethyl-nordazepam), which was quickly withdrawn from the US market again because it didn't sell, however. The other and much more interesting one is quazepam. Quazepam and its metabolite 2-oxoquazepam apparently exhibit much higher selectivity for the sleep-inducing subunits of the GABA receptor than other benzos, similar to the z-drugs zolpidem and zaleplon.


----------



## JacksinPA

This analog of caffeine is said to be 100 times more active at both the A1& A2 receptors.

During WWII the Germans needed coffee to keep their war industry going 24 hours/day. Due to the Allied embargo on coffee beans, ersatz coffee was made using synthetic caffeine. I've seen the synthesis method in an Allied intelligence report & it is not simple, beginning with relatively complex raw materials like ethyl cyanoacetate. A significant amount of German war productivity went into making synthetic coffee, as did the production of their popular soft drink, FANTA. In the case of FANTA, coloring & flavoring came from industrial byproducts because importation of the original drink syrup from Coca-Cola was also blocked..


----------



## Pomzazed

I still hate terminal alkyne, too toxic in most of thr cases not limited to this cafe-analog.

Regarding atomoxetine, it gives me alot of sweat and anxiety, and removes every traces of my appetite.
Me not touching it again!


----------



## JacksinPA

Hodor said:


> Organic azides do not tend to be the most stable compounds, to the point where inorganic azide salts and low-molecular weight organic azides tend to be shock-sensitive explosives.... not to mention azide salts as well as several organic azides being fairly toxic.
> 
> Trifluoromethyl groups shouldn't pose any such problem. I know of trifluoromethyl analogues of nordazepam (triflunordazepam) and clobazam (triflubazam), but these never saw market adoption, probably because you'd only see a modest increase in potency at best, while requiring a harder to obtain precursor.
> 
> Interestingly, benzos containing a trifluoro_ethyl_ group on the 1-nitrogen atom did see pharmaceutical use. One of these is halazepam (N-fluoroethyl-nordazepam), which was quickly withdrawn from the US market again because it didn't sell, however. The other and much more interesting one is quazepam. Quazepam and its metabolite 2-oxoquazepam apparently exhibit much higher selectivity for the sleep-inducing subunits of the GABA receptor than other benzos, similar to the z-drugs zolpidem and zaleplon.



I agree with your comments on quazepam (DORAL) regards inducing sleep.

You got the linear nomenclature for halazepam wrong. See attached graphic. Intermediates derived from 2,2,2-trifluoroethanol, are commonly available on the market. The correct nomenclature is N-(2,2,2-trifluoroethyl)-.


----------



## sekio

> Anyone had any first-hand experience with [atomoxetine]?



I once took 80mg and it made me feel like I'd been hit by a truck while simultaneously having the flu. In retrospect it's probably a massive overdose but I was young and dumb...


----------



## JacksinPA

sekio said:


> I once took 80mg and it made me feel like I'd been hit by a truck while simultaneously having the flu. In retrospect it's probably a massive overdose but I was young and dumb...



40 mg is the *STARTING* dose for ADHD. Assuming you don't have ADHD, it may have acted like someone dropping a case of beer on your brain.


----------



## JacksinPA

I don't have this paper so the details of this synthesis are not clear but the final tricyclic compound is said to be a powerful CNS stimulant:






Interesting from an SAR perspective. But not exactly home lab chemistry.


----------



## Dresden

Elemicin + Zn + HCl + O3+ (g)

--ozonolysis--->






Because I Can.


----------



## Pomzazed

Hello Lignin!


----------



## JacksinPA

Be cautious when contemplating even small lab-scale ozonlysis. I worked in a lab where we made tens of kilos of a perfume ingredient using an industrial-scale ozonator (>$19K) & had to run the ozonolysis in ice-cold methylene chloride in 22-liter flasks. I don't think Walmart sells either CH2Cl2 or elemicin.

Because of both ambient heat & the heat of reaction, keeping those big flasks at around 0 deg C was a lot of work. The product passed & I got paid


----------



## Dresden

JacksinPA,

I already have elemicin.  But as watched as I am [think permanent Saturday Night Live actor status], I am not *about* to do anything funny with it.

And I did 100mg 5-MAPB once.  Hard to describe altered state of consciousness that ended in mild delirium--I desperately called my dad around 11 pm although he was just one room away.  Will not voluntarily repeat.

AMP


----------



## JacksinPA

Thanks for the feedback of 5-MAPB. I just crossed it off my bucket list of things to try before I croak.


----------



## JacksinPA

*Non-benzodiazepine full Bz receptor agonist(s)*

I only have access to the first page of the full journal article but this caught my eye:






For some reason I could not recover the full article through Sci-Pub.

Interesting from the SAR POV. Wonder what other analogs they produced & evaluated. Not lab-scale chemistry in any event.


----------



## Dresden

According to the book QD 1 A355 no. 45 p. 117,






MP-809

Is "particularly effective in the treatment of neurotic depressions" and "is only a weak MAOI."


----------



## Pomzazed

Methyl huh? Interesting!
I am now interested in ethyl analog at the same position then, similar electron density at aromatic ring positions, and also the approximately same size as an MeO-


----------



## JacksinPA

Dresden said:


> According to the book QD 1 A355 no. 45 p. 117,
> 
> 
> 
> 
> 
> 
> MP-809
> 
> Is "particularly effective in the treatment of neurotic depressions" and "is only a weak MAOI."



4-Methylindole-3-carboxaldehyde is a commercially available product.


----------



## JacksinPA

Benzodiazepine partial agonists (R&D):


----------



## Pomzazed

1. i finally can overlay them a bit already with benzos! Thanks jacksin! Albeit you should flip ru32514 by 180 degree, and flip front to back before stacking!
Not looking so well in 2 D tho, but in 3D they do!


----------



## sekio

Ergoline benzodiazepine site agonists?

Could we have a more innately anxiolytic ergoline psychedelic?


----------



## JacksinPA

sekio said:


> Ergoline benzodiazepine site agonists?
> 
> Could we have a more innately anxiolytic ergoline psychedelic?



To get a new molecule therapy candidate this far it had to go through a lot of screens & tests. I don't think it's a psychedelic.


----------



## Pomzazed

This image


>



This is old cross-quoting, as this molecular strikingly reminds me of some bioactive-like structure which I cant recall at that time, but it is intriguing.

I can remember now what it resemble!
It is a deworming agent, Mebendazole!

Does this strange bzp site agonist have antihelminthic activity too?


----------



## JacksinPA

https://thehill.com/policy/defense/416485-cia-considered-potential-truth-serum-for-terror-suspects

[h=1]CIA considered use of anti-anxiety drug in terror suspect interrogations: report[/h]
The CIA considered the use of an anti-anxiety medication for use in questioning terror suspects about upcoming plans for attacks, according to an unreleased agency report.
The Associated Press, which obtained a copy of the document, reports that the agency considered the use of the drug *Versed* for use during terror suspect interrogations in 2002 but ultimately decided against asking government lawyers for permission to use it.



A federal court ordered the 90-page CIA report, which details the existence of "Project Medication," to be provided to the American Civil Liberties Union (ACLU), which spent more than two years in court fighting the Obama and Trump administrations over it.
"Project Medication," the report states, was permanently shut down in early 2003 after the CIA decided against setting up another potential conflict with the Justice Department over the use of enhanced interrogation techniques, according to the AP.
The report states that prior to its closure, CIA researchers looked into old agency experiments with LSD during the 1950s and 1960s as well as experiments done by the Soviet Union, both of which were apparently in search of some kind of "truth serum," the AP reported.
“*Versed* was considered possibly worth a trial if unequivocal legal sanction first were obtained,” the report says, according to the AP. “There were at least two legal obstacles: a prohibition against medical experimentation on prisoners and a ban on interrogational use of ‘mind-altering drugs’ or those which ‘profoundly altered the senses.’”
“At the beginning of 2003, the Office of Medical Services’ review, informally termed ‘Project Medication’ was shelved, never to be reactivated,” the report concludes.


----------



## Dresden

This Last Fruit Of The Spirit Is The Best One Yet!  Bravo.


----------



## sekio

Sulfonamide analogs of fentanyl? Are they active? Do we know anything about 'em?





Or maybe an alpha-CF3 amine instead of an amide?


----------



## S.J.B.

sekio said:


> Sulfonamide analogs of fentanyl? Are they active? Do we know anything about 'em?
> 
> 
> 
> 
> 
> Or maybe an alpha-CF3 amine instead of an amide?



Sulfonamide analogues show up in one patent but were not developed as analgesics.  There are no reports on any alpha-trifluoromethyl compounds that I could find.


----------



## sekio

or even, oxazoline analogs of carfentanyl?


----------



## JacksinPA

This is probably a known compound:


----------



## Hodor

sekio said:


> Sulfonamide analogs of fentanyl? Are they active? Do we know anything about 'em?



The sulfonamide version of methadone ("IC-26"; "methiodone") seems to be active at least, although its exact potency is not exactly known (it seems to be generally in the same ballpark as methadone though).
https://en.wikipedia.org/wiki/IC-26

Wouldn't be surprised if Janssen had actually synthed the sulfonyl version of fentanyl ("sulfontanyl"? wait, that sounds too close to sufentanil...) at one point.


----------



## JacksinPA

Forensic Toxicology
July 2017, Volume 35, Issue 2, pp 232–243| Cite as

*Acryloylfentanyl, a recently emerged new psychoactive substance: a comprehensive review*





*Abstract*

_N_-(1-Phenethylpiperidin-4-yl)-_N_-phenylacrylamide, or *acryloylfentanyl (acrylfentanyl)*, is a synthetic opioid and a close structural analogue of fentanyl, which is widely used in medicine as an adjunct to general anaesthesia during surgery and for pain management. Until recently, acryloylfentanyl was known only from the scientific literature, but in 2016 this non-controlled substance became available on the illicit drug market as a powder and nasal spray in Europe and the USA. By the end of 2016, detection of acryloylfentanyl in six European countries, including 47 deaths associated with the drug, had been reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) through the European Union Early Warning System, which is a part of the system designed to identify and respond to the appearance of new psychoactive substances that may pose potential public health risks similar to drugs controlled under the United Nations drug control conventions. Herein we review what is known about this potent narcotic opioid. In addition to describing its chemical properties and the synthetic routes, analytical methodologies for the identification of the substance, as well as the limited information on the biological properties, including in vitro and in vivo pharmacological studies with the substance, are summarised. Analytically confirmed acute intoxications show that the signs and symptoms of acryloylfentanyl poisoning correspond to the opioid overdose triad of decreased consciousness, miosis and respiratory depression. Importantly, naloxone works as an antidote in life-threatening poisoning. The major human urinary metabolites identified in fatal overdose cases were nor-acryloylfentanyl, as well as mono- and dihydroxylated derivatives and their conjugates.


----------



## JacksinPA

Carfentanyl is likely the most potent in the series.


----------



## JacksinPA

Dainippon Pharma: MT-45 lead & optimized analogs claimed in 1978 patent. Recreational use of MT-45 has been associated with hearing loss and unconsciousness. See
https://en.wikipedia.org/wiki/MT-45 The patent claims that the double bond on the butenyl group can be on either carbon #2 or #3.






These Dainippon pharma opioid analgesics based on MT-45 are very interesting for a number of reasons. They can act as agonists or antagonists. And chemically they are very simple compounds.


----------



## sekio

Are the amide analogs of cocaine, RTI-xx, and/or methylphenidate known, active, etc?


----------



## Gaffy

Variants on L-THP based on similarity with phenidates and dissos!





And Following the same logic on cyclidine substitution with phenylketone, a Carfent variant


----------



## Dresden

sekio said:


> Are the amide analogs of cocaine, RTI-xx, and/or methylphenidate known, active, etc?



Should be.  Not as euphoric but much longer lasting.


----------



## Dresden

Gaffy, lose the p-F on the phenyl and maybe the left side carbomethoxy, and I'd say you will have quite a mindfuck drug there.  But your prediction is as good as mine!


----------



## Pomzazed

Dresden said:


> Should be.  Not as euphoric but much longer lasting.



Any ref?


----------



## Gaffy

Thanks Dresden, I put it there because p-F fentanyl is said to be longer lasting than regular fent; btw what do you guys think of the Phenidate-L-THP?

And talking of cocaine analogs, how about this:




Or this:


----------



## S.J.B.

sekio said:


> Are the amide analogs of cocaine, RTI-xx, and/or methylphenidate known, active, etc?



The _N_-methyl-amide cocaine analogue is known.  A study was done (https://doi.org/10.1021/jm00079a017) comparing a series of cocaine analogues with the methyl ester swapped out for various moieties.  The potency of each compound was tested by seeing what concentration was required to displace a tritiated cocaine analogue in rat striatal membrane.  The results suggest that the _N_-methyl-amide analogue is ~1/30th the potency of cocaine.

The other amides you drew seem to be unreported.


----------



## Gaffy

And last but not least, Sigma receptor (to be supposed) agonist / antagonists
	

	
	
		
		

		
			
		
		
	


	




And some more Sigma, last one shoud be opioid-like:


----------



## Pomzazed

What is the pharmacophore requirement + spacing for sigma receptor?
I still cannot grasps it due to too various structure being able to bind to it.


----------



## Gaffy

I'm in class now but I'll try to explain my thinking when I'll get home.
EDIT: It's basically a wild-guess structure-Wise. 
If you look at the structure of the L-THP derivates, you'll notice their structure incorporates either M?thylph?nidate or BK-Methamphetamine, and disso-like structure, and that's when I thought they might be active at Sigma receptors. Now look at Siramesine and at 4-PPBP, they both slighlty ressemble the core structure of cannabino?ds. Now back to the L-THP, and overlay it with THC; it matches, so "mixing" them should work.. Then take a look at PRE-084, and adapt it to the carbomethoxy on the one which ressembles MPH. If you follow that logic of overlaying bit by bit, at least that's what I did, you end up with Indeed quite a bulky chem but it seems to match the logic. I made some new ones with explaining:​


----------



## sekio

As far as I know, the sigma receptor is pretty promiscuous in its binding, lots of stuff with varying structures have activity. Pregnenolone (steroid), ketamine, methamphetamine, racemethorphan, noscapine, DMT, (es)citalopram, cocaine, etc all have affinity and they have very diverse structures.

Some of those structures remind me of compounds with known hERG blocking activity however, which is Not A Good Thing.

---





So apparently phenylalanol carbamate is orally active as a NDRI? Do we know anything about the SAR? How about aminotryptophol carbamate? O-methyl aminotyrosol carbamate?


----------



## S.J.B.

sekio said:


> So apparently phenylalanol carbamate is orally active as a NDRI? Do we know anything about the SAR? How about aminotryptophol carbamate? O-methyl aminotyrosol carbamate?



Neat... (+)-methamphetamine with a carbamate tacked on.  It can be made in one step from D-phenylalaninol, which is fairly cheap, and the composition-of-matter exclusivity for the compound has expired by now in many countries, so it would seem to be a viable target for research-chemical suppliers.

Interestingly, (+)-methamphetamine itself is only three steps from D-phenylalaninol, or two from the also-widely-available _N_-Boc-D-phenylalaninol.  I wonder if anyone has been using either of these as a precursor for large-scale methamphetamine production?

The tyrosine derivative was patented by the same group as the phenylalaninol carbamate, whereas the tryptophan derivative is unknown.


----------



## Gaffy

,Talking of phenylalanine derivaties, C11H15NO2. Ring a bell?


----------



## sekio

That's actually already an article of commerce, it's just N-methyl methyl phenylalanate.


----------



## Gaffy

Nice, couldn't find anything about its. Is it active?


----------



## Dresden

Gaffy said:


> Thanks Dresden, I put it there because p-F fentanyl is said to be longer lasting than regular fent; btw what do you guys think of the Phenidate-L-THP?
> 
> And talking of cocaine analogs, how about this:
> 
> 
> 
> 
> Or this:



Gaffy,

Those Actually Look Really Impressive To Me.

AMP


----------



## S.J.B.

Gaffy said:


> Nice, couldn't find anything about its. Is it active?



The D-phenylalanine derivative, which overlays (+)-methamphetamine, has been made, but I can't find any reports testing it for CNS activity.


----------



## sekio

It's probably not active as it will be rapidly O-demethylated to plain N-methyl-phenylalanine.


----------



## Gaffy

Thanks Dresden; regarding the Methoxy,N-Methyl-Phenylalanine it might well last for around 30mins-1h not unlike cocaine. And afaIk m?thylph?nidate lasts a good hour(s).


----------



## Gaffy

Cyclic Ketamine : 2',N-Ethoxy-Ketamine


----------



## DotChem

Now! this is one wicked molecule: 

















the trans isomer is a potent SNDRI with no opioid receptor activity whatsover and the cis isomer is a potent opioid agonist with no SNDRI whatsover.. go figure


----------



## Pomzazed

Above images do not load for me. Is the link correct?

It worked now in PC, doesn't work on my ipad.
That is an interesting heterocycle, can that ketone be replaced by an ester?


----------



## DotChem

^It works fine.. maybe something to do with your browser


----------



## Gaffy

Funny how it ressembles ibogaine. recognise the opioid structure, reminds me of dipipanone..

Inspires this: (to me)






  Add a Carbomethoxy next to the phenyl+piperidine and you've got a chem quite similar to yours

More alike: 





I Wonder if it'll compare to CarFentanyl potency wise


----------



## Soulfake

Some stuff I randomly drew. The first ones on the left side are molecules I'm thinking about for a few years now, I have a feeling that there could be something good about them or that something similar could be a great substance. If anyone has thoughts about it I would be thankful for input. They are mainly a combination of the structures from Tilidine, Pethidine, Fencamfamine and Phenmetrazine. As those compounds are all very smooth and have nice effects as well as structures that can resemble opioids and stimulants at the same time I think there would be some potential to find something like a light speedball-like opi-stim. (I used "R" as a placeholder for whatever substitution would fit most.)

(//edit: I made a few mistakes; the nitrogen on the first molecule is not on the third unit for the phenethylamine-core (although the current position could make it more similar to a dissociative?) and the two chems below are the same ones, one should have the reverse ester)

The structures on the right side are just some boring -Phenidates and -Morphenates. I wonder if the N-methyl would make them simple pro-drugs to their parent compound? (I don't know why but I like morpholines and norbornanes somehow, similar to others who love benzodioxole units ^^)
On the left down side are just random chems I drew without much thinking.

I really don't know much about chemistry and have only learned (like many others) what I more or less know from looking at different chems, trying RC's and other substances, reading research papers and combine all that, more or less like the early alchemists who didn't really understand what they were doing ^^ 






//edit: I think this could have potential, HDMP-28 is strong with a short duration, Isopropylphenidate is smooth with a long duration, maybe it would make the HDMP a bit lighter with longer effects. And the methylmorphenate-analogue without isopropyl as it's already weak.


----------



## Gaffy

N-Methylated Phenidates are less potent than the usual ones, around 1/10th the potency.


----------



## Dresden

True statement.


----------



## Limpet_Chicken

Dotchem-reminds me of a phenylated pethidine, with the nitrogen replaced with an ether bridge.

Not surprising that there is potential for both opioid effects and DARI properties.

That said...what is the potential for it's acting as a convulsant, as norpethidine can? 

Another mixed DARI/MOR agonist that comes to mind, is etonitazene, and presumably the other benzimidazole opioids. Although etonitazine is a bit of a hot one to handle, from everything I've read of it. Apparently it surfaced at one point in russia, and was dosed by smoking, a cotton thread being soaked in a solution, and this poked into a cigarette with a needle (and presumably it'd be just as practical to roll your own, with the thread in place). For such a potent sonofabitch of an opioid, not a bad idea, as ideas concerning such potent opioids go to begin with, the slow administration in a cigarette allowing fine control over dosage.

Although the Highsmith case, using via nasal spray, that turned out pretty ugly.

Some of the lower potency benzimidazoles would be safer. Although don't they all have a really short duration of action?


----------



## DotChem

^more like ketobimedone than pethidine.. nor-ketobemidone is not convulsant like norpethidine iirc. the consulvant effect of norpethidine is due to one its metabolites 4-phenyl-piperidine-4-carboxylic acid (GABA-ergic as you might expect!).  
re: Etonitazene make sure you don't put a 4-Nitro or any electron-withdrawing on the benzimidazole.  It increase MOR by 1000x with very narrow TI the most lethal OP imho.. just don't put a nitro, or a fluoro that sort of things!

@Pomazed:"That is an interesting heterocycle, can that ketone be replaced by an ester?".. why not? but one of the problem with amino esters is their potential to get metabolized to amino acids (CO2Et hydrolyzed to COO2H) by esterases.  They tend to give GABA-ergic ligands that are sometime convulsants especially those with piperidine (cf ketobemidone v meperidine).. but who knows with this particular structure?

@Gaffy: "I Wonder if it'll compare to CarFentanyl potency wise" the N-substituted derivative with phenethyl is about 300xmorph or ~ 3X less than carfentanyl. The cis. the trans is inactive at OP but is a SNDRI.  But why would anybody want to do that (increase potency to carfentanyl range!). Besides just being lethal killing people (I mean fentanyl OPs) they're not even euphoric..A lots of people I know hate them.   Maybe put a N-methyl, may not be as potent as fentanyl but most likely more morphine like opiates 

Ketobemidone type are probably one of the most overlooked RCs class yet..  The perfect speed-ball with simultaneous DARI + MOR within same dosage (not insanely potent and lethal like fent-type OP)​​


----------



## Soulfake

Gaffy said:


> N-Methylated Phenidates are less potent than the usual ones, around 1/10th the potency.



I thought for example the para-fluoro substitution of 4F-MPH or the naphtalene of HDMP28 could compensate for the loss of potency on the Morphenates and the n-methylated Phenidates and result in a still potent enough substance. Also Methylnaphthidate is very strong but short acting, Isopropylphenidate is smooth and long acting so Isopropyl-Naphthidate could be a good fusion of those. 

---

some more molecules

Some "speedball-esters" and a giant cyclic opioid...if it just could be that easy, haha


----------



## Gaffy

Anyway; Read DotChem's thread about "Eagle Night", a new "drug" that can keep one awake for 4 night's with no comedown, and that is supposedly non-dopaminergic and not a racetam; that seems quite hard to me. Anyway I looked into non-AMP stims and came up with two little ones, a quinoline and a bromantane derivative; image also includes a novel stim (not of my invention), w/ link to the paper:


----------



## Gaffy

Came up with something, I'll edit post when I'll access a computer.
Edit:





I haven't a program to simulate binding profiles but I presume these to be non-PEA DAT NET SERT (s). 
Didn't yet look at MT antagonists so the ones I drew higher-up might be more agonists at non-MT sights; Might just be getting closer to "the Night-Eagle".​


----------



## Soulfake

Some more simple molecules. If nicotinoyl-GABA has a better transportation across the BBB maybe that would also work with Phenibut or Gabapentin which are known to be only transported into the brain in small quantities. I wonder if nicotinoyl-GHB would be possible (the one below the first structure). Nicotinoyl-Amphetamine/Cathinone/etc. analogues could be nice as the niacine would help against the vasoconstriction and in some countries such analogues would be legal.


----------



## Gaffy

Enough Night Eagle, back to ketobemidone:


----------



## sekio

thiophene is probably a better substitute than benzothiophene...





2- and 3- position isomers of "thiophenyl-ketobemidone".

makes me think of thiambutenes


----------



## Gaffy

Maybe. But TCP is a NMDA antagonist "TCP has slightly different binding properties to PCP, with more affinity for the ​NMDA receptors[FONT=Verdana,Arial,Tahoma,Calibri,Geneva,sans-serif]"[/FONT] unlike BTCP "benocyclidine is a pure DRI with negligible ​affinity for the ​NMDA receptor";  full DRI. Kinda what I aimed for, as we were speaking of speedballs; DRI(DA)/MOR, Nothing else.
Btw your thiophene ring is misplaced (I think).​


----------



## Limpet_Chicken

Cathinones have a carbonyl group in the beta-position, not a hydroxyl group. No ester there, sorry.

There are ways of protecting them though, from that nasty habit of dimerization. Pthalimidopropiophenone, IIRC was sold in israel for a while, it certainly has been used, in humans, that is. Oral administration being mandatory, however, as it's dependent on cleavage to the cathinone and pththalic acid in the acidic conditions of the stomach.

A carbamate could likely be done too, again, oral use. This could be...tweaked, so to speak, pun intended, so as to smooth the comeup, if one were to form the carbamate of an alcohol with a real kick to it.

I've long wanted to get round to preparing and testing the 1-ethynyl-cyclohexan-1-ol carbamate of MDA. Probably relatively small amounts of the alcohol in question released, but it IS known to be a potent little sucker, or maybe an ethchlorvynol carbamate of MDA. Aside from R&D to be done, something novel to explore, the benefit being, ideally, one hopes, a smoothened come-up and ride, the rough edges filed off, not full blown intoxication, just, sanding down the jittery bits for something just that bit nicer.

That at least, is the hope.

As for speedballs, actually some NMDA antagonism in with such a beast, or even a combination of NMDA antagonist+potent opioid, it can really make a difference.

Something like memantine+dipropionylmorphine, 6-AcO-dihydromorphine, or even morphine if one either cannot, or doesn't wish to get out the chemistry set, so to speak.

The two in the same rig, speedball-fashion...the rush is massively prolonged. And potentiation through the roof.

Memantine+prope gear in the same rig..it'll knock you on your ass so hard you'll think Thor himself just wrapped his bedclothes round Mjolnir and went to town on you. I've combined the two also with 6-AcO-dihydromorphine, and despite having at the time, an opioid tolerance larger than I do now, 300mg of the opioid, 100mg memantine, IV, I was staggering around the house for the best part of an hour, at least 3/4 hour, before the IV rush subsided (to an extent) and the high began.

And at the time, I'd still be breathing after 1g-1.5g morphine IV, dissolved in water as hot as tolerable without discomfort or injury, and using a large capacity glass syringe. Hell, had done 1g shots of DPM before, with the bastard of a tolerance I had at the time, and that 300mg 6-AcO-DHM (there'll have been a smaller proportion of dihydroheroin in it, from the route that was responsible for it's creation), with the memantine, fuck ME. Quite literally, staggering, as if I'd chugged a 70cl bottle of vodka and added benzos to it (I'm not much of a drinker, and no, I'm not suggesting I either DO this, or suggest anyone else do it either, it's the comparison that is salient)

Having to hold on to sofas, chairs, tables, had to go down the stairs with great care, partly on my arse, literally. The potentiating effect of NMDA antagonists on opioids, when co-administered, certainly with memantine, it's absolute rocket fuel.

Never tried mixing the two with a stimulant for a three-way NMDA antagonist-speedball.

But I wouldn't say no to a couple hundred mg memantine, 300-400mg 6-AcO-DHM and a decent serving of 3-fluorophenmetrazine
Had opioids+3-FPM, opioids+memantine, but never opioid/stimulant/NMDA antagonist.

Unless you count diphenidine, but I don't mean 'mostly one with bits of the other two', but in all three cases, something that'll really pull it's weight.

Memantine might not be much of a dissociative unless dosed really high, but it DOES potentiate opiates to a staggering degree.


----------



## Soulfake

Sorry for the stupid question but I'm just on stimulants and always like to draw random molecules while I'm on stims ^ ^

I have often read that the nitrogen in Amphetamines, Cathinones and similar drugs isn't always necessary to retain activity, what would putting a methylsulfonylmethane-unit instead of the amine or one at the para-phenyl position do to the molecule? I guess it doesn't really make sense because it's too bulky, reactive or something like that but I have often seen those msm-units in various drugs and find them somehow interesting.


----------



## Pomzazed

Sulfone is not that much reactive.
I have no idea about paramethylsulfonyl, but for the other one it should lost activity as that amine nitrogen is in protonated (ammonium) form during binding


----------



## Gaffy

Missed the 666,666 views, got 666,696

Yay:


----------



## Hodor

Soulfake said:


> Sorry for the stupid question but I'm just on stimulants and always like to draw random molecules while I'm on stims ^ ^
> 
> I have often read that the nitrogen in Amphetamines, Cathinones and similar drugs isn't always necessary to retain activity, what would putting a methylsulfonylmethane-unit instead of the amine or one at the para-phenyl position do to the molecule? I guess it doesn't really make sense because it's too bulky, reactive or something like that but I have often seen those msm-units in various drugs and find them somehow interesting.



Sumatriptan is essentially 5-(N-methyl-sulfoneamido)methyl analogue of DMT. This limits its activity as a serotonin agonist to mostly the 5HT1x receptor subtypes, some of which are apparently responsible for causing vasoconstriction in the brain, thus stopping migraines and cluster headaches. 
Seeing as how meta- and para-substituted amphetamines are also associated with serotonin receptor agonism, one wonders if sticking a bulky-ass methylsulfonyl group there would achieve similar effects. .. it's a long shot, though. IIRC tryptamines generally have some degree of 5HT1x agonism to begin with, whereas phenylethylamines are more selective for 5HT2a/b/c.






I kind of doubt you can replace an amine with a sulfone group, at least not without a massive drop in potency. I believe sulfonyls can sometimes act as bioisosteres for carbonyl (i.e. C=O) groups, though.


----------



## S.J.B.

Soulfake said:


> I have often read that the nitrogen in Amphetamines, Cathinones and similar drugs isn't always necessary to retain activity...



If that is the case, it is exceedingly rare and not, to my approximation, anything that has ever shown up in a recreational drug or approved CNS medicine.


----------



## Pomzazed

In phenethylamine class, nitrogen seems mandatory.
What is not-that-require is in the structure of cocaine and phenidate types, that N can be replaced by O or CH2 with drop in potency but not fully lost.


----------



## white55

some unstandard benzo subs, do you think they would be active/commercially viable to make?








tfm at r7, active?







nitemazepam analog, do you believe the potency would be high enough to be useful?






nimetazepam with a bioisostere for the nitro group? active?


----------



## sekio

> some unstandard benzo subs, do you think they would be active/commercially viable to make?



fluorosulfonyl groups are too reactive to be good subtsituents on drugs


----------



## Pomzazed

That SO2F looks like you’re making an insecticide o.o


----------



## Limpet_Chicken

Yeah, I'd rather not eat that one.

Nitrotemazepam..not  an untempting thought. Nitrobenzodiazepines  are where it's  at, IMO, as  far  as  benzos go. Temazepam is or has been REALLY popular recreationally in the UK, to the point where they had to ban the 'jelly egg' form of it, because addicts were heating it to melt the stuff and banging  it, often causing horrendous damage to vasculature and tissue damage, limb loss etc. Only ever got to have two bottles of jelly egg temazepam, after finding an old lady's stolen handbag as  a young kid, returning the bag to her, her money had been stolen, but her cards and stuff still there, so I returned it all to her, but she said she wasn't gonna take those pills, after the label had gotten wet, near the brook the bag was thrown beside, gave me 20 quid for returning the bag to her with her cards, asked her if I could keep the two bottles of temazepam jellies in there, because they were getting rare as shit even then. She said yeah, go ahead, don't know why you'd want those but sure if you want them, keep them'

That was a fun week or  so, shoveling down those, chomping on 'em like jelly beans (no, I didn't think they were candy, just used them like they were chewy jellybeans)

Apparently, not sure if it still is, but temazepam was  at least at some  point classified differently, class B compared to other benzos I think, or it might have been a different schedule, one step above  the other benzos due to recreational popularity. Pretty fucking stupid IMO, since  they'll most of them get one fucked up, if one has  enough, and  just as, or more, addictive physically. A 1,4-benzo is a 1,4-benzo as long as they are both of the GABAa PAM kind. Horses for courses.

Personally I've never seen why it might be special, I've had it enough, but it's kinda bland to my tastes. Needs a nitro group sticking on it 

Had plenty, especially after several years back, kicking the fucking little psycho borderline waste-of-autism BITCH from hell housemate I ended  up having for a while into the street, after she tried to run me through with her samurai sword. Went through all her stuff before returning any of the bits I didn't decide to take for my own. And among the shit I did (she was a real klepto nutball gorgonslut bitch from Hades), was a LOT of temazepam and valium scripts. Loads of 'em, had the scripts, rarely used them. So naturally I relieved her of them.

She was a wanker. But, a wanker from perdition with a lot of valium, temazepam, plus DFs she'd siphoned off from me over years, just to manipulate me with fucking meptazinol and BZDs, when I'd go into WD, couldn't take them herself, had to use meptid for her own pain because she was allergic to hydrocodone, and severely so, so likely so to codeine and DHC. Ugh, total bitch. Although at least when kicked out, got myself one hell of a party-plate


----------



## Gaffy

Tempt me into Benzos; 





AAAnd Some N?fopam d?rivatives (one of my favorite IVs)




NYA W/Gaffy


----------



## white55

I have a bunch nitrimetazepams/temazepams which could fix is main weakness. It's too weak to survive as a rc.


----------



## Gaffy

white55 said:


> I have a bunch nitrimetazepams/temazepams which could fix is main weakness. It's too weak to survive as a rc.


 Your sentence doesn't make any sence.

Would this be active:





Also new, turns out Fentanyl just had a baby with Nefopam; progeniture seems wonderful:


----------



## sekio

Came across the structure of viscidone, a prenylated acetophenone found in bee propolis, and, well, I had fun with Chemdraw.






The 2C-methyl-(methyleneoxetane) is a cool idea, even if not active. And 2C-Prenyl or 2C-isoPrenyl should have been made before, even if they are low activity. Compare methallylescaline to 2C-isoPrenyl:


----------



## Gaffy

Sekio / Dresden / Pomzazed (or anyone else reading this) do you know of a program that runs on windows that is used to map the activity of chemicals in the brain. I heard some of these exist; I'd like to get a better insight as to how active and good or inactive/poisonous the compounds I've drawn these last few days are.


----------



## sekio

There's no such thing as a "magic SAR prediction black box' whede you feed it structures and it comes back with affinity/efficacy data, unfortunately... most of the predictioms in this thread are the work of human minds drawing conclusions from already published data on drug SAR/effects.

You can find molecular dynamics or protien-ligand docking calculation software like CHARMM or GROMACS. However those programs are meant for situations where you already have a high accuracy model of the receptor in question, preferably from X-ray diffraction studies of the receptor in crystalline form. However because many receptors are typically anchored to the cell wall it can be an uphill journey to find conditions that allow a technician  to both isolate the receptor in question as well as support the growth of flawless homogenous crystals of your receptor protien (plus bound ligand) that are big enough to handle and image with a cyclotron.  A lot of effort is being made to derive means for recovering accurate protien structures in the solution phase just because crystallization of protiens is a black art at the best of times and seemingly impossible in the harder cases.

If you don't have the luck to have access to a good model of your target receptor, you can find a homologous receptor with a solved tertiary structure that shares a significant amount of its amino acid sequence witn your target and modify the structure accordingly, working on the assumption that the structural differences don't wildly change the shape of the receptor. I recall seeing quite a few models of different GPCRs that were based on the structure of bovine rhodopsin, for instance, because it was one of the few GPCRs people could get reasonably pure and coax into a cryatalline form. 

As a last resort there is also _de novo_ protein folding, like what Folding@Home does. However, given that protien folding is NP-complete (easy to _verify_ a correct solution, but incredibly difficult to come up with a solution), this method takes an incredible amount of time and computational power to produce results even for protiens of relatively short length. The amount of possible configurations for each amino acid grows exponentially with every additional one so a GPCR with a few hundred to a thousand amino acids would take longer than the age of the universe to exhaust every potential conformation.

So anyway, unless you have a set of accurate models for _all_ the receptors common to psychoactive drug effects, you're mlre likely to only be able to come up with the predicted affinity at a few receptors. Even then you'd need to mess with some pretty fancy software meant for academics and invsst some serious CPU time.


----------



## Gaffy

Damn. Thinking of it they indeed do not know the exact sequence of most of the receptors mapping our brain, other than DA NE SER MOR Etc.. At least these are the ones I'd like to study qwa affinity vs some of the chems I drew, like the MT antagonists or some of the opioids, even if it isn't telling me the exact affinity etc, at least get an idea of how it binds to the AA sequence. 
Thanks for your insight, I'll take a look at it when I'll get home from vacation.


----------



## Limpet_Chicken

Hell, even MOR, there are MOR1/2/3 subtypes, and a LOT of variety by ways of splice variants, potentially heterodimers or other heterooligomeric receptors between MOR and other receptors. As well as biased ligands, such as those activating strong G-protein signalling whilst producing little beta-arrestin II recruitment, the latter having a lot to blame for causing tolerance troubles.


----------



## Hodor

white55 said:


> some unstandard benzo subs, do you think they would be active/commercially viable to make?



Sulfonyl fluorides tend to form covalent bonds with certain amino acid residues.

This makes them potentially extremely useful as irreversible enzyme inhibitors or dye probes in biochemistry (the field of applying such reactions which are highly energetically favorable yet selective, and which will not violently decompose in an aqueous environment, is called "click chemistry"), although it would probably make more sense to use a single rather than two sulfonyl fluoride groups; in that case, it might actually be a valuable tool for studying the structure of the benzodiazepine binding site on the various GABA receptor subunits.

https://www.sigmaaldrich.com/techni...technology-spotlights/sulfonyl-fluorides.html

But as a pharmaceutical that people would actually ingest to produce a psychotropic effect? Not really.


----------



## Gaffy

Someone draw Benzylthio-A-PVP, call it TH-PVP2

Anyone? Please? I can't access a PC right now..  Dresden?


----------



## Solipsis

Like this:






?

_(RS)-1-Phenyl-2-(1-pyrrolidinyl)-pentane-1-thione_

(technically not "benzylthio")


----------



## Pomzazed

p-Benzylthio-aPVP






Bad synthesis of ethynylcyclohexanol, when one doesn't control the condition right....

Is this still active ala 1,4-B? lol






Shhh... this is a BPA-free polycarbonate!


----------



## Hodor

Solipsis said:


> Like this:



Aren't thioketones highly unstable?

Thiobenzophenone is one of the few stable ones, although there the thiocarbonyl is benzylic to not one, but two benzene rings.

Still, even that one tends to readily get photooxidized (into sulfur and benzophenone).

Not that anyone would ever willingly ingest a thioketone. I am sure Limpet Chicken can come up with a graphic description of what this stuff must smell like, and is consequently going to make the user smell like (_"It's like Andrew Wakefield pooping on Margaret Thatcher's rotting corpse while Jacob Rees-Mogg sits in the background, masturbating and farting."_)


----------



## Pomzazed

During my M.Sc. I have synthesized thioketone deriv. of JWH-018
it is morr stable than i predicted, it survives air and room temp for many days,
it forms a black solid and deep red solution in DCM too.


----------



## Gaffy

Benzylthio like in BTCP, with the ketone on the carbon above the S group


----------



## Hodor

Pomzazed said:


> During my M.Sc. I have synthesized thioketone deriv. of JWH-018
> it is morr stable than i predicted, it survives air and room temp for many days,
> it forms a black solid and deep red solution in DCM too.



That's pretty cool.

Still, "thio-JWH-018" has the advantage of having that thiocarbonyl next to not just one, but two aromatic systems (naphthalene and indole), similar to thiobenzophenone's two phenyl rings.

I wonder how stable something with just a single aromatic system on the alpha carbon could be.



Gaffy said:


> Benzylthio like in BTCP, with the ketone on the carbon above the S group



There is no benzylthio in BTCP. Did you mean benzothiophene?

Also... where is "above"?

Skeletal formulas can be rotated any which way; you need to post the one you mean.





Is it this one?

Because the carbon "above" the sulfur atom here cannot accept any more bonds.


----------



## Gaffy

Hodor

Enough joking, I was indeed wrong about the spelling. What I meant was benzothiophene-PVP, like in methiopropamine with a benzene ring added to the 3-4 position.


----------



## Hodor

Gaffy said:


> Enough joking, I was indeed wrong about the spelling. What I meant was benzothiophene-PVP, like in methiopropamine with a benzene ring added to the 3-4 position.



You mean 1(2-benzothiophenyl)-2-pyrrolidino-pentan-1-one ?





Edit: You said 3-4 position, so maybe this one?:
1(3-isobenzothiophenyl)-2-pyrrolidino-pentan-1-one


----------



## Gaffy

Like naphyrone there are two isomers, but ouidah, those are the ones I meant! Thanks


----------



## Gaffy

These are the ones I had in mind. The double carbon bond should be at the sulfur, makes a more stable compound.

I know it's merged, please Don't edit; shouldn't have been done on the "Hodor" comment, lost its humor.


----------



## Soulfake

Some Taurine analogues of Gabapentinoids. (R= Methyl, Fluoro, Methoxy etc.). Replace the NH2 units with HO and you get the corresponding GHB analogues.

The ones at the bottom are just-for-fun "Nitrophenibut" and "Ethoxy-Nicotinoyl-Nitropheni-GHB" analogues. But who knows (well, probably those who understand chemistry better than me), maybe they would be the ultimate gaba drugs ^^


----------



## Hodor

Gaffy said:


> These are the ones I had in mind. The double carbon bond should be at the sulfur, makes a more stable compound.



No. No, it wouldn't. 
Putting three of its electrons into covalent bonds (and 2 in a lone pair) leaves the last electron on the sulfur unpaired, making it a *radical*, i.e. pretty much *the exact opposite of "stable"*.

Where are you getting the idea that this would be more stable?


----------



## S.J.B.

Hodor said:


> No. No, it wouldn't.
> Putting three of its electrons into covalent bonds (and 2 in a lone pair) leaves the last electron on the sulfur unpaired, making it a *radical*, i.e. pretty much *the exact opposite of "stable"*.
> 
> Where are you getting the idea that this would be more stable?



The sulfur should at least be given a positive charge, but even so, it would immediately lose a proton at the 3 position of the bicycle to quench the positive charge and bring the five-membered ring into aromaticity.


----------



## Pomzazed

Shift the double bond to a 2,3-position then it will be a stable benzothiophene!
Gaffy’s 1,2- double bond version cannot be made (sulfur with 3 bonds huh?)


----------



## Gaffy

Sorry about that. I only have a very basic (if not plain bad) chemistry level.


----------



## Hodor

Gaffy said:


> Sorry about that. I only have a very basic (if not plain bad) chemistry level.



No reason to apologize.  I was genuinely curious as to why you would assume that three bonds on the sulfur atom would make it more stable, so I could better explain it to you.

Maybe this will make it easier to understand:
As I've said, sulfur has 6 electrons in its outer ("valence") shell. Usually, atoms in compounds will enter a certain number of bonds with other atoms in order to achieve a shell with 8 electrons in it.

Take, for example, hydrogen sulfide (H2S): The sulfur enters two of its electrons into single bonds with hydrogens, so it now has 2 x 2 electrons in the S-H bonds, in addition to 2 pairs of electrons not involved in bonds (so-called "lone pairs").
Since (2x2) + (2x2) = 8, it has now achieved the desired 8-electron ("octet") configuration.

Compare this to, for example, carbon or nitrogen:
Carbon has 4 electrons, so it going to try and enter bonds to gain 4 more electrons; nitrogen has 5, so nitrogen needs to form 3 bonds to complete its octet:
Thus the formula for methane is CH4, and that of ammonia is NH3.
In benzene, each carbon is connected to one carbon atom via a single bond, and to another via a double bond. Its fourth bond is to hydrogen, but carbon-hydrogen-bonds are typically not drawn in a skeletal formula so as not to make it overly complicated.





By replacing one of the carbon atoms in benzene with nitrogen, we get pyridine. Note that here, you'd have to draw a hydrogen atom if there was one connected to the nitrogen - but there isn't, because the nitrogen is quite happy with the 3 bonds (a single bond and a double bond) it has formed with the adjacent carbons, giving it the desired 8-electron-configuration.





Now, it is possible to have a compound where the sulfur is connected to the adjacent carbon atoms via 3 bonds, namely by removing one of its electrons. With 5 electrons in its valence shell, it is now "isoelectronic" with nitrogen, and will thus bond to the adjacent carbons just like the nitrogen in pyridine. Removing the electron leaves it with a positive charge; however, it can be stabilized by forming a salt with a negatively charged counterion (e.g. chloride). The image below shows a pyrylium cation; replace the oxygen with sulfur, and you'd have the thiopyrylium cation.


----------



## Gaffy

I got it . Now; 
Up and rolling; Dark and horsing, I present to you:
The world's strongest DRIs (money back if you find better elsewhere)​




The world's most cyclised R-30490s, and one of cebranopadol's relatives, un invite de marque:

​





And to top it off: 







BTW Please kill me; CHARMM costs 600? (if anyone has a torrent, or an invite for uni codes granting access, I'd be honored)


----------



## S.J.B.

Gaffy said:


>



Analogously to the situation with the sulfur-containing molecules you had posted previously, the two structures on the right will quickly rearrange to give enamines, thereby forming indoles.


----------



## Gaffy

That's alright


----------



## Gaffy

Gaffy's MORs


----------



## Hodor

Gaffy said:


> That's alright



This is basically your introduction to a concept called *"aromaticity"*. The term _"aromatic"_ describes ring systems in which electrons can be freely shared between atoms across conjugated double bonds. However, for this to happen the molecule needs to be flat ("planar"), and be able to contribute a specific number of electrons into a pi-system, i.e. a halo of electrons distributed above and below the ring.

Most of these electrons come from double bonds, with each double bond contributing 2 electrons. Benzene and pyridine both have three double bonds, meaning there are 3x2=6 pi electrons. 6 happens to be the exact number of electrons needed for a single ring to achieve aromaticity.

In naphthalene and quinoline, there are 5 such double bonds. 5 times 2 equals 10, and ten happens to be the exact number of electrons needed to achieve aromaticity in a system with two rings.





But what about pyrrole? It only has two double bonds, yet it is still aromatic. How so?
Well, look at the way the molecule is drawn on the left.





As we've established earlier, nitrogen has 5 electrons in its outer shell, 3 of which it uses to form bonds. Notice those two dots above the "N", though? That's the remaining "lone pair" (of electrons), which can be contributed to the pi system, just like the electrons from a double bond. Adding up the 2x2 pi electrons from the double bonds and the two pi-electrons from the nitrogen's lone pair we get 2x2+2=6 electrons, just the right amount to make the whole thing aromatic.

If we fuse such a pyrrole ring with a benzene ring, we get a system with 4 double bonds and, again, a lone pair on the nitrogen, giving it 10 pi electrons. The compound (called an "indole") is thus aromatic, just like the aforementioned quinoline, despite not involving the nitrogen in a double bond:





And as I mentioned in the beginning, an aromatic molecule needs to be *planar*. A carbon with a double bond forms a flat triangle with the atoms it is bonded to, which is what we want. Without the double bond, the 4 bonds would form a 3-dimensional tetrahedron, and it would no longer be planar, and thus not aromatic. This is another reason we need the double bond to be on the carbon instead of the nitrogen.


----------



## Gaffy

Happy New Year Everybody, may Chems be with you.


----------



## Gaffy

Disso cannabinoid? Some new CBs:
	

	
	
		
		

		
		
	


	




A little recap+ some new ones
	

	
	
		
		

		
		
	


	




Novel opioids


----------



## polymath

Is there any information about the cyclic product that forms in the reaction of phenylalanine with 2-chloroethanol? The chlorine end would alkylate the amino group and the hydroxyl end would form an ester with the -COOH.


----------



## Gaffy

2-Br-EtoH would be more suited I guess. I think you hydrolysis between COH-HOC=COC+H2O would take waaaayy longer than the actual reaction between halogen/amine; but anyway here's your product;​


----------



## S.J.B.

Gaffy said:


>



This compound is a hemiaminal, which would be very prone to hydrolysis, in which case an equivalent of formaldehyde would be released.

NOTE: this is not in fact the compound that Polymath was talking about; in that case, a hemiaminal would not be formed.


----------



## Gaffy

Could you explain how and why?


----------



## S.J.B.

Gaffy said:


> Could you explain how and why?



Basic nitrogens have a propensity to donate a lone pair of electrons.  If there is an oxygen connected to a basic nitrogen through a one carbon bridge, the nitrogen can then donate its lone pair to form a nitrogen carbon-double bond and kick out the oxygen.  If there is no water around, the oxygen will just add back and the compound will likely exist mostly as the hemiaminal (especially since it is a five-membered ring, which are particularly stable and are the fastest to form of any ring size).  In an aqueous medium such as the body, however, a molecule of water could add instead, taking the place of the oxygen.  This would lead to a sequence of steps that eventually liberates phenylalanine and formaldehyde.  The entire sequence (what we would call the "mechanism" of the reaction) is shown below:


----------



## Pomzazed

polymath said 2-chloroethanol!
so the product would be a 6-membered ring and that hydrolysis of hemiaminal will not occur.


----------



## S.J.B.

Pomzazed said:


> polymath said 2-chloroethanol!
> so the product would be a 6-membered ring and that hydrolysis of hemiaminal will not occur.



Ah sorry, I was looking at Gaffy's drawing!  That is correct - I will edit my post.  Thanks!


----------



## polymath

Yeah, I meant the compound with a 6-membered ring. I thought that could potentially bind to monoamine transporters. Another possibility is the cyclic amide from 1-amino-2-bromoethane and phenylalanine, but then there would be more polymeric byproducts formed.


----------



## S.J.B.

polymath said:


> Yeah, I meant the compound with a 6-membered ring. I thought that could potentially bind to monoamine transporters.



The N-methyl analogue of that compound has been made, but as far as I can find has not been biologically tested:






Another interesting one would be the product of reduction of the ester to an ether (not a trivial reaction, but doable in some cases):








> Another possibility is the cyclic amide from 1-amino-2-bromoethane and phenylalanine, but then there would be more polymeric byproducts formed.



The reduction of this compound is more standard, and would give a constitutional isomer of BZP:


----------



## Gaffy

My bad, I forgot a carbon; here's the right pic:​


----------



## Pomzazed

Polymeric bypdt can be avoided/minimized using nonstoichiometric ratio of reagents and separation of resulting product later on,

However, in this cases, imo, it seems the oligomeric product will not predominate the rxn as 6-mem ring is favored both kinetically/thermodynamically.

Also, i see that 2-benzylpiperazine got brought up frequently, but there are no studyon it, eh?


----------



## Dresden

Gaffy, 

Add a benzylic phenyl or carbomethoxy!


----------



## S.J.B.

Pomzazed said:


> Also, i see that 2-benzylpiperazine got brought up frequently, but there are no studyon it, eh?



I couldn't find anything, though it's certainly been made.


----------



## Soulfake

Some random chems...some more seriously and some probably quite toxic stuff (or the ultimate panacea, who knows). And yes, I love norbornanes ^^ I don't know why, I first came across camphetamine and somehow liked the structure with the norbornane unit along with it's relation to camphor. With morpholines I feel similar.

I have to look on my old hard drive for all the molecules I had drawn in recent years and which were a little more thoughtful, even though I am still a layman in the field of structure relationship and chemistry in general.
The last one on the right bottom side could be marketed as "Anarchodrone" ^^


----------



## Hodor

Your nitro groups are all wrong. Nitro groups do not carry a proton on the nitrogen, nor do they carry one on the oxygen.

Typically, a nitro group is drawn with a positive charge on the nitrogen, and a negative one on the single-bonded oxygen.


----------



## Gaffy

Any info? :







In the same trend:







Ever had a look at Tetrahydropapaveroline?






S.J.B, you should start a thread called "Gaffy's Chems" and move all my posts there 

Some dissos:


----------



## Soulfake

Hodor said:


> Your nitro groups are all wrong. Nitro groups do not carry a proton on the nitrogen, nor do they carry one on the oxygen.
> 
> Typically, a nitro group is drawn with a positive charge on the nitrogen, and a negative one on the single-bonded oxygen.



Ok thanks for the info. I'm quite a layman in terms of chemistry. 

Some benzos, I really wonder why the fluoro- and bromo analogues of Etizolam haven't been made yet, I guess they would be way better than those other analogues like deschloro-Etizolam or Metizolam. I also wonder why there are no other benzos with a 3-methyl substitution as Meclonazepam was in my opinion a really good benzo, very clearheaded but still with strong muscle relaxing effects and a positive mindset and a wide dosage spectrum. (I know I drew the nitro groups wrong again, I forgot the negative charge on the oxygen.)


----------



## Gaffy

Which one?






Looking at tetrahydropapaveroline I'd say it's the left one.


----------



## S.J.B.

Gaffy said:


> S.J.B, you should start a thread called "Gaffy's Chems" and move all my posts there



The point of this mega-merged thread, I believe, was to keep the speculative molecule drawing to one thread. So carry on posting in here, unless you feel like giving the molecule a funny name, in which case Dresden's thread will suffice!


----------



## Soulfake

Would it be possible to gain active (altough probably very dangerous) analogues of 5-IT (or the isomer AMT) or any other indole based drugs like tryptamines, psych. amphetamines etc. by replacing the indole with indazole? With cannabinoids it works perfectly, also azaindazoles could work, at least the 4N' azaindole analogue of 5F-ADB works almost exactly like it.

Could the PEA's and pyrrolidines with that acetyl ester from methylphenidate have any effects as stimulants or must there be a closed ring / piperidine, morpholine (or pyrrolidine as in the one I drew?) for it to work?


----------



## Gaffy

That PVP you drew top-left would I think be extremelly dangerous as it will probably also be a MAOI

New tryptis:

​





Can (…) being stoned feel like being on acid ;Bee my guest.​


----------



## Soulfake

Gaffy said:


> That PVP you drew top-left would I think be extremelly dangerous as it will probably also be a MAOI



Yes, I guess many of those molecules would be quite toxic ^^ especially the 5-IT analogues and the one with the two methylsulfanyl units.



Gaffy said:


> New tryptis:
> 
> Cannabino?dic tryptamines?https://i.imgur.com/jgy6TGU.png



I guess for cannabinoid activity you must ad e.g. an alkyl-chain or a benzyl-morpholine/piperidine/fluoro-benzyl/cyclohexane etc. unit on the NH2 of the indole, I don't know if that would decrease the activity as a psychedelic or stimulant. 

--

Some norbornane-cocaine & troparil analogues:






Somehow since a new update of the marvin sketch software it only generates molecules in this 2d-form instead of the 3d's you can often see (like that norbornane unit in the picture below), does anyone now how one can change that? (Btw. Marvin Sketch and the Marvin Suite in general is a great free software to draw molecules, it directly shows you errors of the molecule, you can make 3d-overlays and much more while it's still easy to use/understand.)






Edit: Haha, just as I drew those morpholine-phenidates in one of my last posts it is suddenly available as a research chemical,  synchronicities can be quite nice sometimes.


----------



## Gaffy

S.J.B. said:


> The N-methyl analogue of that compound has been made, but as far as I can find has not been biologically tested:
> 
> 
> 
> 
> 
> 
> Another interesting one would be the product of reduction of the ester to an ether (not a trivial reaction, but doable in some cases):
> 
> 
> 
> 
> 
> 
> 
> 
> The reduction of this compound is more standard, and would give a constitutional isomer of BZP:




Looking at it it could be adapted into:







a bit like the constitutional isomer of fent I thought of some posts ago ("would this be active?) later demonstrated with tetrahydropapaveroline's sert analogue.


----------



## S.J.B.

If anyone wants to come up with funny names for molecules please put them in "Dresden's Chemical Fluff Thread."


----------



## Soulfake

Would it be possible to make simple pro-drugs like esters from gabapentinoids such as pregabalin? For example an N-ethyl ester similar to theanine or a nicotinoyl-ester similar to picamilon. Which kind of analogue would make most sense? Would they all hydrolize/metabolize into pregabalin or at least have similar effects as they are simple analogues? Could those inositol-esters make sense as a pro-drug? The norbornane and pyrrolidine's probably won't work and the piracetam-like cyclic one won't work as an gabapentinoid. (Pregabaline is at the moment just a normal-prescription medicine and no narcotic/very controlled substance so the esters would be legal in most countries, also it's quite cheap and easy to produce and has massive recreational potential and gained a lot of popularity over the last years, why not making RC-analogues of gabapentinoids, at least they're a class of drugs with relative low toxicity and huge medicinal and recreational windows/safety).


----------



## Hodor

Soulfake said:


> Would it be possible to make simple pro-drugs like esters from gabapentinoids such as pregabalin? For example an N-ethyl ester similar to theanine or a nicotinoyl-ester similar to picamilon.



There is no such thing as an "N-ethyl ester". Condensation of an acid with an amine forms an amide.



> Could those inositol-esters make sense as a pro-drug?



Why inositol of all things, though? Inositol has a greater molar mass than pregabalin itself, and it is hydrophilic as hell, so its bioavailability might actually be worse.



> (Pregabaline is at the moment just a normal-prescription medicine and no narcotic/very controlled substance so the esters would be legal in most countries, also it's quite cheap and easy to produce and has massive recreational potential and gained a lot of popularity over the last years, why not making RC-analogues of gabapentinoids, at least they're a class of drugs with relative low toxicity and huge medicinal and recreational windows/safety).



Compared to benzodiazepines, pregabalin's recreational potential is far lower. Also, one of the problems with gabapentinoids is that their structure-activity-relationship is still not all that well-understood. Gabapentinoids apparently need to be actively transported into the brain via special amino acid carrier proteins. For years, the search for a successor to pregabalin has been slowed down by the fact that compounds that seemed much more potent in the _in-vitro_ binding assays showed little if any increase in _in-vivo_ potency, as their structural modifications would also decrease affinity for the aforementioned amino acid carriers, no longer justifying the significantly more complex synthesis.


----------



## Hodor

Soulfake said:


> Edit: Haha, just as I drew those morpholine-phenidates in one of my last posts it is suddenly available as a research chemical,  synchronicities can be quite nice sometimes.



"Methylmorphenate" (i.e. methylphenidate with the piperidine ring replaced by morpholine) briefly appeared on the RC market in 2015. The reason its appearance was rather brief was because it was barely active, at only about 1/10th the potency of its parent compound.
http://www.bluelight.org/vb/threads/766592-Novel-stimulant-Methylmorphenate


----------



## Soulfake

@hodor



> There is no such thing as an "N-ethyl ester". Condensation of an acid with an amine forms an amide.



Thx, I got that wrong. Somehow I had in mind that theanine was an ethyl-ester but it's an ethylamide analogue of glutamine. Do esters and amides behave similar in some ways? As far as I have seen/read both esters and amides often hydrolize in the body, depending on the molecule structure more or less fast while I guess most esters do hydrolize quicker than amides (I'm just a layman in chemistry and don't have real knowledge about basic and complex stuff, just a few pieces of information I read over the last 10 years about rc's and substances in general.)



> Why inositol of all things, though? Inositol has a greater molar mass than pregabalin itself, and it is hydrophilic as hell, so its bioavailability might actually be worse.



I read a research paper where esters of GABA with inositol where mentioned as a method of delivering it more efficient into the CNS (I can't find it anymore but these ones also describe it: https://www.researchgate.net/public...de_Analgesia_for_Some_Central_Pain_Conditions https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918363/



> Compared to benzodiazepines, pregabalin's recreational potential is far lower. Also, one of the problems with gabapentinoids is that their structure-activity-relationship is still not all that well-understood. Gabapentinoids apparently need to be actively transported into the brain via special amino acid carrier proteins. For years, the search for a successor to pregabalin has been slowed down by the fact that compounds that seemed much more potent in the _in-vitro_ binding assays showed little if any increase in _in-vivo_ potency, as their structural modifications would also decrease affinity for the aforementioned amino acid carriers, no longer justifying the significantly more complex synthesis.



I don't think it's recreational potential is really lower, maybe different but at least where I live it's very popular, most people I know who have tried pregabalin in higher doses (300-500mg) rate it much higher than benzos. I only have tried once 150mg+150mg a few hours later and it was really strong, when I stood up I always stumbled around and the muscle relaxation was really heavy, a bit like alcohol just without the mind feeling of it, much more clear and bright with a heavy euphoria, I was in a social setting with friends and although I also find some benzos euphoric this was way stronger, I guess to get such a strong muscle relaxation you would need so many benzos that it'll cause blackouts.

But I also guess that it would be hard to make/find really good gabapentinoids as "research chemicals", but that's why I thought that some kind of pro-drug for known ones like pregabalin would make most sense. I believe that there could be some simple analogues/pro-drugs that would be as cheap as for example phenibut, GABOB, picamilon etc. Pregabalin is just GABA with that ethyl-isopropyl unit or like gabapentin with an cyclohexane, GABOB with an OH-unit etc. I also think the chance for severe toxicity of simple amino acid analogues is a bit lower than for example all those cannabinoid and cathinone analogues, or not? I know that some strong poisons have amino acids build into their structure but quite differently than those mentioned structure modifications.


I know about methylmorphenate, I guess that making a para-fluoro or (di)chloro-substitution could increase it's effects? But I plan to get a small sample just for the collection as I really like it's structure and morpholines in general. Maybe it's just an imaginary delusion to think morpholine and norbornane stimulants are much smoother and enjoyable but I really liked camfetamine and 3fpm so I'm a bit framed about this.


----------



## Soulfake

some more random chems. PsyMDPV (third below on the right side), gives you a 10m-min psychotic trip and you can't stop using it until the supply runs out ^^ on the left of it a indole-cannabinoid mix with psilocin. Is it possible to replace the indole of psilocin or other indole-based psychedelics with indazole or azaindole as easy as it's being made with the synthetic cannabinoids? If they are so similar that they fit into the target neurons in a similar way when they are replaced in various synthetic cannabinoids why wouldn't it be possible to work similar for psychedelis? The "serotonin stem" doesn't seem to be only based on indoles as for example in Agomelatin it is replaced by naphtalene but still works at the target receptors (would that be possibly for psychedelics, too?)





's


----------



## atara

So this is the least creative molecule ever, but I'm honestly a tad curious as to whether this one was ever characterized. HDMP actually sounded kind of interesting to me.

As an old man with a job, short-acting comfortable-but-not-euphoric stimulants sound perfect lmao


----------



## aspiringdrugdesign




----------



## Pomzazed

atara said:


> So this is the least creative molecule ever, but I'm honestly a tad curious as to whether this one was ever characterized. HDMP actually sounded kind of interesting to me.
> 
> As an old man with a job, short-acting comfortable-but-not-euphoric stimulants sound perfect lmao



Doesnt work like MDMA, still works as pure stimulant and abit stronger than MPH itself, 
methylphenidate doesnt take phenetylamine?s SAR,
It overlays well with cocaine, so use cocaine?s SAR to design on that!


----------



## Hodor

aspiringdrugdesign said:


>



Regarding the molecule on the top left, it's probably not going to be particularly potent. Shulgin made thio-substituted analogues of DOM, and noted that replacing even a single methoxy with a methylthio group decreased their potency by a factor of ~10 if the substitution was at the 5-position ("5-TOM"), and by a factor of ~15 if it was at the 2-position ("2-TOM"). Unsurprisingly, replacing *both* oxygens with sulfur resulted in a compound ("bis-TOM") that produced what might at best have been threshold effects at a dose as high as 160 mg. Compare this to the parent compound, DOM, already producing strong psychedelic effects at 5 mg.

Thus, _bis-thio_-Bromo-DragonFLY would probably require a relatively high dose to be psychoactive, which would likely fail to justify the complex synthesis from a financial standpoint.


----------



## Soulfake

atara said:


> So this is the least creative molecule ever, but I'm honestly a tad curious as to whether this one was ever characterized. HDMP actually sounded kind of interesting to me.
> 
> As an old man with a job, short-acting comfortable-but-not-euphoric stimulants sound perfect lmao




I think I have seen this one somewhere in an phenidate-analogues research paper where the different affinities where listed but I can't find it anymore. But it would be nice to see more analogues without halogens, I know they are not "bad" themself or something like this but somehow I like compounds that look more "natural". I guess it should be certainly active similar to the 3,4-dichloro version but I can't remember the potency and affinities from the paper. It would be really great if there would be a complete website with all the informations about affinities, potency and other structural differences etc. and going a bit more in depth than usual drug-wikis.


----------



## aspiringdrugdesign




----------



## aspiringdrugdesign

Interesting Read:


https://en.wikipedia.org/wiki/Amfonelic_acid 

"In studies it proved to be a potent and highly selective dopamine reuptake inhibitor (DRI) in rat brain preparations.[4][5] A study found a moderately long half-life of approximately 12 hours and a dopaminergic potency approximately 50 fold that of methylphenidate in rat brain preparations.[6] Despite lack of direct serotonin activity, rats treated with subchronic doses of amfonelic acid display subsequent decreases in 5HT and 5HIAA.[7] Amfonelic acid displays no activity in the norepinephrine system.[8]Despite its different mechanism of action, amfonelic acid displays discriminatory substitution with 150% the stimulant potency of dextroamphetamine.[9] Amfonelic acid has been shown to be neuroprotective against methamphetaminedamage to dopamine neurons.[10] It also increases the effects of the antipsychotic drugs haloperidol, trifluoperazine and spiperone.[11] Rats are shown to self-administer amfonelic acid in a dose-dependent manner.[12]
Though AFA was discovered in the course of antibiotic research, there is very little data available on the drug's antimicrobial activity. In 1988 the biologist G.C. Crumplin wrote, "[AFA] is less active against bacteria than are many other 4-quinolones, but studies in our laboratory on selected mammalian cell lines have shown it to be markedly more toxic to these cells than are the 4-quinolones that are more active antibacterial agents. Furthermore, it can be shown that sublethal doses induced marked changes in the pattern of proteins produced by the cell, thus suggesting a possible effect of 4-quinolones on gene transcription in mammalian cells."[13] When evaluated via broth microdilution the MIC of AFA for Escherichia coli is 125 μg/mL, a concentration thirty times higher than the MIC for nalidixic acid in the same E. coli strain.[1]"

Seeing a lot of similarities led me to these ideas:
























Would love insight or some studies to read about either nalidixic acid or amfonelic acid


----------



## Hodor

_More_ toxic than the fluoroquinolones? Ugh.

Fluoroquinoloes are extremely effective at killing bacteria, but nowadays they are no longer a preferred first-line-treatment unless the infection is *really* serious (ex.: pneumonia), due to the chance of suffering rare, but potentially crippling side-effects involving damage to tendons, muscles, cartilage and bones.


----------



## Soulfake

Wasn't amfonelic acid available as a "research chemical" once or am I confusing it with something similar?
--------------------
some random chems





---------------------------------------------------------------------------------------------------edit 20.02





edit: more chems, camfetamine is said to have opioid properties although I still couldn't find that damn paper that explains it's mechanism besides dopamine-induced pain resistance but you can see the similarity to drugs like tilidine, tramadol or pethidine so I drew some molecules with those ester and 3-hydroxy substitutions you can find on many analogues of the named opioids (as well as some nonsense diphenyl-substitutions and cocaine-like stuff along my usual camfetamine/norbornane analogues) The last ones are hypothetical pro-drugs to some phenmetrazine-derivates similar to bupropion's metabolites (if you change the fluoride from the first one with chlorine you get bupropion) although they probably won't be really recreational.


----------



## S.J.B.

Soulfake said:


> Wasn't amfonelic acid available as a "research chemical" once or am I confusing it with something similar?



Yeah, it's definitely been available in the past, not sure about now.


----------



## sekio

"Acetylmethadone"





"Butyrylmethadone"





"Ethadone"





Thiophene analog of methadone. Reminds me of the thiambutenes

Also consider e.g. isomethadone and dipipanone modified as per above... and also, changing the ketone to an alcohol or ester a la LAAM / methadol.





Or even reversed ester... a bit of a kludge but maybe.





there's also the ketone -> sulfone analogs which are known... IC-26





So maybe also...




There's probably a SAR paper on these out there... clubcard?


----------



## MmmLysergamides

"DimethyltryBtamine"
If its even active I wonder how potent it would be because MAO most likely wouldn't be able to metabolize it easily.


----------



## Pomzazed

It seems to autoignite on air exposure like many alkylboranes...

Also, that BR3 is a strong lewis acid, and wont work in the same way as N in tryptamine


----------



## Hodor

MmmLysergamides said:


> If its even active I wonder how potent it would be because MAO most likely wouldn't be able to metabolize it easily.



Boron is less electronegative than even hydrogen. You do not need a catalyst for it to undergo rapid oxidation. In fact, organoboranes tend to spontaneously ignite upon exposure to air, even at temperatures below 0 degrees Celsius.

Boron also lacks a lone pair of electrons, which is likely to render the compound non-psychoactive (unless you consider neuropathic damage to be a form of psychoactivity).


----------



## S.J.B.

MmmLysergamides said:


> "DimethyltryBtamine"
> If its even active I wonder how potent it would be because MAO most likely wouldn't be able to metabolize it easily.



Replacing the boron with a phosphorous would make this more analogous to the parent compound, but even those are highly unstable to oxidation.


----------



## Dresden

I would be highly surprised if Boron substituted for Nitrogen.


----------



## sekio

I've worked with a few boron compounds but never alkylboranes, only borate esters. The borate esters tend to fall apart pretty fast in the presence of water and also burn with a pleasing "Green Goblin" fire. In the end I came to the conclusion that trying to make trimethyl borate from boric oxide and methanol was a fool's errand and that buying it from Aldrich was the way to go.

Alkylboranes tend to burst into flames instead of just depositing a fog of boric acid as alkylborates do. I think triethylborane was actually used to light the special heavy fuel engines on the SR-71 / Oxcart due to its pyrophoricity.


----------



## Hodor

sekio said:
			
		

> Alkylboranes tend to burst into flames instead of just depositing a fog of boric acid as alkylborates do. I think triethylborane was actually used to light the special heavy fuel engines on the SR-71 / Oxcart due to its pyrophoricity.



Yep. The SR-71 had very special requirements when it came to its jet fuel. As with the fuel utilized by its predecessor, the U-2 spy plane, the SR-71's JP-7 propellant was designed to withstand high-altitude flight without freezing from the cold or evaporating from the low air pressures; however, the SR-71's vastly greater speed also produced massive amounts of heat due to air friction, making fuel volatility even more of a critical concern.

While the JP-7 fuel was able to meet Lockheed-Martin's requirements, it had a very high flash point, meaning that starting the SR-71's engines and afterburners required triethylborane to ensure a reliable ignition.
Missions thus had to be planned not just around aerial refuels of the actual JP-7 propellant, but also around conserving the triethylborane igniter.


----------



## sekio

Cyclic analogs of propoxyphene / methadone as substituted pethidine / ketobemidone / prodine analogs









US4219652A compounds, opioid analgesics













Related





9,10-seco-oxymorphone


----------



## Soulfake

@ekio the ones from the third one are looking a bit similar to mesembrine, mesembrenone and similar alkaloids from kanna, I guess they could have serotonergic activity? 

---
some (very) random chems: (It would be great to have a computer program that could analyse the structure to give you all the infos like possible binding sites, probable hydrolysis-parts, most similar known molecules etc. I use Marvin Sketch from ChemAxon (it's a free and really good software) but it can only give very general analysis data like melting point, elemental mass etc.)


----------



## Hodor

Please, fix your nitro groups 
Nitro groups have the nitrogen accept a positive charge, with a double bond to one oxygen, and a single bond to the other oxygen, which carries a negative charge. That way, all of the atoms achieve a full octet of electrons in their valence shell. There are no protons in nitro groups, neither on the oxygen nor on the nitrogen.

Also, you generally wouldn't want to put that many electron-withdrawing groups on a single carbon, as these tend to readily hydrolyze in acidic conditions.


----------



## Gaffy

For the pollinators:


----------



## polymath

^ Wouldn't that (the compound above) be hydrolyzed immediately like most acid anhydrides?


----------



## Gaffy

Most probably if you say so.. Again I'm not a Chemistry Genius


----------



## sekio

yes, it'd quickly hydrolize to the "pethidinic acid" equivalent + acetic acid and would therefore be inactive, better to leave it as an ester or ketone than make it an acid anhydride...





eseroline, metabolite of physostygmine, is apparently an opioid agonist but is also neurotoxic at uM levels. (apparently) ... i hypothesize that if the Ki for interaction at the opioid receptors is in the nM range that it would still be an interesting cmpd to try once or twice


----------



## polymath

Quite interesting, as it would be easy to make by hydrolyzing the physostigmine extracted from the seeds of the plant that produces it. Probably would be best to dose it with some atropine or scopolamine to prevent cholinergic side effects.


----------



## Hodor

polymath said:


> ^ Wouldn't that (the compound above) be hydrolyzed immediately like most acid anhydrides?



Not only that, but it would basically be impossible to make, since any attempt at acetylating the carboxyl group (to make the anhydride) would first acetylate the phenolic OH group.
Sure, you could try using a protecting group on the phenol to protect it during the acetylation step, but how are you going to remove that protecting group without also cleaving the anhydride?


----------



## sekio

from US20050154002A1, carbonate ester prodrug of 3-Ac-dihydromorphine

Apparently this is suitable for _transdermal_ applications!


----------



## S.J.B.

sekio said:


> from US20050154002A1, carbonate ester prodrug of 3-Ac-dihydromorphine



This brings up an interesting legal question: is the dimer of a compound an analogue of it?  That would be an interesting case to see!


----------



## sekio

I would think it is, but that's just me. Especially because you'd expect to see it hydrolyse fairky easily to the parent cmpd.


----------



## Hodor

S.J.B. said:


> This brings up an interesting legal question: is the dimer of a compound an analogue of it?  That would be an interesting case to see!



The UN Single Convention on Narcotic Drugs specifically mentions that the various isomers, salts, ethers and esters of schedule I drugs are to be put in the same schedule by default, unless specified otherwise (ex.: DXM is a stereoisomer and ether of the potent opioid levorphanol, but is specifically excluded from schedule I due to the lack of opioid activity).

When national governments and international regulatory bodies around the world were passing laws regulating the sale of heroin, some of the companies producing it were quick to switch to other morphine esters, such as benzoylmorphine or propionylmorphine. In 1929, German pharm companies were reported to be converting around 19 tons of morphine into then-uncontrolled esters and ethers of morphine. After Germany passed ze _Opiumgesetz,_ that amount dropped to just ~4 tons within two years, most of which was codeine and its homologue ethylmorphine, representing the actual medicinal demand for these substances.

Sekio's dimer is really just a fancy ester (_3'-acetyldihydromorphinylcarbonyl-3-acetyldihydromorphinate_?), if you think about it, and as such it would probably be subject to UN regulations, not to mention various blanket bans, analogue acts and opium laws at the national level.


----------



## sekio

Technically speaking, it's an ester of carbonic acid. I'd call it bis(3-acetyldihydromorphinyl)carbonate.

I wonder if malonic, succinic, glutaric, adipic acid or others would work too. Terephthalic acid? Fumaric/maleic acid?


----------



## Gaffy




----------



## Soulfake

Can anyone explain where the difference between a pentyl-chain like usually found in cannabinoids and a pentene-yl chain like you can find in some of today's overly potent cannabinoids (thanks governments for "protecting" people so well through laws...). I know that some metabolites of many cannas like JWH122-pentenyl exist but if they can be effective (like that overly potent one 5-CL-ADB-A)  why aren't they more widely used? Seems like a simple change in chemistry design. (For example there is a pentene-yl chain on the third cannbinoid above the bottom left one)


----------



## sekio

(+-)-HBMP resorcylate, formerly called (+-)-RTI-4793-14, ligand for "PCP site 2" & monoamine uptake inhibitor



> Can anyone explain where the difference between a pentyl-chain like usually found in cannabinoids and a pentene-yl chain like you can find in some of today's overly potent cannabinoids


simply put, the pentenyl chain 'looks' a lot like the pentyl chain, and is still nonreactive enough that it doesn't mess with the drug's binding or half life by too much.


----------



## Hodor

Soulfake said:


> why aren't they more widely used? Seems like a simple change in chemistry design. (For example there is a pentene-yl chain on the third cannbinoid above the bottom left one)



While alkanes are based on a tetrahedral geometry (as in: if your carbon atom is in the center of a tetrahedron, then the 4 atoms it is bonded to are located in the corners), alkenes have a planar (i.e. flat) geometry.
Additionally, there is little to impede the rotation of a single bond, whereas the double bond of an alkene is much stiffer.

This means that the actual 3-dimensional structure of the molecule, and thus the way it interacts with receptors, can be slightly different.

However, the problem with alkenes is that these "unsaturated" hydrocarbons are _generally_ more reactive than their saturated cousins. For example, exposure to acids like HCl can result in hydrohalogenations (turning the alkene into a saturated haloalkane); exposure to Br2 or Cl2 will turn them into alkanes substituted with two halogens; oxidants can cause the alkene to be converted into a highly reactive epoxide, or to be cleaved apart.

This can sometimes complicate the synthesis of a compound, or result in poor storage-lives or biological half-lives, and possibly even lead to the formation of toxic metabolites.


----------



## Hodor

Hodor said:


> For example, exposure to acids like HCl can result in hydrohalogenations (turning the alkene into a saturated haloalkane)



Actually, looking at the structures of 5-Cl-ADB-A and comparing it to that of regular 5-Cl-ADB, it looks like what they did was the opposite of the reaction mentioned above: They first made the compound with a chloropentyl chain on it, then treated it with a very strong base in order to achieve a _dehydrohalogenation_, i.e. the removal of HX (X = any halogen) from a haloalkane to turn it into an alkene.

Still, even if you only did it at the very end, that's an extra reaction step compared to regular 5-Cl-ADB... and there's always the risk of side-reactions (although these can usually be minimized by using a very bulky base that can attack the protons on the exposed alkyl chain of the molecule, but not the carbonyls of the ester and amide groups).


----------



## sekio

most hydrohalogenations need to be run with anhydrous HCl to be effective as the covalent species H-Cl is not present in a high enough concentration in aqueous solutions (being a strong acid, it dissociates completely to H₃O+ and Cl-)

alkenes are actually pretty unreactive, save for some exotic conditions (MnO4-, OsO4, dihalogens, Hg2+, ozone, Pd/O2 (wacker))


----------



## Dresden

For computational chemistry and x-ray crystallography, ball and stick figures may be necessary; but, for the organic chemist, Kekule structures are *the* Au standard.


----------



## blueberries

I call this one DOP!
Nothing to do with opiates but it could use a little work with nomenclature!



Pete556 said:


> I prefer the 3D versions thats what they actually look like after all
> 
> View attachment 11372


No offence but I can hardly understand what's going on here, could you make this a flat drawing so I can figure it out?!
PS: I realise that some habits can't be helped but I really wouldn't mind finding out the structure!


----------



## Gaffy

With DMT being investigated to suppress "voices" in Skizo patients and H1 being a general antipsychotic, maybe these could be antidepressive antipsychotics, give me a try I'd say!  with chlorphenamine being well supported as a downer (sold with Ephedrine in France), it's widely used as a somniferum.








Would mixing and heating too much methanol with tyrosine make 4-methoxy Methoxyphenylalanine? Tyrosine on itsef is a bit boring.


----------



## atara

Have been away. Was wondering if this one ever popped up on the scene?






I think it's got a better chance of being a triple inhibitor than the methylenedioxy version (cf. analogy naphyrone:HDMP-28::MDPV:methylenedioxymethylphenidate)

blueberries: you get no points if you draw a triple-bonded phosphorus


----------



## Gaffy

Oxazolino-Amphetamines, what else?


----------



## JacksinPA

*BUNODOSINE 391

Isolated from a sea anemone, this N-acylamino acid is a potent analgesic. Its effects are not reversed by naloxone but are reversed by serotonin receptor antagonists. Interesting lead for discovery work in the area of non-opioid analgesics. It would be interesting to evaluate the effects of different substituents on the indole & histidine nuclei. The occurence of this molecule in such an early life form may indicate a basic evolutionary role in nerve function.

It is interesting to note that 5-brominated tryptophan residues are found in so-called 'sleep peptides' produced by some cone snail species. These are 'post-translational' enzymatic modifications of the tryptophan residues in these peptides, the enzyme involved being a bromoperoxidase & the reaction mechanism being free-radical in nature. The key raw material is bromide ion, which is abundant in seawater.*


----------



## Gaffy

Psychedelic Innovation


----------



## Dresden

What does ethylamphetamine feel like in comparison to amphetamine or methamphetamine?  Dosage?  Duration?  Any 5-HT2a agonism?






2-ethylamino-1-phenylpropane
N-ethyl-amphetanine
Ethylamphetamine
ETH


----------



## Gaffy

Ephylone compared to Pentylone is miles away, in a good way.

New atypical antipsychotic






And to make the treated patient's life easier, some undead cathinones, because yes, being on stims and antipsychoticum at the same time is just better.
And if China keeps banning chems one by one every two years, I might live to see my little babys.
(I'd personnaly choose the 4-MethoxyHexen over the 4-MEE-CATH). 2F-EPD is for studying or everyday adderall replacement.






And for the 3-FPM lovers:
2-(3-fluorophenyl)-3-ethylmorpholine AKA 3-FPE
3-ethyl-2-phenylmorpholine AKA PE
3-ethyl-2-(3'-4'-Furan-4"-yl)-phenylmorpholine AKA FUPE







God do I want to try my chems.

FUPE's IUPAC might be wrong.

Morpheus






I'm so good a this

FUFUF:


----------



## polymath

^ Has anyone ever tested compounds where the n-phenethyl of fentanyl is replaced with n-methyl, or where the n-methyl of meperidine is replaced with n-phenethyl (or n-phenylisopropyl) group ?


----------



## Hodor

polymath said:


> ^ Has anyone ever tested compounds where the n-phenethyl of fentanyl is replaced with n-methyl, or where the n-methyl of meperidine is replaced with n-phenethyl (or n-phenylisopropyl) group ?



They actually did do that with carfentanil.




_N-methyl-N-nor_-carfentanil is roughly as potent as morphine. Considering that carfentanil is several thousand times the potency of morphine, this does not suggest that doing this to regular fentanyl (which is, after all, approximately 1% as potent as carfentanil) would result in a particularly impressive compound.

The _N-phenethyl,N-nor-_analogue of meperidine was also made... well, almost: PEPAP (*P*hen*E*thyl*P*henyl*A*cetoxy*P*iperidine) also shortens the propionyloxy group to an acetoxy; at any rate, it is roughly 6-7 times as potent as morphine.


----------



## Gaffy

Safety Reason. But here's the Dangerous one, FLUFUFUFUFENT, AKA 5F, a piece of masterpork (yes you read that right).






I'd love a virtual reality where my brain would be remade molecule by molecule, in which every one of my drugs could be tested in the virtual brain. It will be a virtual Nirvana to it, yet feel so really unreal because it's so good.

I'm betting this could be a game in 30-40 years. Create the most pleasured brain. (Music sounds and body "ressentis" will of course be a big part of it")

In some words, life.
This should've been my 100st post.


----------



## Hodor

Minor correction to my post above: I just realized I was confusing the structure of meperidine with that of MPPP.
Meperidine does not contain a propionyloxy group; it contains an ethyl carboxylate group, of which PEPAP's acetoxy group is the reverse ester.


----------



## polymath

Someone should definitely put a n-phenethyl on:

-methadone
-dextropropoxyphene
-tramadol
-eseroline

and so on...


----------



## Gaffy

Stronger isn't per see more pleasurable. The strongest DRI like tryptamime with phenylpiperazine at the N moiety isn't pleasurable afaik


----------



## Dresden

1-carbomethoxy-1-phenyl-2-(1-pyrrolidinyl)pentane

_because I'm bored_


----------



## Gaffy

There's a website where you can just throw a chem at it and it gives you an idea about the SAR activity; it's called swiss target prediction, I asked for Something like it some while ago, I think I'm going to post a thread with some of my bestest chems and a link to their SAR. Anyway more seriously, carfentanyl SARs http://www.swisstargetprediction.ch/result.php?job=1777385148&organism=Homo_sapiens 
compared to: http://www.swisstargetprediction.ch/result.php?job=1428025724&organism=Homo_sapiens and http://www.swisstargetprediction.ch/result.php?job=1558530886&organism=Homo_sapiens that is stronger than carfent (!)


----------



## Gaffy

Here I'll be posting my best inventions, selected for their binding profiles.

It'll take some time to finish this thread (if I ever do as I've litterally thousands of chemicals to sort out and run through, and test with the SAR machine), but I'll post what I think deserves to be posted.

We'll start with Ketamine and Ephenidine analogs I've invented, and switch to BTCP analogs which will permit us to switch to DRIs: (And from there it'll be pretty random, as I can't classify all my compounds)
Ketamine
PCP
Ephenidine


Seven ringed Ketamine,
CycloHeptylKetamine : C1(C(CCCCC1)=O)(C2=CC=CC=C2)N(C)[H]






Seven ringed Methoxetamine,
CycloHeptylMethoxetamine: C1C(C(CCCC1)(C2=CC=CC(=C2)OC)NCC)=O






Adding a benzene group to the cycloheptyl:
3-MeO-PCPy with a PhenylCycloHEptyl ring: C1CC(CCC2=C1C=CC=C2)(C3=CC=CC(=C3)OC)N4CCCC4






a little extra


(With very interesting SARs)
MorphoKetamine: ClC1=C(C=CC=C1)C1NCCOC1C1=CC=CC=C1







PCP with a N-PhenylPiperazine
PCPP:  C1=CC=C(C=C1)N2CCN(CC2)C3(CCCCC3)C4=CC=CC=C4






BTCPP, BTCP with a phenylpiperazine
BTCPP: C1=CC=C(C=C1)N2CCN(CC2)C3(CCCCC3)C5=CC4=CC=CC=C4S5






Three analogs between Ephenidine and BTCP:

BTPhenEthylPiperidine : C(C(N1CCCCC1)C1=CC2=C(S1)C=CC=C2)C1=CC=CC=C1







BTPhenEthylPyrrolidine: C12=C(C=CC=C1)SC(=C2)C(CC3=CC=CC=C3)N4CCCC4






BTBKPhenEthylEthylamine: C12=C(C=CC=C1)SC(=C2)C(C(C3=CC=CC=C3)=O)N(CC)[H]






The morpholine analog of ketamine applied to BTCP:
MorphoBTCE: C1COC(C(N1)C1=CC2=C(S1)C=CC=C2)C1=CC=CC=C1






Mono-methylated alpha-phenylated tryptamine, a SNDRI that stands out:
N-Methyl-Alpha-Phenyl-Tryptamine: C1=CC=CC2=C1C(=C[N]2)CC(C3=CC=CC=C3)NC






Its N-Pyrrolidino analog

5-MeO-AMT
C1(=CC=C2C(=C1)C(=C[N]2)CC(N([H])[H])C)O






*Cocaïne analogs: probably my best inven**tions*

I Don't know what to call these, but they're wonderously promising
COC(=O)C(CC1=CC=CC=C1)C1CCCN1







The N-Methyl, even more promising
C1(=CC=CC=C1)CC(C(=O)OC)C2CCCN2C






The local anaesthetic version, it's got high HERG activity:
C1=CC=CC=C1C(OCC(C(OC)=O)C2CCCN2[H])=O






The N-Methyl version, with even more HERG activity, which makes it cardiotoxic
COC(=O)C(COC(=O)C1=CC=CC=C1)C1CCCN1C






An outstanding one,both SNDRI and MOR (!)






N'-N-Methyl version

2-FA Light
C1(=CC=CC=C1OC2CCN(CC2)[H])F






4-MethylMethylphenidate N-pyrrolidine analog
C1=CC=CC=C1C(C(N2CCCC2)=O)C3CCCCN3[H]







PVP Methylphenidate: Surprisingly good
C1=CC=CC=C1C(C2CCCC3CCCN23)C(OC)=O






N-pyrrolidino Version


3-MeO-PhenEtrazine
C1=C(C=CC=C1C2C(CC)N(CCO2)[H])OC







CyclopentylEthylCathinone
CCNC(C1CCCC1)C(=O)C1=CC=CC=C1






Two Ketobemidone variants, go guess how I guessed 

BTKETO1
C1=CC=C2C(=C1)C=C(S2)C3(CCN(CC3)C)CN4CCCC4






BTKETO2
C1=CC=C2C(=C1)C=C(S2)C3(CCN(CC3)C)C(N4CCCC4)=O







Should be opioïd, is Dopaminergic and Opioïd sigma active:
C2(CC(CC1=CC=CC=C1)N(CC2)[H])(C(=O)CC)C3=CC=CC=C3






Ketobemidone analog:
C1(C(CN(CC1)C)=O)(C(=O)CC)C2=CC(=CC=C2)O[H]







Chlorphenamine derived Antihistaminergic Psychedelics, or chillaxed tripping!

5-Meo one
C1=C(C=CC2=C1C(=C3C=CC=C[N]23)CCN(C)C)O







Chlorphenamine inspired
C1=CC(=CC2=C1C(=C3C=CC=C[N]23)CCN(C)C)Cl






5-Meo DIPT one
C1=C(C=CC2=C1C(=C3C=CC=C[N]23)CCN(CC=C)CC=C)OC







Now let's switch to killer opioïds, Fentanyl analogs and some others:

Cyclic R-30490
C1(=CC=CC=C1)CCC2CCC3(CC2)COCC(N3C4=CC=CC=C4)=O







Its (probably) more potent analog, 2'-Fluoro-3-Methyl-Cyclic R-30490
C1(=CC=CC=C1)CCN2CC(C4(CC2)N(C3=C(C=CC=C3)F)C(COC4)=O)C







My FuranylFentanyl
C1(=CC=CC=C1)CCN2CCC(CC2)(C3=CC=CO3)N(C4=CC=CC=C4)C(CC)=O






Non-Brominated Cyclic BDPC
C1=CC=C(C=C1)C2(CCC3(CC2)OCCC(C3)C4=CC=CC=C4)N(C)C






Fentanyl with the phenethyl displaced
C2(CC(CC1=CC=CC=C1)N(CC2)[H])N(C(CC)=O)C3=CC=CC=C3







And an already seen one, but it has its place here:
An outstanding one,both SNDRI and MOR (!)






Some weird cannabinoïd, related to JWH-018
C1=CC=CC2=C1C(=C[N]2CC3CCCCC3)C(=O)CC4=CC=CC=C4






What do I call this:
C1=CC=CC2=C1C(=C[N]2CC3CCCCC3)C(=O)C5C4CCCCC4CCC5








For more fun, go see ILTDPORM or Dresden's thread.

From here on the thread is dedicated to chems that aren't of my invention, mine are above ^.

Some of polymath's inventions:

N-PE-Nor-MEthadone

Polymath's Funny little beast, Fenmyrtin:
[C@H]1(CC(CC2CCCCN12)(C3=CC=CC=C3)O[H])C






S.J.B.'s constitutional isomer of BZP
C1=CC=CC=C1CC2CN(CCN2[H])[H]






Dresden's Carbomethoxy PVP:
C1=CC=CC=C1C(C(CCC)N2CCCC2)C(=O)OC






Sekio's Oxazolino Carfentanyl
C1(CCN(CC1)CCC2=CC=CC=C2)(C3=NCCO3)N(C4=CC=CC=C4)C(CC)=O


----------



## polymath

Here's my N-phenethyl-nortramadol submitted there...






						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				




and here is the N-phenethyl-nor-eseroline with the 2-phenylethyl put on the nitrogen that is a longer distance away from the aromatic ring...






						SwissTargetPrediction
					






					www.swisstargetprediction.ch


----------



## Gaffy

Very nice! Go take a look at my morpho Ketamine BTCE dérivatives (My new thread), they've got promising SARs as well


----------



## polymath

^ It must have been a bit of work drawing all of those and making predictions...

I tried to put a non-amine version of methylphenidate, with a sulfur atom in place of nitrogen, in the Swiss target prediction app as an input (the oxygen version is known to be a likely DAT ligand). Didn't get a very high likelihood of binding to dopamine transporter. But when checking the list of similar structures it identified that with, I saw this crazy biphenyl compound that is known to inhibit both dopamine and serotonin uptake:









						Compound: CHEMBL101986
					

Molecule Type: Small molecule, Molecular Formula: C14H11ClO2, Molecular Weight: 246.69




					www.ebi.ac.uk
				




probably the strangest stimulant candidate I've seen...


----------



## Gaffy

Mixing Tryptamines and Dissos

5-Meo-α-3-MeoPhenyl-DIPT: C1=CC=C(C=C1OC)C(CC2=C[N]C3=C2C=C(C=C3)OC)N(CC=C)CC=C






Mono-methylated alpha-phenylated tryptamine, a SNDRI that stands out:
N-Methyl-Alpha-Phenyl-Tryptamine: C1=CC=CC2=C1C(=C[N]2)CC(C3=CC=CC=C3)NC





And to reply to your Tramadol PolyMath, here's my little baby, a cocaine analog that's SNDRI and MOR(!) Perfect if you ask me.


----------



## polymath

For some reason, it thinks my N-phenethyl-normethadone can also be a cannabinoid agonist in addition to being an opioid...



			SwissTargetPrediction
		


And here's a non-amine version of desoxypipradrol, which I mentioned here as an idea some months ago.






						SwissTargetPrediction
					






					www.swisstargetprediction.ch


----------



## polymath

A final one for today:

I also mentioned the alkaloid epimyrtine, found in blueberries, some time about half a year ago...






With its 4-piperidone structure, it could obviously be a precursor for an MPPP like drug. Putting that MPPP-like structure in the Swiss Target Prediction app didn't predict high mu affinity. but some DAT and SERT binding instead.

Leaving the propionyl ester away from that MPPP like compound gave this, where the predicted DAT binding probability is well over halfway the scale (!).






						SwissTargetPrediction
					






					www.swisstargetprediction.ch


----------



## Gaffy

Can I add it to the Gaffy's Analog act? I'll clarify it isn't my invention.


----------



## polymath

Sure...

Let's call it "fenmyrtin".

Edit: Replacing the phenyl group in that compound with a 3,4-dichlorophenyl doesn't increase its likelihood of being a dopamine reuptake inhibitor, but it does make it less likely to have a cholinergic effect...





__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch


----------



## garym

the knowledge that people have of chemistry on here absolutley blows my brain. i'm a simple junkie from the uk that doesn't have much of a clue about these matters. i take heroin and crack cos i like it (both) and wouldnt in a million years know the chemical composition of either crack or gear. kudos to those that do though.


----------



## Gaffy

Some weird cannabinoïd, related to JWH-018
C1=CC=CC2=C1C(=C[N]2CC3CCCCC3)C(=O)CC4=CC=CC=C4






What do I call this:
C1=CC=CC2=C1C(=C[N]2CC3CCCCC3)C(=O)C5C4CCCCC4CCC5






Doesn't seem to maintain CB acivity, but has an interesting profile:

Already posted but it's profile was unknown, really promising! 
5-Meo DIPT one
C1=C(C=CC2=C1C(=C3C=CC=C[N]23)CCN(CC=C)CC=C)OC


----------



## polymath

There's also this compound lupinine, which is quite similar to epimyrtine:









						Lupinine - Wikipedia
					






					en.wikipedia.org
				








Making same kind of changes (doable by oxidation, phenyl grignard) to it as I did with epimyrtine, produces these two compounds that are likely to be serotonin or dopamine reuptake inhibitors:





__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				








__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				




 

I don't know about the rest of the world, but those lupin plants grow everywhere around here... The lupinine itself is a mild cholinesterase inhibitor, could it possibly have a nootropic effect?

Edit: Also check out the benzoate ester of lupinine. Note the 3 carbon distance between the ester oxygen and the amine nitrogen, just like in cocaine...





__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch


----------



## Gaffy

5-MeO-aMT
And yes it does have similaritys with my cocaine derivative, funny ^^


----------



## polymath

It felt a bit unrealistic that it is this easy to draw molecules with a high probability of DA reuptake inhibition... However, even cocaine itself retains some activity after removal of the carbomethoxy group, but none if the benzoate is missing, so it may not be unrealistic that this bicyclic amine would also become a stimulant when esterified with benzoic acid.

I read the peer reviewed article about the STP application, but didn't completely get whether it actually tries to superimpose the functional groups of the estimated 3D structure on the structures of known ligands, or just checks whether the 2D version can be converted to a known ligand by addition/removal of carbons somewhere in the molecule.

Edit: Putting an amino group with N-phenyl and N-propionyl on epimyrtine did produce something with a chance of being mu agonist...





__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch


----------



## Gaffy

So many chemicals, yet so little research or availability


----------



## polymath

^ You could probably get more reliable data by doing an actual molecular docking simulation... I'm not sure whether anyone here does drug design as a profession.

Here is a lupinine version of methylphenidate:





__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch


----------



## Gaffy

Did you see my PVP version of méthylphénidate in Gaffy's Analog Act? It's very similar to your molecule and has a great profile as well.


----------



## polymath

Gaffy said:


> Did you see my PVP version of méthylphénidate in Gaffy's Analog Act? It's very similar to your molecule and has a great profile as well.



Yeah, a similar fused ring structure...

I noticed that it's possible to copy and paste images from STP to these forum posts (at least on my Linux browser), and added some to my earlier posts.


----------



## Gaffy

N-Pyrrolidino-LSD : CN1CC(C=C2C1CC1=CNC3=CC=CC2=C13)C(=O)N1CCCC1

Go check out my new synth; Never seen before route to (MD)MethAMPH


----------



## polymath

A strange possible 5-HT2A agonist





__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				






The STP algorithm sees similarity to the compounds in this publication, most of which are 5-HT6 ligands but some also 5-HT2A.









						Structure–activity relationship of 5-chloro-2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole analogues as 5-HT6 receptor agonists
					

To further investigate the structure–activity relationship (SAR) of the 5-hydroxytryptamine type 6 (5-HT6) receptor agonist 5-chloro-2-methyl-3-(1,2,3…




					www.sciencedirect.com
				




Edit: And, the SwissTargetPrediction wants to draw the dextromethorphan molecule in a really annoying way, but here's DXM with two chlorine atoms (usually 3,4-dichloro increases DAT affinity) instead of methoxy group on the aromatic ring...





__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch


----------



## MmmLysergamides

A candidate for a psychedelic/entactogen. It's reported to be a possible 5HT2A agonist and a Dopamine re-uptake inhibitor.

SwissTargetPrediction


----------



## Nicomorphinist

This is a complete shot in the dark, of course, but what I have wondered for a long time, based on the example of 2,4-dinitrophenylmorphine, where a metabolic and respiratory stimulant was glued on to morphine in Vienna in 1931 in the search for narcotics with less impact on vital signs (the same search that gave us the divine Scophedal), is there the possibility of sticking an orphenadrine molecule to morphine like that to get a stronger narcotic with built-in potentiation and anti-spasmodic and quasi-Nsaid effects without the bleeding stomach?  Or naproxen or nefopam for that matter?

A drug I have heard a lot about and took a long time ago was Codeonal, which is codeine diallylethylbarbitone I think it is, it is a molecular level combination of codeine and the barbiturate Dial and was introduced in 1912 for pain with insomnia -- I've never seen the structural formula for the drug, though.


----------



## S.J.B.

Nicomorphinist said:


> A drug I have heard a lot about and took a long time ago was Codeonal, which is codeine diallylethylbarbitone I think it is, it is a molecular level combination of codeine and the barbiturate Dial and was introduced in 1912 for pain with insomnia -- I've never seen the structural formula for the drug, though.


From the (translated) abstract of the article "Codeonal, a Narcotic and Hypnotic" from Berliner Klinische Wochenschrift (1913), volume 49, pages 260-261:


> Codeine will react with diethylbarbituric acid to form a crystallizable salt containing 63% codeine and 37% diethylbarbituric acid.  This compd., however, is impracticable in the production of narcosis or hypnosis because of the large codeine content. To overcome this difficulty, a mixt. consisting of I part codeine diethylbarbiturate and 5 parts Na diethylbarbiturate was used.  The com. codeonal consists of 11.76% codeine diethylbarbiturate and 88.24% Na diethylbarbiturate. This is made up into tablets each containing 0.02 g. codeine diethylbarbiturate and 0.15 g. Na diethylbarbiturate.


Diethylbarbiturate is also known as barbital or barbitone.


----------



## Nicomorphinist

S.J.B. said:


> From the (translated) abstract of the article "Codeonal, a Narcotic and Hypnotic" from Berliner Klinische Wochenschrift (1913), volume 49, pages 260-261:
> 
> Diethylbarbiturate is also known as barbital or barbitone.


There that article is -- that makes more sense; I think the other three codeine barbiturates were invented in the 1930s.  Barbital is also used by dragon chasers, sometimes with caffeine as well, to modify the melting point of heroin, and opium ash-aspirin-barbital is a classic morning tea recipe for opium smokers . . .

_Phantastica _by Dr Louis Lewin, often called the father of toxicology,  has a really good lowdown on the medicinal and unsupervised drugs scenes in 1920s Europe and elsewhere in the world, including some very early data on peyote, and it mentions other gnarly things like Trivalin, which was morphine valerate, cocaine valerate, and caffeine valerate mixed in  a tablet.


----------



## S.J.B.

Nicomorphinist said:


> _Phantastica _by Dr Lewis Lewin has a really good lowdown on the medicinal and unsupervised drugs scenes in 1920s Europe and elsewhere in the world, including some very early data on peyote, and it mentions other gnarly things like Trivalin, which was morphine valerate, cocaine valerate, and caffeine valerate mixed in a tablet.


Thanks, I will have to check that one out.


----------



## MmmLysergamides

Here's a dump of some random compounds and their activity predicted by SwissTargetPrediction



*2-{5,10-dioxatricyclo[7.3.0.0²,⁶]dodeca-1,6,8-trien-7-yl}ethanamine*












*(2-{1-azatricyclo[6.3.1.0⁴,¹²]dodeca-2,4,6,8(12)-tetraen-3-yl}ethyl)dimethylamine*












*5-Methyl-LSD












Lysergic Acid Ethylbutyraldehyde












4-Fluoro-DMT












17-azatetracyclo[7.7.1.0²,⁷.0¹⁰,¹⁵]heptadeca-2,4,6,10(15),11,13-hexaene












β-Cyclopropyl-Phenethylamine 












β-Cyclobutyl-Phenethylamine 












2,4-Dimethyl-3-phenylpyrrolidine 












1-Benzyl-1-methyl-propylamine 









*


----------



## polymath

The simple compound N,N-dimethyl-3-phenyl-1-aminopropane (probably not the correct IUPAC name) also is predicted to have affinity to both 5-HT2A and DAT...





__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				






It's a bit difficult to believe that no one has bioassayed this before, though. It has quite obvious similarities to methadone and dextropropoxyphene.


----------



## polymath

Also, a mixed halogen version of chloral hydrate...



or nitrogen mustard...


----------



## JacksinPA

polymath said:


> Also, a mixed halogen version of chloral hydrate...
> 
> View attachment 13619
> 
> or nitrogen mustard...
> 
> View attachment 13620


Stay away from any of the 'mustards.' They are potent alkylating agents: https://www.ncbi.nlm.nih.gov/pubmed/30834842 used as cancer chemotherapeutic agents.

*Nitrogen Mustards as Alkylating Agents: A Review on Chemistry, Mechanism of Action and Current USFDA Status of Drugs*


----------



## polymath

It wasn't meant as a recreational drug, I just thought that some mixed halogen version of it could have a better selective toxicity for cancer cells vs normal ones...


----------



## Nicomorphinist

allopseudocodeine


----------



## JacksinPA

polymath said:


> It wasn't meant as a recreational drug, I just thought that some mixed halogen version of it could have a better selective toxicity for cancer cells vs normal ones...


Can't tell from your OP.


----------



## sekio

Nitrogen mustards with 'bigger' halogen/pseudohalogen groups are even more unstable and reactive (i.e. I > Br > Cl >>> F for leaving group strength). I would be suprised if you could isolate some _alpha_-amino-_omega_-haloalkanes other than chloro cmpds... even then IIRC the tertiary "pseudo-mustard" 2-dimethylamino-1-chloropropane (used in methadone chemistry) has to be shipped and handled as the HCl salt because the freebase -N(Me)2 group wants to quaternize to an aziridine chloride badly.

Now make it go to a 5/6 member ring and change Cl to I or OTf/OTs... watch those piperidiniums pop out...


on a different tip, someone should give some bored grad students a half kilo of lysergic acid and a $50,000 merck millipore gift card and have them (after getting suitably goggle eyed on homemade LSD of course) throw a bunch of fluorination reagents at the ergoline structure. Would be neat to see, e.g. 2-fluoro-LSD, 5-fluoro-LSD, etc.


----------



## blueberries

Erm...Am I right in thinking this compound would be absolutely beautiful or not?!

I looked it up on SwissTargetPractice though and got these results:



Serotonin transporter _ (by homology) _SLC6A4​P31645​CHEMBL228​Electrochemical transporter​0.100578902067


490 / 0   

​Dopamine D2 receptorDRD2​P14416​CHEMBL217​Family A G protein-coupled receptor​0.100578902067


440 / 0   

​Norepinephrine transporterSLC6A2​P23975​CHEMBL222​Electrochemical transporter​0.100578902067


352 / 0   

​Dipeptidyl peptidase IIDPP7​Q9UHL4​CHEMBL3976​Protease​0.100578902067


53 / 0   

​Nitric-oxide synthase, brainNOS1​P29475​CHEMBL3568​Enzyme​0.100578902067


15 / 0   

​Nitric oxide synthase, inducibleNOS2​P35228​CHEMBL4481​Enzyme​0.100578902067


18 / 0   

​Nitric-oxide synthase, endothelialNOS3​P29474​CHEMBL4803​Enzyme​0.100578902067


10 / 0   

​Serotonin 2a (5-HT2a) receptor _ (by homology) _HTR2A​P28223​CHEMBL224​Family A G protein-coupled receptor​0.100578902067


163 / 0   

​Neuronal acetylcholine receptor subunit alpha-3CHRNA3​P32297​CHEMBL3068​Ligand-gated ion channel​0.100578902067


3 / 0   

​Serotonin 1d (5-HT1d) receptorHTR1D​P28221​CHEMBL1983​Family A G protein-coupled receptor​0.0


37 / 0   

​Serotonin 2b (5-HT2b) receptorHTR2B​P41595​CHEMBL1833​Family A G protein-coupled receptor​0.0


97 / 0   

​Serotonin 2c (5-HT2c) receptorHTR2C​P28335​CHEMBL225​Family A G protein-coupled receptor​0.0


130 / 0   

​Kappa Opioid receptor _ (by homology) _OPRK1​P41145​CHEMBL237​Family A G protein-coupled receptor​0.0


230 / 0   

​Dipeptidyl peptidase VIIIDPP8​Q6V1X1​CHEMBL4657​Protease​0.0


48 / 0   

​HERGKCNH2​Q12809​CHEMBL240​Voltage-gated ion channel​0.0


45 / 0   

​Dipeptidyl peptidase IXDPP9​Q86TI2​CHEMBL4793​Protease​0.0


36 / 0   

​Serotonin 3a (5-HT3a) receptorHTR3A​P46098​CHEMBL1899​Ligand-gated ion channel​0.0


20 / 0   

​Neuronal acetylcholine receptor; alpha3/beta2CHRNA3 CHRNB2​P32297 P17787​CHEMBL2109234​Ligand-gated ion channel​0.0


3 / 0   

​Cytochrome P450 2C19CYP2C19​P33261​CHEMBL3622​Cytochrome P450​0.0


1 / 0   

​Neurokinin 1 receptorTACR1​P25103​CHEMBL249​Family A G protein-coupled receptor​0.0


23 / 0   

​ThrombinF2​P00734​CHEMBL204​Protease​0.0


16 / 0   

​Monoamine oxidase BMAOB​P27338​CHEMBL2039​Oxidoreductase​0.0


20 / 0   

​Serotonin 1a (5-HT1a) receptorHTR1A​P08908​CHEMBL214​Family A G protein-coupled receptor​0.0


155 / 0   

​Lysine-specific histone demethylase 1KDM1A​O60341​CHEMBL6136​Eraser​0.0


42 / 0   

​Rho-associated protein kinaseROCK2 ROCK1​O75116 Q13464​CHEMBL2111459​Kinase​0.0


27 / 0   

​


Absolutely no (real) opioid content...which is really fucking odd since it should be an incredible opioid; NMDA antagonist with mu, delta annd bit of SRI/ SA, maybe even a DRI and some sigma agonisn but no....Ht2a, b & c & 3a, D2, some NAch, !!KAPPA!! and a little bit of 1a to make things a bit nicer. Is this a psychedelic?! A completely out-of-the-wall, random splurge of psychedelic in a wildly opioid landscape!!


----------



## Nicomorphinist

sekio said:


> Nitrogen mustards with 'bigger' halogen/pseudohalogen groups are even more unstable and reactive (i.e. I > Br > Cl >>> F for leaving group strength). I would be suprised if you could isolate some _alpha_-amino-_omega_-haloalkanes other than chloro cmpds... even then IIRC the tertiary "pseudo-mustard" 2-dimethylamino-1-chloropropane (used in methadone chemistry) has to be shipped and handled as the HCl salt because the freebase -N(Me)2 group wants to quaternize to an aziridine chloride badly.
> 
> Now make it go to a 5/6 member ring and change Cl to I or OTf/OTs... watch those piperidiniums pop out...
> 
> 
> on a different tip, someone should give some bored grad students a half kilo of lysergic acid and a $50,000 merck millipore gift card and have them (after getting suitably goggle eyed on homemade LSD of course) throw a bunch of fluorination reagents at the ergoline structure. Would be neat to see, e.g. 2-fluoro-LSD, 5-fluoro-LSD, etc.



They use uracil mustards to treat some kinds of cancer -- have they found nitrogen mustards with that effect too?

This makes the list of weapons that can be used as medicines longer -- the other ploughshares beaten from swords in common use are, for example:


Nitroglycerine and PETN, both for angina pectoris; there are soldiers, factory workers, and other people who eat C-4 (RDX), Cyclonite (RDX), and Semtex (which has both RDX and PETN) because the dizziness makes them high and presumably it is the same mechanism for the RDX
Carfentanil is considered a Weapon of Mass Destruction 
There was a proposal in the 1960s of a similar declaration when there was some worry about the Bentley Compounds, etorphine in particular 
Then there is Kolokol-1 the Russian agent used in the theatre hostage crisis in 2002 which sounds like carfentanil and one or two other even stronger fentanils dissolved in halothane 
Radiopharmaceuticals and tracers like Caesium 137, Strontium 90, Samarium 156, and Cobalt 60 are special concerns for people purloining them and making radiological dispersion devices out of them
Cholinergic and anticholinergic medications are weaker versions of nerve agents, BZ and Agent 15 being examples of the latter
The organochlorine headlice killer lindane has been used in the past to spray on people in conflict situations

In the reverse, the apartheid era South African government considered using coumadin analogues, MDMA, C-Jam, methaqualone, and a number of other drugs as crowd control agents and weapons . .. they also used mixtures of two or three surgical muscle relaxants like succinylcholine and D-tubocurarine in a syringe disguised as a screwdriver on political prisoners before pushing them out of helicopters over the ocean around the country, hundreds of kilometres from land.  Project Coast was what the whole thing was called.


----------



## blueberries

Welp; it seems STP can't handle metabolism :/

So what do you think of this, would it work how I think it should? Plus am I right in thinking when it splits at the amine, it'll be a racemic split between MMDA-2 and MMQ, so the dosage should be double the common dose for each (which is fairly similar), 20-30mg (so a total of 40-60mg)?
It's just unfortunate qualones don't last that long, it'll cut out halfway through the MMDA-2. However...


----------



## sekio

> Welp; it seems STP can't handle metabolism :/





			https://smartcyp.sund.ku.dk/mol_to_som


----------



## Rectify

blueberries said:


> Welp; it seems STP can't handle metabolism :/
> 
> So what do you think of this, would it work how I think it should? Plus am I right in thinking when it splits at the amine, it'll be a racemic split between MMDA-2 and MMQ, so the dosage should be double the common dose for each (which is fairly similar), 20-30mg (so a total of 40-60mg)?
> It's just unfortunate qualones don't last that long, it'll cut out halfway through the MMDA-2. However...



I would possibly try your levo thingy.  The one on the left looks dodgy to me.  Just my 91 cents.


----------



## Asante

ACETAMINOFENTANYL.  When Tylenol just won't cut it ^_^

Structure: para-hydroxy-acetylfentanyl or, the 4-(N-phenethyl)piperidinyl derivative of acetaminophen.

Works too, says Swiss.

.


----------



## polymath

These compounds look similar to loperamide and some of them (especially the n. 23 with R=benzyl) seem to have good affinity to mu receptors:



Is there any similarity of these with some opioid painkiller (other than loperamide) that has been in actual clinical use?

Edit: Actually, according to the article I got this from, the compound obtained from loperamide itself by hydrolysis of the amide and decarboxylation (compound 1B), is a mu receptor ligand but is only a partial agonist.

Not that it would be a good idea to try to produce that substance, some of the product could dehydrate to form something like MPTP.


----------



## sekio

> Is there any similarity of these with some opioid painkiller (other than loperamide) that has been in actual clinical use?



MT-45?


----------



## polymath

Sorry for the SciHub links that required editing of the previous post... MT-45 is quite a strange opioid as it doesn't have any oxygen atoms in it. The article where they determined mu receptor affinities for loperamide derivatives (decarboxylated, amide converted to methyl ester, etc...) was not the same one where I got that table in the attached image. Opioids that are also agonists of the nociceptin receptor seem to not have the euphoric and addictive effects of morphine and other typical opioid analgesics ( https://www.ncbi.nlm.nih.gov/pubmed/30158150 ). Maybe that's why the "high" from megadoses of loperamide is so crappy.


----------



## sekio

so efavirenz sort of overlays 5-meo-dmt... hmm






i like the efavir-lsd ...


----------



## polymath

^ Quite unusual that this only has the N atom corresponding to the indole nitrogen... I tried to think of an ibogaine/harmala kind of derivative but you obviously can't build that from this compound.


----------



## polymath

Pawhuskin A is a cool compound, non-nitrogenous kappa receptor (mainly) blocker.



You could probably use that as an addition to a non-selective opioid agonist like the _akuamma_ alkaloids, which bind more to kappa than mu receptors and therefore aren't very euphoric by themselves. Much like the "blue velvet" mixture of pentazocine and an antihistamine (I guess that mixture works because the sedative antihistamine potentiates only the mu agonist effect and not the kappa).

Edit: someone with any level of actual physical dependence to opioids probably shouldn't try balancing like that, tho...


----------



## roi

Etifoxine/Flualprazolam hybrid


----------



## polymath

The 4-amino version of methylphenidate is significantly more potent than MPH itself, but can't know if it has aniline-like toxicity...



The SwissTargetPrediction also gives it a slim chance of binding to mu receptor.

If someone were to make a non-amine MPH with the piperidine nitrogen removed or replaced with oxygen, it would be easier to purify if it had an amino group on the benzene ring.

Edit1: Also, making it a 4-amino_ethyl_phenidate gives it a little bit more likelihood of binding to mu receptor, similar to meperidine SAR.

Edit2: And, by reducing the shit out of antibiotic chloramphenicol, you could obtain an equivalent 4-amino version of amphetamine.


----------



## polymath

The essential oil of _aniba canelilla_ tree is unusual in containing a nitro compound, 1-nitro-2-phenylethane... That could be used in producing alpha-benzylphenethylamine, but unfortunately that compound doesn't seem to be an amphetamine-like stimulant.









						Pharmacological characterization of BNMPA (α-benzyl-N-methylphenethylamine), an impurity of illicit methamphetamine synthesis
					

α-Benzyl-N-methylphenethylamine (BNMPA), an impurity of illicit methamphetamine synthesis, has previously been reported to produce convulsions in mice…




					www.sciencedirect.com


----------



## polymath

Some new compounds here (the first and the third image):








						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				









						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				









						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				




For some reason the Swiss Target Prediction thinks that the N-(indolylethyl)piperazine is a better dopamine reuptake inhibitor than either N-benzylpiperazine or N-(indolylmethyl)piperazine.


----------



## polymath

A really dangerous idea:

make a quaternary ammonium compound from the antiglucocorticoid mifepristone, and take it as a peripheral glucocorticoid blocker with a huge dose of dexamethasone to get only the CNS effects of the latter.





			SwissTargetPrediction


----------



## polymath

A compound that is both a kappa antagonist (Ki = 8.13 nM) and dopamine D2 and D3 agonist (Ki = 64.4 nM and 21.8 nM)... Maybe this could be some kind of an atypical antidepressant or ADHD medication. No chiral carbon atoms in there, so no confusion about the affinity of each isomer.



			https://pubs.acs.org/doi/10.1021/jm301258w


----------



## polymath

3,4-dichloropemoline








						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				




Nothing seems to be known about this. If its dosage in mg is like 10 times less that that of pemoline, it could have less liver toxicity, but that advantage disappears with stimulant tolerance.


----------



## blueberries

Hydrolicyclomethylamine (HCMA):


----------



## Nagelfar

polymath said:


> The 4-amino version of methylphenidate is significantly more potent than MPH itself, but can't know if it has aniline-like toxicity...
> 
> View attachment 17784
> 
> The SwissTargetPrediction also gives it a slim chance of binding to mu receptor.
> 
> If someone were to make a non-amine MPH with the piperidine nitrogen removed or replaced with oxygen, it would be easier to purify if it had an amino group on the benzene ring.
> 
> Edit1: Also, making it a 4-amino_ethyl_phenidate gives it a little bit more likelihood of binding to mu receptor, similar to meperidine SAR.
> 
> Edit2: And, by reducing the shit out of antibiotic chloramphenicol, you could obtain an equivalent 4-amino version of amphetamine.



I've always mused about near methylphenidates that were also near fentanyls.

...

Wishing I had the specs to this one below, tried against the phenyltropanes.

Note the C1 position substitution, not a mistake, though maybe add a C2 position carbmethoxy


----------



## polymath

Nagelfar said:


> I've always mused about near methylphenidates that were also near fentanyls.



I drew some amine compounds like this in another thread:



It's a possible dopamine reuptake inhibitor and also looks a bit like fentanyl or meperidine, and a pharmacology app predicts it's a possible mu receptor ligand.


----------



## Nagelfar

polymath said:


> I drew some amine compounds like this in another thread:
> 
> View attachment 21584
> 
> It's a possible dopamine reuptake inhibitor and also looks a bit like fentanyl or meperidine, and a pharmacology app predicts it's a possible mu receptor ligand.



Reminds me of Org 6582:






or Butyltolylquinuclidine:






Really they all turn out to be Zoloft analogues, more or less.


----------



## sekio

https://patents.google.com/patent/WO2017053574A1/en
		

"cannabinosides", glycosylated cannabinoids

*NSFW*:


----------



## S.J.B.

sekio said:


> https://patents.google.com/patent/WO2017053574A1/en  "cannabinosides", glycosylated cannabinoids


Sweet!


----------



## polymath

Nagelfar said:


> Reminds me of Org 6582:
> 
> 
> 
> 
> 
> 
> or Butyltolylquinuclidine:



Those have a quite different connectivity, because the shortest distance between phenyl and nitrogen is only two carbon atoms. The compound in my post is more like 4-benzylpiperidine.


----------



## blueberries

No-one want to to comment on my "Hydrolicyclomethylamine" ??

**_Got the nomenclature wrong in the first!**_


----------



## sekio

ibuprofen-phenylephrine prodrug
(phenylephrine is garbage unfortunately)





so why not




in the spirit of dibenzoylmorphine / dinicotinylmorphine, morphine di-acetylsalicylate aka morphine di-aspirinate
fix your headache "for real"


----------



## Nagelfar

polymath said:


> Those have a quite different connectivity, because the shortest distance between phenyl and nitrogen is only two carbon atoms. The compound in my post is more like 4-benzylpiperidine.



Still reminds me of them. 4-BP is like a once lengthened phenmetrazine

P.S. would somebody direct me to a on phone free molecule renderer


----------



## sekio

Oxycodone 14-(3-phenylproprionate) is apparently some ~400x more potent than oxycodone, 14-pentanoyl 133x, 14-heptanoyl 200x,  even the 14-acetyl is more potent by almost 10x.

Reading through _Opiates_ by George Lenz... cool book.


----------



## blueberries

14's a pretty magic spot for opioids. It sems like you just stick anything on there and it's a winner. Case in point; 14-PPOM.


----------



## Nagelfar

That sweet spot oxygen on those morphinans, has it ever been just given a nitrogen? or a sulfur with crazy direct attachments.

My thought as morphine family goes is 6-(every hard pressed ether) 3-(every rapidly cleaved ester) in a cocktail with the top twelve or so HCl or perhaps even protonated differingly a la Adderall's 4 salts. Somehow I think that would be warmer, quaint, and more natural (well, spans it wider) than some other semi-synthetics. 3-(easily cleaved and more solute) 6-(hard to cleave without blocking coupling) morphine. Call it maybe multilaudiphine after laudinum


----------



## polymath

Nagelfar said:


> That sweet spot oxygen on those morphinans, has it ever been just given a nitrogen? or a sulfur with crazy direct attachments.



There are compounds like beta-naltrexamine, with an amino nitrogen on 6-carbon, and nalfurafine with amide nitrogen there, but they are usually not agonists at mu receptor (they're either mu blockers, kappa agonists or both).









						Functionalization of the Carbonyl Group in Position 6 of Morphinan-6-ones. Development of Novel 6-Amino and 6-Guanidino Substituted 14-Alkoxymorphinans
					

The well-known opioid agonists, oxycodone and oxymorphone, and the opioid antagonists, naloxone and naltrexone, are commonly used clinical agents and research tools in the opioid field. They belong to the class of morphinan-6-ones, and produce their pharmacological effects by interacting with...



					www.eurekaselect.com
				




Then there's the strange compound N-naphthoyl-β-naltrexamine, which targets mu-kappa receptor dimers without having much of the side effects of either mu or kappa agonists (but seems to produce some place aversion at high doses).

And if you meant a 14-amino substituent, then there are these 14-cinnamoylamino compounds, some of which are buprenorphine-like partial agonists: https://link.springer.com/chapter/10.1007/128_2010_89

Maybe there's some easier way to get a 14-hydroxy on codeine than full conversion to oxycodone... Then it would be easy to make those phenylalkanoate esters Sekio posted about.


----------



## Nagelfar

Yes I meant 14, the 6 position was my addition since I can't find a chemical drawing prog. for my phone


----------



## polymath

Codeinone can be air oxidized to 14-hydroxycodeinone with a heavy metal catalyst, but I'm not sure if this can also be done to codeine or morphine. The cinnamic acid ester of oxycodeinone is about the potency of fentanyl: https://en.wikipedia.org/wiki/14-Cinnamoyloxycodeinone


----------



## Nagelfar

Do that cinnimate 14 to acetorphne see what happens, that, or nearest in synth., is my imaginary pic contribution: edit the pesky endoetheno bridge by inverting the ring one space removed, (up one side, down other) but who knows what that'd do. New biomimetic synth of morphine anyone?


----------



## sekio

> The cinnamic acid ester of oxycodeinone



I suspect that it's actually oxycodone cinnamate, i.e. the double bond is reduced.... the same paper that details the other 14-esters has 14-cinnamate as 175 +/- 75 x morphine potency (oxycodone itself at 0.3x).

I was under the impression that codeinone and 14-hydroxycodeinone are crap analgesics.


----------



## Nagelfar

Nagelfar said:


> Do that cinnimate 14 to acetorphne see what happens, that, or nearest in synth., is my imaginary pic contribution: edit the pesky endoetheno bridge by inverting the ring one space removed, (up one side, down other) but who knows what that'd do. New biomimetic synth of morphine anyone?



Came to the library (shift + PrtScn-SysRq & ctrl v have been the same since the '90s, yay for me. Getting old)







(Edit: change above by putting the bottom bridge end to the seven position where the alcohol is, so it's symmetrical)

And because I can't resist the speedball:


----------



## polymath

sekio said:


> I suspect that it's actually oxycodone cinnamate, i.e. the double bond is reduced.... the same paper that details the other 14-esters has 14-cinnamate as 175 +/- 75 x morphine potency (oxycodone itself at 0.3x).
> 
> I was under the impression that codeinone and 14-hydroxycodeinone are crap analgesics.



You can even make that cinnamoyl ester from naltrexone and it will be a weak mu partial agonist. The 3-methylated codeine-like version of that has more of agonist effect:



			https://pubs.acs.org/doi/10.1021/jm8012272


----------



## Nagelfar

I just did a search and found a 1992 findings article on pethidine derivatives made with a tropane substitution, I can't figure how to copy words and addresses with my phone so if someone has access to the article (top of Google search nearly for me)  would someone so willing post one or two here for me?

The words "pethidine", "opioid" and "tropane" seem to work

Also: if you go to molview.org and type in Anthraxiton you get a strange compound. WP has no such entry. Could somebody identify it?


----------



## sekio

Anthraxiton is brand name for sodium salt of diclofenac which is shown


----------



## S.J.B.

Nagelfar said:


> I just did a search and found a 1992 findings article on pethidine derivatives made with a tropane substitution, I can't figure how to copy words and addresses with my phone so if someone has access to the article (top of Google search nearly for me)  would someone so willing post one or two here for me?
> 
> The words "pethidine", "opioid" and "tropane" seem to work


I believe this is the article you are referring to.


----------



## Nagelfar

sekio said:


> Anthraxiton is brand name for sodium salt of diclofenac which is shown


Thank you sekio


----------



## Nagelfar

Above the synthesis of both those allosteric modulators at DAT in my recent threads nobody has responded to yet. ; -P







compound 11a (PMID: 23022052 Click here)
+
compound SoRI-20041 (PMID: 19244097 Click here)

I made sure to overlay with how the tropanyl in the one would match the benztropanes analogy in the other. Viable as *anything* that can be said for QSAR having theoretical probability (which I believe is null in most cases, but certainly not in divergent drugs spliced into one portmanteau)


----------



## sekio

That has a Texas carbon. Not sure how stable a hydroxy/amidine (apparently a carbamimidic acid? thanks chemdraw) would be either?


----------



## Nagelfar

sekio said:


> That has a Texas carbon.


The middle arene beside the penta-spiro and opposite other aryl? That what it's called? Yeah just now wishing I could rotate the faux pi-symmetry cake walk / Chinese firedrill style one carbon around.

Oh yes the fifth link on the spiro, I just thought it'd look cleaner but yeah it's still be five. At least Texas, as you say, is between the hydroxy and the nitrogens then ; -j : -P


----------



## sekio

I would think that the compound with the "right" structure would rearrange to a N-hydroxy-amide...


----------



## Nagelfar

All cyclopentanes or just the above? Other ones from the paper, such as the one that works on SERT may be more viable? And if you mean my verbal correction of it I was already beginning to think I was right the first time around.


----------



## polymath

Just another thought about the 3-methyl-14-cinnamoyl-naltrexone: if this is almost a full mu agonist, and the 3-demethylated metabolite is almost a full antagonist, it could possibly cause some kind of 'hangover' even after single dose because the activation of mu receptors is suddenly replaced with blockage of them.

And start redosing at that point and you're soon in real trouble...


----------



## Nagelfar

^poor naive sod who starts that regimen unknowingly.


----------



## polymath

^ Yeah, that's how someone would end up trying to rob a box of fentanyl patches or eat 500 pills of Imodium in a couple of days when they try to get out of that situation. And even then it would be difficult to balance the amount of opioid and antagonist in their body to not OD instead. About as demonic as "normal" people see drug use is.


----------



## Nagelfar

Someone kind enough to help me find a mobile application, structure drawing molecular chemistry, program for Android phone that's free?

Even one that works online that'll screen capture and host for you at a click? I know how to supposedly screen capture on this phone (volume down and off pressed at same time) but I can't figure where it goes or if it even saves.


----------



## Nagelfar

If the benzene can afford substitution when it is chelated as a chromium tricarbonyl, if so, I've found my personal very own 'methylenedioxy' to put (OK typo gods, pit) up against, well, everything  ; -b

e.g. chromium tricarbonyl para cis propenyl phenyltropane.


----------



## Nagelfar

Chromium tricarbonyl 3,4-methylenedioxymethamphetamine. ; -j


----------



## sekio

The chromium tricarbonyl of methamphetamine/ephedrine was used in a (very silly) paper detailing the synthesis of pseudoephedrine from "readily availiable" methamphetamine!

Unfortunately deprotection is simple ass O2 exposure.


----------



## polymath

Nothing's said anywhere about the cinnamoyl ester of tramadol, or a dextropropoxyphene with the propionate replaced with cinnamate... Difficult to tell which hydroxyl in these is 'equivalent' to the one at 14-position of oxycodone.


----------



## Nagelfar

sekio said:


> The chromium tricarbonyl of methamphetamine/ephedrine was used in a (very silly) paper detailing the synthesis of pseudoephedrine from "readily availiable" methamphetamine!
> 
> Unfortunately deprotection is simple ass O2 exposure.



and unfortunately my phone doesn't have a .PDF reader apparently. Shouldn't it's browser, googleGo, be able to?


----------



## draculic acid69

sekio said:


> The chromium tricarbonyl of methamphetamine/ephedrine was used in a (very silly) paper detailing the synthesis of pseudoephedrine from "readily availiable" methamphetamine!
> 
> Unfortunately deprotection is simple ass O2 exposure.


That's stupid.very stupid.


----------



## Nagelfar

sekio said:


> Unfortunately deprotection is simple ass O2 exposure.



Since it's nonplanar, probably even with a napthyl, eh?






^7-(((1R,3r,5S)-9-Azabicyclo[3.3.1]nonan-3-yl)oxy)-2H-chromen-2-one, w/o the chromium tricarbonyl it is:
5-HT-uptake IC50(μM)
0.0013
DA-uptake IC50(μM)
0.24
NE-uptake IC50(μM)
0.076

The 9-methyl azabicyclo has even better affinity for DA @ 0.15, and is more selective for it.


----------



## Nagelfar

Here is the above that I mentioned, drawn & quartered (with snipping tool, a rectangle is a quartered kind of situation, isn't it?)






^Life's goal is to ICV inject the above while listening to the following on headphones on full blast:
You never forget the first album of your favorite recording artist....


----------



## sekio

I suspect that chromium carbonyl makes for a poor drug. as most metal carbonyl compounds tend to be amazingly toxic as they are effective delivery devices to give lipophilicity to zero valent metals and direct them to the places they can do the most harm to enzymes. c.f. nickel carbonyl

also they add extra bulk and block pi-stacking of the phenyl group = less effective binding


----------



## Nagelfar

sekio said:


> also they add extra bulk and block pi-stacking of the phenyl group = less effective binding



except in the case of troparil and the phenyltropanes, the study found them to bind better and have higher affinity at DAT. I am assuming the DAT ligands, at least, have in general a chance at benefiting in many chance cases because of which.

Anyway, due to that simple finding, something else novel has to jump at me in terms of QSAR until my biometallic fetish runs it's course. In the meantime, what *would* the tricarbonyl aryl of methamphetamine do in vivo?? No in vitro studies? I'm still guessing it couldn't find its way into MAT as a substrate but may work as a really tight fitting pump ligand. If it did work as a substrate, that in itself would be worth finding out.


----------



## sekio

you kind of answered your own question then, either (1) the induced acidity of the benzene ring (which would probably make 4' hydroxylation by CYP easier, if the molecule can fit and nothing de-chromiums the whole deal), (2) the sterics involved, or (3) some electrostatic attraction from some moiety "across the pocket" in the DAT protien towards the carbonyl ligands is increasing affinity. I think you are also a prime contender for "most Ivory Tower academic chemical 'tool' misrepresented as a drug" contest.

also, I would be very suspicious of any binding figures unless there's some rigorous proof that nothing silly happens metabolism wise. I have a hard time nothing happens to the Cr or its ligands in the variety of environments in a cell and its environ. Displacement of the CO ligand by thiols, amines etc could account for differing species present and also is a source of nasty CO.

I do not think there's any magnetic attractions going on as most amino acids and protiens lack any way to sense or respond to magnetism.

while we are on the topic of tropanes, mr. lenz says that this is an opioid:


----------



## Nagelfar

> I think you are also a prime contender for "most Ivory Tower academic chemical 'tool' misrepresented as a drug" contest.


I'll take that. Esp. if it's "purposeful" misrepresentation. 


> also, I would be very suspicious of any binding...
> I do not think there's any magnetic attractions going on as most amino acids and protiens lack any way to sense or respond to magnetism.



I think the Singh article, comparing it to the cyclopentanes Ruthenium pi stacked, comes to the opposite conclusion, as the size would be equivalent to the Chromium tricarbonyl, and it's all magnetic


> while we are on the topic of tropanes, mr. lenz says that this is an opioid:


Like a tropaned Demerol


----------



## sekio

> as the size would be equivalent to the Chromium tricarbonyl


Uhh, they are also electrostatically quite different, but IIRC 3 CO molecules are way smaller than a tetramethylcyclopentadiene.



> it's all magnetic



From what I understand, chromium and nickel carbonyl both are diamagnetic thanks to the CO ligands pushing electrons from singly occupied states to lower energy states where they are paired up. 

I was under the impression that single atoms/molecules in solution are too rapidly scrambled by thermal motion to form effective magnetic domains. 

(Did anyone ever manage to get a NMR spectrum of the metallocarbonyl bound tropanes?)


----------



## Nagelfar

sekio said:


> Uhh, they are also electrostatically quite different, but IIRC 3 CO molecules are way smaller than a tetramethylcyclopentadiene.


Solid cone angles he noted were around 130° to 180° respectively. 30% larger and on that scale he noted it as equivalent.

The binding to selectivity of the Ru was much closer, 1.7, so interesting in that capacity



> The discrepancy in binding for the two benzene metal chelates is assumed to be due to electrostatic differences rather than their respective size difference. The solid cone angles, measured by the steric parameter (_i.e._ _*θ*_) is _*θ*_=131° for Cr(CO)3 whereas Cp*Ru was _*θ*_=187° or only 30% larger. The tricarbonyl moiety being considered equivalent to the cyclopenta dienyl (Cp) ligand.


----------



## sekio

A constellation of methadone analogs (& one propiram analog):









I have no data on the cyclized analogs but I bet they are active if not also very potent.

The phosphorous methadone analog is very neat even though it isn't super duper potent.
Also neat to see an aldehyde as an active opioid, are there any others?


----------



## S.J.B.

I saw this in the _Journal of Natural Products_ today and thought it was neat. I can't remember ever having seen an (_N_-methyl-2-aminopropyl)phenyl moiety in a natural product before... and with an (_S_) configuration, no less!






The authors propose that this moiety is biosynthetically derived from a tetrahydroisoquinoline:






So where does the alpha-methyl come from? Most tetrahydroisoquinolines in nature start with dopamine (see compounds *17* and *18* in the figure above, for example) or another biological phenethylamine. Does this mean there's an alpha-methylphenethylamine biomolecule involved here? Unfortunately, no. Strangely enough, these naphthoisoquinolines get their entire carbon structure via polyketide biosynthesis:


----------



## sekio

> I can't remember ever having seen an (N-methyl-2-aminopropyl)phenyl moiety in a natural product before



maybe I'm a smartass, but, ephedrine/cathine/cathinone?

Are these psychedelic?


----------



## S.J.B.

sekio said:


> maybe I'm a smartass, but, ephedrine/cathine/cathinone?


Sure, but I was thinking of an _N_-methyl-2-aminopropyl without further substitution.


----------



## Nagelfar

Nitropane. DRI, opioid, or tool compound?






Naphthyladamancaine:


----------



## sekio

This Chemical Does Not Exist


----------



## sekio




----------



## Nagelfar

sekio said:


> This Chemical Does Not Exist


What did I miss?




Why does it remind me of 1-(3-Chlorophenyl)-4-(2-phenylethyl)piperazine?


----------



## sekio

> What did I miss?



keep refreshing the page


----------



## Nagelfar

Oh sure tell me now that I got home from the library ;-p page is all black to begin with now. (Free gov't phone doesn't do much) have to check tomorrow


----------



## sekio

MANY weird cannabinoids








CUMYL-PEGACLONE
dem tricyclics





A-836,339
CB2 selective but... look at that structure, it makes my head hurt.





"more aromatics, more money"


----------



## polymath

This chemical has an IC50 of 780 nM for the mu receptor and 610 nM for the delta receptor, probably an agonist for both.








			https://pubs.acs.org/doi/10.1021/jm980374r
		


Could also be a monoamine releaser because of the similarity to BZP...

Edit: And to increase the mu affinity, you could try to add a methyl group on that piperazine ring (akin to 3-methylfentanyl), or change one of those benzylic N-substituents to a 2-phenylethyl type substituent.


----------



## Nagelfar

PCParil




sekio said:


> keep refreshing the page







^Looks like an opioid, morphine (even if not morphanin) style.


----------



## polymath

Anyone know whether the N-demethylated derivative of cyclizine binds significantly to muscarine receptors? It could be a dopamine reuptake inhibitor because of the similarity to benzylpiperazine, and if it doesn't have anticholinergic effects it could even be interesting. There seem to be some new methods to N-demethylate amines with oxidizers and metal ion catalysts, but that of course can't be discussed here in detail.

Edit: You could possibly also make norcyclizine build up in your system by somehow making your urine alkaline (slowing down the renal excretion) and then taking small repeated doses of cyclizine, but a slow buildup isn't really the way how stimulants are used.


----------



## sekio

desproprionyl bezitramide/fentanyl analog


----------



## Nagelfar

I was thinking 'ebati-'aryl SNDRIs or releasers. Where the arene has a nitrogen heteroarom. Wonder how those'd go over.

Also, there's got to be some affinity with those Prozac / Effexor analogs where both rings are just plain cyclohexanes.


----------



## draculic acid69

polymath said:


> Anyone know whether the N-demethylated derivative of cyclizine binds significantly to muscarine receptors? It could be a dopamine reuptake inhibitor because of the similarity to benzylpiperazine, and if it doesn't have anticholinergic effects it could even be interesting. There seem to be some new methods to N-demethylate amines with oxidizers and metal ion catalysts, but that of course can't be discussed here in detail.
> 
> Edit: You could possibly also make norcyclizine build up in your system by somehow making your urine alkaline (slowing down the renal excretion) and then taking small repeated doses of cyclizine, but a slow buildup isn't really the way how stimulants are used.


Are you talking about forming the N-oxide with hydrogen peroxide and then using iron sulfate to remove the alkyl group?


----------



## polymath

draculic acid69 said:


> Are you talking about forming the N-oxide with hydrogen peroxide and then using iron sulfate to remove the alkyl group?



Yes, the same thing as in the article that talks about that. In a similar paper the same is done to morphine or codeine and atmospheric oxygen is used as one possible oxidant. The problem is that the demethylated compound can't be separated from the reaction products with simple acid-base extraction, and it will possibly even require chromatography unless there's a significant difference in the boiling points at some reduced pressure.


----------



## Nagelfar

Here it is, no phenyl shortening so everything is optimum in dimension. "God Of 'Caine" I call it. The ortho-acetoxy gives the enhanced stimulation of the phenyltropanes, the styrene is optimum for the length of the benzoyloxy, the nitrogen tail is about twice cocaine, and the C-1 addition ten times it at DAT and even has SERT & DAT at the expense of NET. I could have used the vinylogous 2beta but went with the more compact isoxazole, which gives a modest boost over the carbmethoxy.


----------



## sekio

The N-sulfonylisocyanate screams reactivity (covalent inhibition anyone) to me, I wouldn't put anything like that in my body.  Spoilers: if your substrate binds permanently, Ki doesn't matter much any more, it's just a matter of time before all the enzyme gets inhibited because the rate of reaction between the substrate and enzyme greatly outpaces how fast your body can reform new active enzyme.

I've worked with isocyanates as precursors to polyurethanes. They are nasty sensitizers and also stink - the same things that make them useful to make urethane rubber via reactions with polyols also permit reaction with amines and thiols of protiens, covalently linking bulky groups onto reactive sites of enzymes, crippling activity in general.





One of the most potent piperidine analogs, note that apparently the potency goes N-phenylpropyl >> N-phenylbutyl > N-phenethyl > N-methyl > N-benzyl. This also suggests N-cinnamyl would be active, similar to bucinnazine. Also, esters of tertiary alcohols (MPPP-type) are more potent than 4-carboxypiperidines.


----------



## Nagelfar

I considered that, and now that you bring it up I figure that the assay of improved activity may be off. Everything else gimps activity at the nitrogen though, so either plan old methyl or desmethyl.


----------



## polymath

Nothing seems to be easily found about the derivatives of fentanyl with an N-(3-phenylpropyl) substituent or longer. Maybe it only increases affinity with meperidine-like compounds.

The desmethylcyclizine is also difficult to find information about, but it seemed that in repeated administration of cyclizine the blood levels of norcyclizine remain much lower than of cyclizine itself. The strange, almost fully aromatic DAT inhibitor 4-diphenylmethylpyridine becomes much less active if one of the phenyls is removed, but I'm not sure if there is the same trend with N-benzylpiperazines where there's an aliphatic ring with two nitrogens.


----------



## sekio

Rimazolium, a charged compound analgesic.


----------



## sekio

aromatase inhibitor


----------



## polymath

^ That looks like it could try to act as a substrate for aromatase and then destroy it by binding covalently due to that ketone-double bond arrangement.


----------



## polymath

The N-demethylated metabolite of sertraline has only 5 times more affinity to SERT compared to DAT, but the affinities are so small that it's useless if it binds to plasma proteins in the same extent as sertraline.






The oxidized non-amine compound below is a dopamine reuptake inhibitor with IC50 = 20 nM. The missing amino group probably affects the amount of protein bound fraction, but not sure in which way. At least this would be easy to separate from amine impurities by extracting from low pH solution.














						Non-amine-based dopamine transporter (reuptake) inhibitors retain properties of amine-based progenitors
					

Without exception, therapeutic and addictive drugs that produce their primary effects by blocking monoamine transporters in brain contain an amine nit…




					www.sciencedirect.com


----------



## sekio

> That looks like it could try to act as a substrate for aromatase and then destroy it by binding covalently due to that ketone-double bond arrangement.











drugs like metandienone and chlordehydromethyltestosterone also have the dienone moiety and yet are not aromatase inhibitors, indeed metadienone is aromatized to 17-methylestradiol.

The fully hydrogenated analogue is also known. but not documented as to its pharmacology. I would call it 16-oxa-androsta-3,17-dione.







> The oxidized non-amine compound below is a dopamine reuptake inhibitor with IC50 = 20 nM.



are there any other non-amine DAT substrates? Maybe one of these, based on fencamfamine/phenmetrazine/RTI-xx?





I seem to recall there is - there's also JWH171/176 which are fully hydrocarbon cannabinoid ligands.





RTI-371 is apparently a cannabinoid allosteric modulator, as well as DAT inhibitor like you'd expect from its tropane nature, and displays no locomotor stimulant activity in mice(!?).


----------



## Nagelfar

Yes there are phenyltropanes with the nitrogen replaced with an oxygen, a whole series of them in fact.

As for the lack of locomotor stimulation, maybe that *has to do* with the cannabinoid modulation.


----------



## Gaffy

It's funny how 4-FA had no dipeptyl peptidase IV activity whatsoever but adding a fluoro on the 5,4 - 3,5 - 2,4 gives it a sugar-blood lowering trough incretin inhibition effect that makes 3,4 fluoroamphetamine, despite its almost identical pharmacodynamics to 4-FA, maybe even better , a no-go IMO as a replacement for 4-FA, unless you like to see psycho sugar deprived tweaks at festivals.. It's a shame


----------



## polymath

sekio said:


> are there any other non-amine DAT substrates? Maybe one of these, based on fencamfamine/phenmetrazine/RTI-xx?
> 
> 
> 
> 
> 
> I seem to recall there is - there's also JWH171/176 which are fully hydrocarbon cannabinoid ligands.
> 
> 
> 
> 
> 
> RTI-371 is apparently a cannabinoid allosteric modulator, as well as DAT inhibitor like you'd expect from its tropane nature, and displays no locomotor stimulant activity in mice(!?).




The article I linked also describes a non-amine methylphenidate and some kind of non-amine tropane compound. I had seen that article many times before but for some reason I hadn't noticed that it's actually sertraline that one of those non-amines was derived from. A tranylcypromine derivative 1-(3,4-dichlorophenyl)-2-hydroxycyclopropane is something I'd be curious to see.

Some DAT inhibitors don't have any obvious locomotor stimulant effects, presumably because they don't tend to cause any wrong-direction flow of dopamine through the transporter.

That full hydrocarbon cannabinoid is interesting, maybe some of the terpene type benzodiazepine binding site ligands are also hydrocarbons. A hydrocarbon opioid wouldn't be completely unbelievable either, but with 5-HT2A psychedelics the SAR is so restrictive that you probably can't even replace the nitrogen with oxygen and have it retain any activity. There aren't really many hydrocarbons found in active ingredients of present-day pharmaceuticals, unless you count paraffinum liquidum and cyclopropane (still used as general anesthetic somewhere, I think).

And by the way, Nagelfar, if you have difficulty using ChemDraw like apps on your phone, it's possible to get a mouse cursor on phone screen with a Bluetooth mouse or with some kind of USB-microUSB adapter cable:









						How to Connect Mice, Keyboards, and Gamepads to an Android Phone or Tablet
					

Android supports mice, keyboards, and even gamepads. On many Android devices, you can connect USB peripherals to your device. On other Android devices, you may need to connect them wirelessly via Bluetooth.




					www.howtogeek.com


----------



## Nagelfar

Thank you polymath, I'll look into that. In the meantime I've been looking into a cheap laptop.


----------



## Nagelfar

Here's a sans-screensshot question. Can two overlapping arene rings be made between two sulfurs?


----------



## polymath

Nagelfar said:


> Here's a sans-screensshot question. Can two overlapping arene rings be made between two sulfurs?



I'm not sure what you mean by "overlapping", but it's even possible to make cyclic compounds that have a mechanical chemical bond with interlocked ring structures, as in the image.






Those molecules are called catenanes. I'm not sure if it's possible with some kind of large aromatic ring (6 carbons is too small for this).


----------



## Nagelfar

I have a screenshot on my phone but can't upload, it's just two sulfurs with three methylene units between, four bonds to each sulurs, and each sulfur at the 1 and 4 position of two arene rings overlapping in 3D and completely covering each other in 2D

i.e. both 1 and 4 position are for the same arene.


----------



## sekio

https://imgur.com/upload maybe. Or use SMILES if you can figure that out. I have a feeling you're talking about some disgusting hypervalent knot of bonds that would make the atoms cry out in steric pain.

You probably don't mean this:





(joke: you fail @ describing strucures )

also, AFAIK sulfur does not bond to more than 2 carbons, that is there are no quaternary S centers with 4 seperate C bonded to them. so "no" is my answer

tetrasulfur tetranitride is pretty cool though.


----------



## Nagelfar

I'll have to make it to the library. But if it links to no more than two carbons, I'll have to try something else. Mostly oxygens then? What if it was two nitrogen heteroatoms next to each sulfur on one side. Again have an image soon (trying to make a ball rather than a circle arene but with only two dimensional additions)


----------



## sekio

Try your best to draw it in ASCII text and I can replace it with a chemdraw image.

edit: a "ball arene?" so two benzene rings superimposed on each other, with one rotated 90 degrees so the apexes of the hexagons are shared? like barrelane?
proposed:




barrelane:











"Capsinoids", ester analogs of capsacin and its family. These are still TRPV1 agonists but do not manage to make it to the TRPV1 receptors in your oral mucosa (somehow) so they don't taste spicy but still produce systemic effects (vasodilation, probably pain relief)


----------



## polymath

If you're able to draw molecules in swisstargetprediction.ch with your phone, it will immediately tell the SMILES code for the chemical structure you drew and you can write it on paper and post here.


----------



## sekio

Oh, re: non-nitrogen drugs, dimembfe is a close one (benzofuran analog of 5-meo-dmt) but still has that tail N.


----------



## Nagelfar

sekio said:


>


Very similar, where the gray and black meet at points, sulfur, then one of each out from sulfur, nitrogen twice. At least that was my original thinking, so there is as many double bonds as two arenes.

Though that tetrasulfur you gave is nice looking.


----------



## sekio

I don't think you can do that. Sulfur is only hypervalent with oxygen or itself (as double bonded ligands) and can only have 2 sigma bonded groups on it. Also, it's gotta be tetrahedral - VSEPR doesn't like having all 4 groups jammed onto one "face" of the atom. Now, swap sulfur and nitrogen, and reduce the symmetry to 3-way rather than 4-way, and maybe...




"dinitrogen(III) hexasulfide" or N2S6
This might actually work, though I have a feeling it may be unstable...

even worse, the disulfide (c.f. amine oxide)




N2S8, I bet you money this will want to go to N2 and S8 if possible.





(Indole carbons numbered for posterity)
Shulgin mentions these are MAOIs - N-cyclopropylmethyl-tryptamine and its 5' and 7' methoxy relatives.





Lespedamine, or 1-MeO-DMT - named because it was isolated from _Lespedeza bicolor_ or "shrubby bushclover" - and its demethylated homolog 1-OH-DMT. The former is an interesting N-methylhydroxylamine analog of DMT. Unknown activity in humans as of yet. Both compounds have similar SwissTargetPrediction results: most likely binding sites being 5-HT2a/b/c, 5-HT1a, SERT, and DAT. (For what it's worth, the predictions have low "probability", which I assume prediction accuracy of the model? STP results seem to be what the "cool kids" are using these days so I figured I'd try doing it too.)

STP results for 1-MeO-DMT
STP results for 1-OH-DMT


----------



## Gaffy

My latest discoveries, no images jusqu'à nouvel ordre, just smiles:

NC1CCCC1C1=CC=CC=C1

CC(N)CC1CCCCC1C1=CC=CC=C1

COC1=CC2=C(NC=C2C2CCCC2N)C=C1

CN(C)C1CCCC1C1=CNC2=C1C=CC=C2

O=C(C1CCCN1)C1=CC=CC=C1

CC1CCNC1C(=O)C1=CC=C(C)C=C1

Gaffy


----------



## polymath

sekio said:


> even worse, the disulfide (c.f. amine oxide)
> 
> 
> 
> 
> N2S8, I bet you money this will want to go to N2 and S8 if possible.



And possibly do that explosively, like these difficult-to-make unstable nitrogen allotropes.









						Octaazacubane - Wikipedia
					






					en.wikipedia.org


----------



## Gaffy

This one seems like my favorite, most novel:





						SwissTargetPrediction
					






					swisstargetprediction.ch


----------



## sekio

merged some posts here.

I want to mention that anyone taking the results of STP as gospel truth of binding, rather than a wild-ass guess, needs to have their head looked at


----------



## polymath

sekio said:


> I want to mention that anyone taking the results of STP as gospel truth of binding, rather than a wild-ass guess, needs to have their head looked at



I'm not anywhere near that stupid. The most important feature of the STP is that it tells you if something is known to definitely bind to some receptor.


----------



## Gaffy

Would salting amphetamine base with HO- be possible and how would you get at it?


----------



## Gaffy

Does ascorbic amphetamine exist? Does the salt's structure modify its pharmacology? In the way that I actually never understood if the drugs like meth turned to a base in the blood or if the bloods dynamics permitted the drug to remain a salt eventhough in "solution". For example some drugs tend to cause disruption to the blood if IV'd, thus first made into a base and an acid as a real "solution", like with coke giving orc blood, and not if absorbed through the mucosa, where the surface is humid but ionised differently than water. Sekio?


----------



## sekio

"amphetaminium hydroxide" would be unstable and would decompose to water + freebase amphetamine. 
the ascorbate salt of amphetamine is also known but the problem is that the counterion does not really matter - given the enviroment of the body where there is chloride, sulfate, acetate etc the counterions will swap around. so no, salts usually do not influence the pharmacology only the pharmacokinetics (how fast they dissolve etc)

at ph 7 most of the common drugs exist as the free base in the blood, some solvated in plasma directly but most either binding to plasma protiens or fatty cell membranes





Einsteinium-253 in a quartz vial glowing due to its radioactivity. Cool shit.


----------



## Gaffy

Cleared my mind. Thanks

Edit: putting my posts together.
Sekio have you tried synthing "blæzøcaïne"? The COC(=O)C(COC(=O)C1=CC=CC=C1)C1CCCN1C
Should be UK legal
Blaezocaine or "blowsallcaine", 
I think the way to go is beta-alanine, ketopyridine and benzoic acid.

Pure dopa: http://swisstargetprediction.ch/result.php?job=642486740&organism=Homo_sapiens
Look at the known actives! http://www.swisstargetprediction.ch/result.php?job=1641719302&organism=Homo_sapiens


----------



## Nagelfar

Look how close nicotine and phenmetrazine are. Add a further nitrogen on the cyclopentane and a methyl tail a là n-methylamphetamine?


----------



## sekio

Interesting to see the common toad makes something close to, but not quite, 5-OH-DMT. Guess that's for the fancy desert toad only?

[edit] _Bufo bufo bufo_ hehehe


----------



## Gaffy

The real Fhexine.. Made a mustake on naming the original one.
NC1CCCCC1C1=CC=C(F)C=C1


----------



## sekio

dissociatives








						Synthesis and Pharmacological Properties of 1-(6-Aminohexylamino)-1-Phenylcyclohexyl Dihydrochloride (IEM-2062) as Compared with Memantine - Pharmaceutical Chemistry Journal
					

1-(6-Aminohexylamino)-1-phenylcyclohexyl dihydrochloride (IEM-2062) had significantly greater antihypoxic, anticonvulsant, antidepressant, and analgesic activity than memantine and similar antiparkinsonism activity as memantine; it had low toxicity and was safer for use. IEM-2062 produced...




					link.springer.com
				











						Synthesis and biological activity of phencyclidine and its adamantylamine derivatives
					

1-(2-Phenyl-2-adamantyl)amines 2a-c were synthesized and their biological activity evaluated by in vitro testing of their effects on the proliferative…




					www.sciencedirect.com
				








G. Lenz says this has a longer duration and is more potent than pethidine. never would have thought of an adamantanol ester


----------



## Gaffy

That is indeed quite surprising


----------



## Gaffy

Reposting:


Gaffy said:


> Here I'll be posting my best inventions, selected for their binding profiles.
> 
> It'll take some time to finish this thread (if I ever do as I've litterally thousands of chemicals to sort out and run through, and test with the SAR machine), but I'll post what I think deserves to be posted.
> 
> We'll start with Ketamine and Ephenidine analogs I've invented, and switch to BTCP analogs which will permit us to switch to DRIs: (And from there it'll be pretty random, as I can't classify all my compounds)
> Ketamine
> PCP
> Ephenidine
> 
> 
> Seven ringed Ketamine,
> CycloHeptylKetamine : C1(C(CCCCC1)=O)(C2=CC=CC=C2)N(C)[H]
> 
> 
> 
> 
> 
> 
> Seven ringed Methoxetamine,
> CycloHeptylMethoxetamine: C1C(C(CCCC1)(C2=CC=CC(=C2)OC)NCC)=O
> 
> 
> 
> 
> 
> 
> Adding a benzene group to the cycloheptyl:
> 3-MeO-PCPy with a PhenylCycloHEptyl ring: C1CC(CCC2=C1C=CC=C2)(C3=CC=CC(=C3)OC)N4CCCC4
> 
> 
> 
> 
> 
> 
> a little extra
> 
> 
> (With very interesting SARs)
> MorphoKetamine: ClC1=C(C=CC=C1)C1NCCOC1C1=CC=CC=C1
> 
> 
> 
> 
> 
> 
> 
> PCP with a N-PhenylPiperazine
> PCPP:  C1=CC=C(C=C1)N2CCN(CC2)C3(CCCCC3)C4=CC=CC=C4
> 
> 
> 
> 
> 
> 
> BTCPP, BTCP with a phenylpiperazine
> BTCPP: C1=CC=C(C=C1)N2CCN(CC2)C3(CCCCC3)C5=CC4=CC=CC=C4S5
> 
> 
> 
> 
> 
> 
> Three analogs between Ephenidine and BTCP:
> 
> BTPhenEthylPiperidine : C(C(N1CCCCC1)C1=CC2=C(S1)C=CC=C2)C1=CC=CC=C1
> 
> 
> 
> 
> 
> 
> 
> BTPhenEthylPyrrolidine: C12=C(C=CC=C1)SC(=C2)C(CC3=CC=CC=C3)N4CCCC4
> 
> 
> 
> 
> 
> 
> BTBKPhenEthylEthylamine: C12=C(C=CC=C1)SC(=C2)C(C(C3=CC=CC=C3)=O)N(CC)[H]
> 
> 
> 
> 
> 
> 
> The morpholine analog of ketamine applied to BTCP:
> MorphoBTCE: C1COC(C(N1)C1=CC2=C(S1)C=CC=C2)C1=CC=CC=C1
> 
> 
> 
> 
> 
> 
> Mono-methylated alpha-phenylated tryptamine, a SNDRI that stands out:
> N-Methyl-Alpha-Phenyl-Tryptamine: C1=CC=CC2=C1C(=C[N]2)CC(C3=CC=CC=C3)NC
> 
> 
> 
> 
> 
> 
> Its N-Pyrrolidino analog
> 
> 5-MeO-AMT
> C1(=CC=C2C(=C1)C(=C[N]2)CC(N([H])[H])C)O
> 
> 
> 
> 
> 
> 
> *Cocaïne analogs: probably my best inven**tions*
> 
> I Don't know what to call these, but they're wonderously promising
> COC(=O)C(CC1=CC=CC=C1)C1CCCN1
> 
> 
> 
> 
> 
> 
> 
> The N-Methyl, even more promising
> C1(=CC=CC=C1)CC(C(=O)OC)C2CCCN2C
> 
> 
> 
> 
> 
> 
> The local anaesthetic version, it's got high HERG activity:
> C1=CC=CC=C1C(OCC(C(OC)=O)C2CCCN2[H])=O
> 
> 
> 
> 
> 
> 
> The N-Methyl version, with even more HERG activity, which makes it cardiotoxic
> COC(=O)C(COC(=O)C1=CC=CC=C1)C1CCCN1C
> 
> 
> 
> 
> 
> 
> An outstanding one,both SNDRI and MOR (!)
> 
> 
> 
> 
> 
> 
> N'-N-Methyl version
> 
> 2-FA Light
> C1(=CC=CC=C1OC2CCN(CC2)[H])F
> 
> 
> 
> 
> 
> 
> 4-MethylMethylphenidate N-pyrrolidine analog
> C1=CC=CC=C1C(C(N2CCCC2)=O)C3CCCCN3[H]
> 
> 
> 
> 
> 
> 
> 
> PVP Methylphenidate: Surprisingly good
> C1=CC=CC=C1C(C2CCCC3CCCN23)C(OC)=O
> 
> 
> 
> 
> 
> 
> N-pyrrolidino Version
> 
> 
> 3-MeO-PhenEtrazine
> C1=C(C=CC=C1C2C(CC)N(CCO2)[H])OC
> 
> 
> 
> 
> 
> 
> 
> CyclopentylEthylCathinone
> CCNC(C1CCCC1)C(=O)C1=CC=CC=C1
> 
> 
> 
> 
> 
> 
> Two Ketobemidone variants, go guess how I guessed
> 
> BTKETO1
> C1=CC=C2C(=C1)C=C(S2)C3(CCN(CC3)C)CN4CCCC4
> 
> 
> 
> 
> 
> 
> BTKETO2
> C1=CC=C2C(=C1)C=C(S2)C3(CCN(CC3)C)C(N4CCCC4)=O
> 
> 
> 
> 
> 
> 
> 
> Should be opioïd, is Dopaminergic and Opioïd sigma active:
> C2(CC(CC1=CC=CC=C1)N(CC2)[H])(C(=O)CC)C3=CC=CC=C3
> 
> 
> 
> 
> 
> 
> Ketobemidone analog:
> C1(C(CN(CC1)C)=O)(C(=O)CC)C2=CC(=CC=C2)O[H]
> 
> 
> 
> 
> 
> 
> 
> Chlorphenamine derived Antihistaminergic Psychedelics, or chillaxed tripping!
> 
> 5-Meo one
> C1=C(C=CC2=C1C(=C3C=CC=C[N]23)CCN(C)C)O
> 
> 
> 
> 
> 
> 
> 
> Chlorphenamine inspired
> C1=CC(=CC2=C1C(=C3C=CC=C[N]23)CCN(C)C)Cl
> 
> 
> 
> 
> 
> 
> 5-Meo DIPT one
> C1=C(C=CC2=C1C(=C3C=CC=C[N]23)CCN(CC=C)CC=C)OC
> 
> 
> 
> 
> 
> 
> 
> Now let's switch to killer opioïds, Fentanyl analogs and some others:
> 
> Cyclic R-30490
> C1(=CC=CC=C1)CCC2CCC3(CC2)COCC(N3C4=CC=CC=C4)=O
> 
> 
> 
> 
> 
> 
> 
> Its (probably) more potent analog, 2'-Fluoro-3-Methyl-Cyclic R-30490
> C1(=CC=CC=C1)CCN2CC(C4(CC2)N(C3=C(C=CC=C3)F)C(COC4)=O)C
> 
> 
> 
> 
> 
> 
> 
> My FuranylFentanyl
> C1(=CC=CC=C1)CCN2CCC(CC2)(C3=CC=CO3)N(C4=CC=CC=C4)C(CC)=O
> 
> 
> 
> 
> 
> 
> Non-Brominated Cyclic BDPC
> C1=CC=C(C=C1)C2(CCC3(CC2)OCCC(C3)C4=CC=CC=C4)N(C)C
> 
> 
> 
> 
> 
> 
> Fentanyl with the phenethyl displaced
> C2(CC(CC1=CC=CC=C1)N(CC2)[H])N(C(CC)=O)C3=CC=CC=C3
> 
> 
> 
> 
> 
> 
> 
> And an already seen one, but it has its place here:
> An outstanding one,both SNDRI and MOR (!)
> 
> 
> 
> 
> 
> 
> Some weird cannabinoïd, related to JWH-018
> C1=CC=CC2=C1C(=C[N]2CC3CCCCC3)C(=O)CC4=CC=CC=C4
> 
> 
> 
> 
> 
> 
> What do I call this:
> C1=CC=CC2=C1C(=C[N]2CC3CCCCC3)C(=O)C5C4CCCCC4CCC5
> 
> 
> 
> 
> 
> 
> 
> 
> For more fun, go see ILTDPORM or Dresden's thread.
> 
> From here on the thread is dedicated to chems that aren't of my invention, mine are above ^.
> 
> Some of polymath's inventions:
> 
> N-PE-Nor-MEthadone
> 
> Polymath's Funny little beast, Fenmyrtin:
> [C@H]1(CC(CC2CCCCN12)(C3=CC=CC=C3)O[H])C
> 
> 
> 
> 
> 
> 
> S.J.B.'s constitutional isomer of BZP
> C1=CC=CC=C1CC2CN(CCN2[H])[H]
> 
> 
> 
> 
> 
> 
> Dresden's Carbomethoxy PVP:
> C1=CC=CC=C1C(C(CCC)N2CCCC2)C(=O)OC
> 
> 
> 
> 
> 
> 
> Sekio's Oxazolino Carfentanyl
> C1(CCN(CC1)CCC2=CC=CC=C2)(C3=NCCO3)N(C4=CC=CC=C4)C(CC)=O


----------



## sekio

you get a pass this time because your thread was merged here, but please don't repost things 
also if you want people to be able to understand the structures you post, try either using iupac names or posting images of said compounds... to me SMILES is all greek & i have to plug every one into chemdraw to figure out what you are talking about. 

also keep in mind STP is not a replacement for "real" pharmacological data  you may have noticed it has some problems where it will erroneously assign strange binding sites for known ligands... BDCP is one 

but in the interest of other cool tools, there is also supposedly a bioisostere replacement tool as well as a ADME prediction tool.
again these should be treated as no more than suggestions until verified oterwise
http://www.swissbioisostere.ch/
http://www.swissadme.ch/

there is also SMARTCYP to predict CYP450 metabolism sites
https://smartcyp.sund.ku.dk/mol_to_som






some steroid stuff... 4-Cl analogs of norboletone/THG





turns out "2c-b-fentanyl" (??) compound is a real thing, cayman will (not) sell it to you if you are dumb enough to spend $75 on a single milligram of some total unknown. no word as of yet on if it is psychedelic though. i would bet it would be at least moderately active as a mu opioid ligand & totally inactive as a psych (due to the general rule of thumb for PEAs being that primary amines are needed) but damn, talk about turning a (precursor to a) safe drug into a deadly one :/
i can see it now... "super potent psychedelic heroin vapes: the latest drug threat????"





possible pcp analogs without piperidine:
a. 1-adamantyl
b. 2-adamantyl
c. cyclohexyl
d. isopropyl
e. cyclopentyl
f. 3-methylpyrrolidine

[edit]
Midaflur, a wierd sedative?




It looks like... well, I've never seen a drug quite a sstrange as it, that's for sure.





Fenpentadiol, a "swiss army knife"?
_In three articles the properties of a new psychotropic agent from the series of araliphatic alcohols — phenpentanediol (CXV) — were described (477-479). It is not easy to place this substance anywhere in the pharmacodynamic system of psychotropic agents: on the one hand it potentiates the barbiturate narcosis, on the other it increases motility and exploratory activity in mice and potentiates the effects of amphetamine._





Its close relative phenaglycodol is a sedative like meprobabmate. Only 3 heteroatoms and no N!


----------



## Gaffy

Could you explain how Fenpentadiol potentiates amphetamine?

AcryloylFentanyl was a winner, so why not:
3M-AcryloylFentanyl





						SwissTargetPrediction
					






					swisstargetprediction.ch
				



Beta-OH-AcryloylFentanyl





						SwissTargetPrediction
					






					swisstargetprediction.ch
				



And Alpha-Methyl-AcryloylFentanyl





						SwissTargetPrediction
					






					swisstargetprediction.ch
				



Last but not least,
1[2,6 CycloHexyl]-AcryloylFentanyl





						SwissTargetPrediction
					






					swisstargetprediction.ch
				





In my souvenirs, this:





						SwissTargetPrediction
					






					swisstargetprediction.ch
				



was being sold as 4-CDC, up for women 40+, good for their libido, or maybe it was the 4-Chloro, which would resemble Fenpentadiol a lot.
Edit: The 4-Chloro is alnost inactive.

Another Dopaminergic chemical with CB activity (this one of my own invention):
CN1C(C1C1=CC=CC=C1)C1=CC2=C(S1)C=CC=C2









						SwissTargetPrediction
					






					swisstargetprediction.ch
				




And talking of dissociatives, I like zis one:

CC1CCCC1(N1CCCC1)C1=CC=CC=C1




I committed to naming it

IZNOGOOD

As
He'll be seen flying on his magic carpet..






						SwissTargetPrediction
					






					swisstargetprediction.ch
				




Adding a methyl group on the cyclopentyl seems to make up for the size of it, as in:





						SwissTargetPrediction
					






					swisstargetprediction.ch


----------



## sekio

> Could you explain how Fenpentadiol potentiates amphetamine?


nope. It's a mystery from an age in pharmacy where people threw compounds against the wall and saw what stuck.



> Adding a methyl group on the cyclopentyl seems to make up for the size of it



journal references? I was always taught the cyclohexyl ring is kind of scared as such, reduction to a cyclopentyl or enlargement to the cycloheptyl doomed activity.





a benzomorphan





the trimer of piperidine produced from reaction of N-chloropiperidine formed from interaction of piperidine & chlorinating oxidisers like hypochlorite bleach, chlorine gas, trichlorotriazine etc


----------



## Nagelfar

sekio said:


> nope. It's a mystery from an age in pharmacy where people threw compounds against the wall and saw what stuck.


It threatens discovery to rely on what's already known.

Hopefully some mad scientist is finding everything chemically safe just for form and testing it on a large pool of research specimens.


----------



## Gaffy

I once hoped for biologically modified chdren who would produce new chemicals trough photosensitivity and new liver enzymes


----------



## Nagelfar

Plants are more easily tended to.


----------



## Gaffy

The perfect cardiotoxin, I present to you:





CNC1C2CCCC2CC1C1=CC=C2C=CC=CC2=C1






						SwissTargetPrediction
					






					swisstargetprediction.ch
				




5HT2B and an out of the roof non-anaesthetic related HERG activity! :D Let's call this one Moliere, die on the scene..


Full serotonin 6 agonism:
8-Methyl-DMT




CN(C)CCC1=C(C)NC2=C1C=CC=C2






						SwissTargetPrediction
					






					swisstargetprediction.ch
				




It seems serotonin 6 is a regulator of Alzheimer development in elderly brains, here are some candidates: (it's quite hard to find non-5HT2b and orally active ones, that son't cause too many alterations of the senses with enough 5HT6, and a duration long enough for a day/half a day.)






CC(C)N(C)CCC1=C(C)NC2=C1C=CC=C2






						SwissTargetPrediction
					






					swisstargetprediction.ch
				








CC(CC1=C(C)NC2=C1C=CC=C2)N1CCCC1






						SwissTargetPrediction
					






					swisstargetprediction.ch
				








CC(C)N(CCC1=C(C)NC2=C1C=CC=C2)CC=C






						SwissTargetPrediction
					






					swisstargetprediction.ch
				




Or a combination of NC1CC2=C(C1)C=CC=C2 http://swisstargetprediction.ch/result.php?job=1013218982&organism=Homo_sapiens or NC1CCCC1C1=CC=CC=C1 http://swisstargetprediction.ch/result.php?job=1091801380&organism=Homo_sapiens





With
8-Methyl-DMT




CN(C)CCC1=C(C)NC2=C1C=CC=C2

Like 20 mg MAOI and 5 mg 8M-DMT.

Let's call it Dazimer, in I am.

Edit: Thanks for merging, it's a real hassle on my mobile phone.


----------



## Nagelfar

Does everyone here assume, across this whole visible universe, the greatest concentration of diverse molecule types is here on earth? Even if in tiny pockets. 

It is kind of like asking if you believe in life on other planets, unless there is some compact quantum form of natural phenomenon displaying many permutations at once which I haven't learned about.

I like to think, far out there, the periodic table works differently so the number rises so drastically with what you can do in any one place, the point is moot 

Entertaining the 'No life elsewhere and no aliens' theory - this, the Earth alone is the pinnacle epicenter of all molecular designs of carbon(?)


----------



## S.J.B.

@Gaffy : would you please post real structures not SMILES structures it is pointless as nobody is going to bother converting them. You can use this website if you do not want to host images.


----------



## Gaffy

S.J.B. said:


> @Gaffy : would you please post real structures not SMILES structures it is pointless as nobody is going to bother converting them. You can use this website if you do not want to host images.


That's why I use the STP link to host the image, and as soon as I'll have access to a computrr again I will definitly edit all my posts with images


----------



## sekio

I will add images... just maybe in future you can start posting images, IUPAC names or even derivatives of "common names",  like "4a-allyl-morphine" instead of "OC1=C2O[C@]3(CC=C)[C@]45C2=C(C=C1)C[C@@H](N(CC5)C)[C@]4([H])C=C[C@@H]3O".


----------



## Gaffy

Hahah.. Sorry.. And thanks a lot! 

BIG NEWS! I have found a supplier who is ready to look into producing BLÆZØCAINE! It seems dimethocaine isn't very popular anymore so they are looking for a legal replacement, and this fits perfectly! Yay! 

Edit: Sekio, you're the best!

Could someone tell me the IUPAC of the blæzøcaine,  COC(=O)C(COC(=O)C1=CC=CC=C1)C1CCCN1C

Would this be right? :
1-(2-(N-MethylPyridine))-2-Carbomethoxy-3-Benzoyloxylate


----------



## Nagelfar

^I'd like to see that one


----------



## sekio

I personally don't see this being active at all (ester hydrolysis will be rapid) and it looks nothing like any active NDRIs


----------



## Gaffy

It's one carbon link away from cocaine.. Check it out on STP!


----------



## sekio

I could care less what STP says, I'm just pointing out that methyl esters tend to get cleaved very rapidly (cocaine's does...)

also in general deleting single bonds out of compounds reduces the affinity towards transporters, c.f. 2,3-seco-fentanyl or diampromide vs fentanyl... orders of magnitude difference in potency

also your "8-methyl dmt" is really 2-methyl dmt..





						Erowid Online Books : "TIHKAL" - #34 2-ME-DMT
					

Entry #34 2-ME-DMT from TiHKAL by Alexander & Ann Shulgin.



					www.erowid.org


----------



## Gaffy

I would still like to try it in the least. And yes, I was more interested in its affinity for the HT6 and the compounds derived thereof; also I used the counting of carbons you pointed out a few posts ago, which goes like a phenyl compound 

Oh, and finally it seems synthing Blæzøcaïne small scale is around ten to one which is just too much for an RC that is aimed to replace Dimethocaine which goes for three/four to one. This is not a price naming..


A funny compound, active at GABA receptors that are completely unknown to me. I wonder if it has any addictive properties and if it's euphoric. Any input on these receptor? I've got time for reading 











						SwissTargetPrediction
					






					swisstargetprediction.ch
				



(Found a way to host this image as it was already uploaded)

Found a way to screenshot/upload on imgur but the linking add-on from BL disappears upon entering the link, I don't know why it worked with the one above..

Anyway, here's the STP link.





						SwissTargetPrediction
					






					swisstargetprediction.ch
				




I've got an interesting new fentanyl I'll post tomorrow.

Edit: Searching for theanine derivatives active at orexine ligands (found one, might post if someone is interested in it) I came across some dopamine activity and after 2-3 changes came up with this, which is I think what I was looking for searching for HT6 activity without visuals! I present:





						SwissTargetPrediction
					






					swisstargetprediction.ch
				





Sekio, you were talking about unknown format NDRIS, here's a SNDRI to for your liking  :




CCC(C(CC)C1=CC=CC=C1)C1CCCN1C






						SwissTargetPrediction
					






					swisstargetprediction.ch
				




New MDMA alternative??


----------



## sekio

Isn't that a prolintane analogue? (remember please post images and not just SMILES)

What's the fascination with 5HT6 agonism? What's that supposed to do?



> Oh, and finally it seems synthing Blazocaine small scale is around ten to one which is just too much for an RC


probably because it's not as trivial a synthesis as you think 

if you remove the ester linkage and a methylene, and swap the methylpyrrolidine for a piperidine, you get methylphenidate.


----------



## Gaffy

sekio said:


> Isn't that a prolintane analogue? (remember please post images and not just SMILES)
> 
> What's the fascination with 5HT6 agonism? What's that supposed to do?
> 
> 
> probably because it's not as trivial a synthesis as you think
> 
> if you remove the ester linkage and a methylene, and swap the methylpyrrolidine for a piperidine, you get methylphenidate.



With my small knowledge, I'd guess=>
Start with Beta-MethoxyAlaninol, Chloride => Chlorinated right next to the ketone. First step. Then N-Methylpyrridine, Chlorinate the 2 position - 2 step. React the two, you got yourself precursor n°3. Then dilute benzoic acid, the precursor n°3 and heat for 2-3 days, removing water. Extract with ether, gas with HCl and there you've got Blæzøcaïne! 

Check these out, decided to make a Dump, too many to post one by one. Tonight's thinking results: 




Edit: it seems just posting ttheimgur link and not trying to add it via the image link add-on works

HT6 seems to play a role in alzheimer, I was tired of inventing drugs so i wanted to come up with some kind of a medecine ^^

And yes it is prolintane inspired .


----------



## sekio

> Start with Beta-MethoxyAlaninol, Chloride => Chlorinated right next to the ketone. First step. Then N-Methylpyrridine, Chlorinate the 2 position - 2 step. React the two, you got yourself precursor n°3. Then dilute benzoic acid, the precursor n°3 and heat for 2-3 days, removing water.



This is like, textbook example of how organic synthesis doesn't go. Do you just magically get the intermediates to just link together? (with expulsion of chlorine gas, natch) 
Are you aware of any other side reactions in your proposed synthesis? What reagents do you propose to chlorinate a non-activated ester (presumably you mean methyl 3-methoxypropanoate as "beta-methoxy-alaninol" (don't you mean serinol ?) has no ketone - only an amine, and 2 primary alcohol last I checked) and/or the 2' position of a pyrrolidine selectively?

Dilute benzoic acid? Why?

Anyway I could go on... it's not as simple as you would make it out to be. Do some reading on process chemistry and maybe come back to the drawing board next year 

Or pull out the stops and make a compound actually tenable to large-ish scale synthesis:





You can have that one, for free...



> I was tired of inventing drugs so i wanted to come up with some kind of a medecine ^^



You're not bringing genius innovation to pharmacy with your brilliant observations here. There is binge-generating a bunch of structures and feeding them into STP during a bender, & then there is rational pharmacy design, and the venn diagram doesn't see a lot of overlap...



> 5-ht6 and alzheimers



(sarcasm aside) What in the brain _hasn't_ been found or speculated to have some role in Alzheimers disease?

You will notice nobody else in this thread takes themselves too seriously ...


----------



## sekio

Isophenidine analog?


----------



## Gaffy

No words on my beautiful inventions? 

I'll just post some from time to time.

And yes I'm quite bad at chemistry ^^

I meant beta alanine where the amime is an alcohol and where the carbohydroxy is methylated


----------



## Gaffy

The prolintane analog posted above has the wtong image, that of its 4F analog. This is the tight one:


----------



## Nagelfar

Replace/substitute the phenols on phenolphthalein with different cyclohexanes ring systems having any kind of branches or heteroatoms and try to make a drug with abuse liability.

That's what I would do if I could here quarantined with just my phone, maybe I could entice someone else to do so, I just want to see something like it.


----------



## Gaffy

SIGMA, MU, KAPPA, DELTA, DOPA, NE, SER, NMDA, etc, all on one molecule, I present:





						SwissTargetPrediction
					






					swisstargetprediction.ch
				





As for the IUPAC, Phenyl-1-CycloHexyl-1-MethylCyclopentyl-(2-Pyrridinemine)


----------



## sekio

^ somehow I doubt that binds mu, with no oxygens & 1 nitrogen
frankly i dont think it will bind dat either, that's a big ball of lipophilic goo

same for a lot of some of your other "inventions" which seem to be "take a large lipophilic group and jam a 2-methylaminopropane onto it"

in fact I would say you are doing a good job of illustrating the limitations of STP, many of those compounds are thoroughly too bulky to be DAT substrates. You will notice there is no pyrene analog of amphetamine nor buckyball analogs.






1,6-di(phosphocholine)-_alpha_-glucopyranose
i dont know, a nootropic maybe


----------



## Gaffy

Is that taurine in there?




WORMTAIL


----------



## polymath

Gaffy said:


> Is that taurine in there?



Taurine is a bit like the amino acid glycine, except that it's a sulfonic acid and not carboxylic. The one in Sekio's post is a phosphate ester and a quaternary ammonium compound (not a normal amine).


----------



## Gaffy

Got it, thanks Poly 
So it won't cross the BBB?

Thanks for this one btw  



But I don't think I'd try it, it's pure Cholinergic activity, a no go for me 

Maybee zis iz bether? 






						SwissTargetPrediction
					






					swisstargetprediction.ch
				







Or even zis ouane my dear acolyte:




__





						SwissTargetPrediction
					






					swisstargetprediction.ch


----------



## polymath

Gaffy said:


> Got it, thanks Poly
> So it won't cross the BBB?



I think if you have a small enough quaternary ammonium molecule, or one that's actively transported through membranes, it can cross the BBB in some situations. But usually quat compounds won't.


----------



## Gaffy

And what do you guys think of my PEW PILLS,, good 4-FA replacement?

60mg FACAP



And
20mg TWO BEE ONE


----------



## sekio

personally, I find alpha-substitutions on cathinones that are not linear alkanes to be strange... yes they are active but it screams "long duration" to me

I don't know how long the half life of naphyrone would be but almost certainly the _alpha_- cycloalkyl (cyclopentyl/cyclohexyl) analogs would have even longer half life and higher logP.


----------



## sekio

presumably an analog of fentanyl


----------



## Gaffy

PPAFENTANYL





__





						SwissTargetPrediction
					






					swisstargetprediction.ch
				






sekio said:


> personally, I find alpha-substitutions on cathinones that are not linear alkanes to be strange... yes they are active but it screams "long duration" to me
> 
> I don't know how long the half life of naphyrone would be but almost certainly the _alpha_- cycloalkyl (cyclopentyl/cyclohexyl) analogs would have even longer half life and higher logP.


That's not persee bad as I think FACAP will have quite a longer duration than 4-FA which means a pill will get you trough the whole night 

Maybe exchanging the pyridine for a piperidine will shorten half-life, or at least make it smoother? Look up a-PCYP, it doesn't seem to have a longer half life than the other a-PxP.

And in my experience length of half-life is greatly depending on setting, consumptions and ROA. Smoked Ephylone had a half-life of 20minutes up to an hour before subsiding with vasoconsfriction lasting up to 2 hours, IV a bit longer and snorting having a totally different feeling to it, almost incapacitating, whereas Eutylone I prefer snorting. Hexen was much more euphoric with a smoother rush snorted than IVd but IVing had a more spaced-out high, duration was the same. So what I'm trying to say is, can't know without some experiencing ^^. From day to day same package ritalin has totally different effects for me; the only drugs that kept the same until breaching psychosis or tolerance issues were real amphetamine speed and hash before I started using stimulants, as hash now has a totally different effect on me.

And whem will China start pushing this:


Alpha-(M)Ethylamine-Iso(Hexyl?)pentyl-Phenyl-1-One

The Ethylamine one has as strong Norepinephrine as Dopa but a stronger ppbility for both of them than the methyl  with 2x the known actives for dopa/ne


Edit: Thanks for Merging.

Viable Precursor?



Aand a Naphtalene group on PCPy seems more active with a methylmethylpentane than a cyclohexane. Interesting  :






Must be quite euphoric given the Ser/dopa ratio


----------



## clubcard

sekio said:


> presumably an analog of fentanyl



Well, closely related compounds are VERY potent opioids. I think that an N-benzyl works here and a methyl side-chain (chiral) increases duration & potency. I mean, N-benzyls are removed by the body too fast.


----------



## paracelsius

^ the benzyl compounds are nociceptin agonist in addition to potent mu-agonist. Nociceptin agonists are dysphoric iirc!! The most potent among these compound Brorphine (ie the 2-bromobenzyl) has (is having ) a pretty bad review from I gather. Not sure about the phenethyl.


----------



## sekio

Assuming the SAR is that of fentanyl, benzyl substituents should be massively less active than 2-phenylethyl.
And curiously, brorphine technically does have a phenethyl group, just 1-phenylethyl instead of 2-phenylethyl. Alpha-phenethyl rather than beta- if that nomenclature gets your fancy. It actually adds a chiral center too.

I just wonder how close a conformationally restricted urea (as it seems) compares to a propionamide. Maybe going from a benzimidazolone to an oxindole would change things for the better? Or if the usual tricks to enhancing fentanyl's affinity like 3-methylation, beta'-hydroxylation, 4-carboxymethyl, etc. do anything useful.


----------



## Gaffy

Work out the isomers, otherwhile it's a fentanyl that keeps you breathing..



No nociceptin, and given its H1 a activity might just be used as a tofu fent


----------



## Gaffy

Phenyl-substitution to phenylcyclohexyl-2-substitution=


----------



## S.J.B.

Hey Gaffy, if you right click the image on the Imgur page and "Copy image address", then click on "Insert image" in the Bluelight posting toolbar and paste the URL, you should be able to insert these images without having a huge banner around them. For example, here is the image from your latest post:


----------



## Gaffy

I tried but it doesn't work using this mobile phone.. I ordered a screen for my PC but the postal package distribution center is closed, I've been waiting on a predator's parcel for 3 weeks because of that!


----------



## sekio

Someone should get Gaffy set up with Autodock so he starts being more compliant with SAR rules. 

For instance, I know for a fact that such bulky substrates don't bind well at DAT: as far as I know you want a 4' position substitution like a biphenyl rather than a 2' position subtitution like you drew. There is a bit of leeway though - I was suprised to learn the chromium carbonyl pi-stacked compound of one of the RTIs actually has better affinity than the parent.

Cool 3d model:














Both of these analogs are less potent at DAT than cocaine is, IIRC. But some analogs with more flexible linkers are better though:





(this is all from ACTUAL binding data, not STP - I am indebted to the hard work of Nagelfar for the almost too-comprehensive wiki page on phenyltropanes & their affinities. One would do well studying the data there before coming up with new ideas for DAT substrates.)


----------



## Nagelfar

^thank you sekio, I also started a list of methylphenidate analogs, though no where near as rich in showing how slight changes can greatly alter binding affinity. My strictly cocaine analog page has C1 substitutions that I've yet to see made on phenyltropanes which add binding affinity too.

I wish I could host the picture. It is somewhere on commons.m.wikimedia.org File:1-phenylcocaine.svg


----------



## Gaffy

I will visit it this afternoon, seems interesting! As for the phenyl=>phenyl-cyclohexyl-2 it is sometimes a better option than phenyl-cyclohexyl-1, in the case of the previous compound for exemple, according to the untrustable STP prediction of receptor binding probabilities  Which isn't always the case, like with PEA PC1 substitutions, here in the case of PC1ethylalphamethylmethylamine, PC1 sub of Meth



As for the PC2 amphetamine it has a lot of dopa with lesser activity at other receptors  vs the PC1 which maintains other activity, according to the untrustable STP predictions . (But you can trust Gaffy)

I would like to add that ring-substititions of the phenyl on these PCs seems to make them almost inactive, maybe substitutions makes these bulky compounds "too" bulky? ^^
Nagelfar, would you mind if I asked you to add this one to your methylphenidate analogs? 





I would like to add that ring-substititions of the phenyl on these PCs seems to make them almost inactive, maybe substitutions makes these bulky compounds "too" bulky? ^^


----------



## sekio

If I were a betting man, I would say that N-methyl-1-(1-phenylcyclohexyl)propan-2-amine and relatives would be poorly active as dissociatives or as stimulants. Sorry Gaffy, nothing personal, but almost every structure you post makes me roll my eyes. The monkeys-at-typewriters approach might yield something eventually but it's not my preferred school of thought.

Curiously enough it overlays with a structure that is an isomer of PCP plus a methylene linker. Sort of reminds me of desoxypipradol, so there is still some hope for it having activity. The wacky high LogP and single heteroatom (no metabolic handles) would suggest a compound of rather long duration.






I have to wonder how STP works... does it actually do 3d modelling behind the scenes or is it predicting binding off of strictly 2d structures? Maybe I will have to play with feeding chiral compounds into it and see what changes, if anything. I have a bad feeling that it is a simple machine learning type thing that takes a SMILES/2D structure and matches similarity versus certain known standard compounds. This would explain why it says _(by homology)_ on some results. Maybe it's doing prinicpal component analysis or something?

If you want a concerning demonstration on how STP is not as accurate as you'd like, loperamide seems to be a scaffold that it has a very hard time with. Lope itself is correctly identified as a mu-ligand, and as I understand it it is reasonably selective for that receptor. Now for some reason, STP says that it binds at 5-HT2b, Histamine H2, Adrenergic beta, SERT, Adrenergic alpha-1a, mu opioid, Dopamine D3, delta opioid, kappa opioid, sigma opioid, CYP2D6, tyrosine kinase TIE-2, Adrenergic alpha-2a, Adrenergic alpha-2b, Dopamine D4, Histamine H1, and Histamine H3, all with very high probability.  Last I checked that's 16 extra targets predicted that don't actually factor into loperamide's activity at all.

Doing things like adding a 3-methyl (on the piperidine), or swapping dimethylamide to pyrrolidine amide, or substituting the _para_-chlorine for another halogen or a methoxy, all things that should result in moderate changes in affinity at mu but very little else, don't help either. It just makes things even weirder.

This all seems to point to STP not doing anything too fancy and certainly not doing any actual modelling or docking simulations.



> Nagelfar, would you mind if I asked you to add this one to your methylphenidate analogs?



I think you'd need to track down a paper where it was synthesized and tested before it gets an official entry. I don't like putting words in other people's mouth - but if you look at the carefully curated pages Nagelfar's assembled, they are all backed by peer-reviewed data. (You will notice a definite lack of any STP guesstimates there!) That is, the compounds have actually been made and tested and had their binding affinities measured. That's part of why I find it so impressive and useful.



> I would like to add that ring-substititions of the phenyl on these PCs seems to make them almost inactive, maybe substitutions makes these bulky compounds "too" bulky? ^^



Or it could just make the compounds different enough from a structural standpoint, decreasing the quality of matches to known actives, and reducing the probability thusly.


----------



## polymath

^ That looks a bit like tramadol, except that it is a cyclic amine.


----------



## sekio

Technetium? In _my_ cocaine? _It's more likely than you think._

Also, does anyone know about the pharmacology of GHB-amide? Presumably, it would be metabolically converted to GHB, but does it also have activity on its own?
I know the cyclic lactam is not anywhere near GBL in activity, as I have never hard of anyone abusing pyrrolidinone.





And Gaffy - this compound below is known in the literature, and looks similar to your doodles, but unfortunately has a >5000 nM DAT Ki. In other words, maybe blazeocaine is not so hot after all.


----------



## Gaffy

Yeah, that one sucks.. As for Blæzøcaine, as you write it, Who knows ^^ It should be freezing cold by the way, that's what I designed it for. Give it a try, a small scale synth, I'm sure you'll enjoy yourself just by doing it  .
Either way, here are some NMDA/Mu/DA spulletjes as I like to say in dutch.







Them stats I keep bringing out.. Won't last
As for the mechanism of STP, go guess  Anyway, show me the way to Autodock! Is it available on Android?


----------



## Gaffy

sekio said:


> Technetium? In _my_ cocaine? _It's more likely than you think._
> 
> Also, does anyone know about the pharmacology of GHB-amide? Presumably, it would be metabolically converted to GHB, but does it also have activity on its own?
> I know the cyclic lactam is not anywhere near GBL in activity, as I have never hard of anyone abusing pyrrolidinone.
> 
> 
> 
> 
> 
> And Gaffy - this compound below is known in the literature, and looks similar to your doodles, but unfortunately has a >5000 nM DAT Ki. In other words, maybe blazeocaine is not so hot after all.


Could yhat technetium cocaine be responsible for hallucinations? Or kinesic capabilitys


----------



## sekio

What makes you think it would do that? As far as I can tell, it's just another cocaine analogue, albeit one with a tethered radionuclide on it. Probably just another variety of stimulant.

You could probably use it to take some cool pictures that show you where your dopamine transporters are located though.


----------



## Gaffy

Because it's emitting gamma


----------



## Gaffy

Bulk cocaine must be 1 to 1,  maybe less, for 4-fluorococaine to be just 3 to one. This isn't a price naming, just some random stats

As for nuclear receptor activity, I sometimes feel like a prophet making designs of molecules  always finding the right one fitting the situation: 





						SwissTargetPrediction
					






					swisstargetprediction.ch
				




Triple nuclear receptors


----------



## sekio

> Because it's emitting gamma



Why do you think gamma radiation would give you hallucinations or otherwise? Many gamma-emitting radiopharmaceuticals are used for various different imaging uses, and to the best of my knowledge, the radiation doses are too low to cause any major damage or strange effects.

A related radiopharmaceutical, ioflupane, brand name DATScan, is used for a similar purpose, imaging the DAT protiens. It uses radioactive iodine instead of technetium.
I think the dosage is below that needed for a reliable stimulant effect, but it still produces some mild mental changes, as described below.





_Common side effects of ioflupane (123I) are headache, vertigo, increased appetite and formication (crawling sensation on the skin). Less than 1% of patients experience pain at the injection site.

The radiation risks are reported as low. The committed effective dose for a single investigation on a 70 kg individual is 4.6 mSv. Pregnant patients should not undergo the test. It is not known if 123I-ioflupane is secreted in breast milk however it is recommended that breastfeeding is interrupted for three days after administration._



> Bulk cocaine must be 1 to 1, maybe less, for 4-fluorococaine to be just 3 to one. This isn't a price naming, just some random stats



Stats about what? If you're making some obtuse reference to pricing, then on paper 4-fluorococaine should not be that much more expensive in bulk, if you can come up with a nice way to cleave the benzoyl ester selectively then you can easily make it from cocaine, or from ecgonine.


----------



## Nagelfar

Gaffy, as sekio said, it needs a referrece to be included in WP, otherwise it violates WP's "original research" rules. (people dig into WP as inaccurate, but what you need to pay attention to are the links to the references and trust those)

Anyway, I am limited to my phone right now, and I cannot so much as cut and paste a link with it to add an image here.


----------



## sekio

> As for nuclear receptor activity, I sometimes feel like a prophet making designs of molecules always finding the right one fitting the situation:



Another interpretation might be that any old crap you punch into STP has a reasonably good chance of having a high probability at at least one receptor, especailly small "druglike" compounds that adhere to Rule of 5.

I don't get where you infer the activity of that compound at all. The probability rankings are all very low. If anything, the 2nd and 3rd rank are COX1 and COX2, meaning it's an anti-inflammatory. But those have equally as bad probability.


----------



## Nagelfar

Found out how to paste with my phone (it's not easy, don't expect a lot from me)

The above is a phenyl C1 substitution of cocaine, which not only has greater affinity than cocaine at DAT, but is also a more potent sodium channel blocker (topical/local anesthetic). I wonder what a phenyltropane version would turn out as.


----------



## Nagelfar

^not showing up? It showed up in my text box! Oh well.


----------



## sekio

Like a ghost in the mid-morning, I swooped in and fixed it for you. The forum software doesn't like SVG files, it needs to be a bitmap format - so use the links at the bottom of a Wiki image.







> I wonder what a phenyltropane version would turn out as.



Reminds me of the very simple diphenyltropanes.


----------



## Nagelfar

sekio said:


> Like a ghost in the mid-morning, I swooped in and fixed it for you. The forum software doesn't like SVG files, it needs to be a bitmap format - so use the links at the bottom of a Wiki image.


Whoops, think I edited it in the meantime. But thank you sekio


----------



## Gaffy

It's Funny how a 3-OH on that dimethylpentanephenylpiperidine changes stats to opioid action



Gaffy said:


> Bulk cocaine must be 1 to 1,  maybe less, for 4-fluorococaine to be just 3 to one. This isn't a price naming, just some random stats
> 
> As for nuclear receptor activity, I sometimes feel like a prophet making designs of molecules  always finding the right one fitting the situation:
> 
> 
> 
> 
> 
> SwissTargetPrediction
> 
> 
> 
> 
> 
> 
> 
> swisstargetprediction.ch
> 
> 
> 
> 
> 
> Triple nuclear receptors



Please excuse me, I've had 19 alcohol doses today. Confinement isn't really a good thing to me, I normally get high..

Nagelfar, take a look at these: I prefer thse to cocaine as they are faster to draw but still reflect the overall pharmacology (do they?)

As in your picture, one carbon away from the carbomethoxy- and from the N-methyl
On the other side, one carbon away from the n-Methyl





Differences in SER binding probability, approx same dopa. Have you got any references on the second substitution done on cocaine ?

Here done with phenyltropane





And to take our mind off things,

OH-JWH018


----------



## Nagelfar

Except for your one, they don't have the bridge that makes the boat formation in 3D. One that does puts phenyl on at the five position, quite different from the one position. From studies every change at the six or seven position hinders binding to some degree, since it's opposite the carbmethoxy side I'd figure it would hinder binding also.


----------



## Gaffy

Where are my posts?


----------



## sekio

moved to the doodles thread


----------



## Gaffy

Oh, ok, no problem!


----------



## sekio

Cyclovalone, which is "a choleretic and cholagogic agent", or so I'm told. An analog of the active principle of tumeric - curcumin.
Exercise fot 1st year organic synthesis students: devise a 1 step synthesis from commercial reagents.


----------



## Gaffy

I cheated, but maybe vanilline and cyclohexylone with HCl and dimethylamine? I absolutely do not understand how though.

STP doesn't seem to differ between agonism and antagonism, as I think we can all agree this should act as a antipsychotic, thus an antagonist, but it isn't clarified, which I just noticed!^^






1-Ethyl-3-CarboEthoxy-4-Phenyl-Piperidine. Very high mu binding affinity (around 80%, highest I've seen), higher than ketobemifone, the holy grail of opioids; higher than for dopa, as well as a higher binding probability for M1-4 (×2 at least) than its father compound 1-Methyl-3-CarboMethoxy-4-Phenyl-Piperidine wich has a 100%  binding probability for dopa but only around 20 for mu.


----------



## sekio

^ I could swear a very similar compound was in Lenz's _Opiates_. Don't think they were more effective than pethidine though. I know that the meta-isomer of pethidine is less effective.


----------



## sekio

I am going to go through this thread and replace the bulky STP images with links to the STP results and a much smaller image that _just_ shows the stucture.

In future, can we please not post the whole STP results in an image? I am almost considering restricting all STP discussion to a single thread, because it dorwns out the more academic discussion of everything else...


----------



## Gaffy

The stats! :* Links to the results last for around a month, not more, as I noticed with the posts of my "Gaffy's analog act". Replacing them on the usual would be a real hassle. What i can do is post just the image and comment on the % of binding probability underneath!


----------



## Gaffy

So I was wondering, just how much difference is there between 3,4 MD and 4,5 MD. As you can see in the picture, the double carbon bond position differes from one to another's, maybe that's what's wrong with today's MDMA?


----------



## Bagseed

there is no real carbon double bond because in an aromatic ring system, all the electrons are delocalized....


----------



## Nagelfar

sekio said:


> ^ I could swear a very similar compound was in Lenz's _Opiates_. Don't think they were more effective than pethidine though. I know that the meta-isomer of pethidine is less effective.


Yes, piperidine homologues of cocaine have been studied multiple times.


----------



## Gaffy

Bagseed said:


> there is no real carbon double bond because in an aromatic ring system, all the electrons are delocalized....


Thanks bagseed, what is your explanation for the difference between MDMA made from safrole and the one made from MDP2P? One is euphoric, stimulant and enjoyable, the other is stressful, disphoric and makes you tired.


----------



## S.J.B.

Gaffy said:


> Thanks bagseed, what is your explanation for the difference between MDMA made from safrole and the one made from MDP2P? One is euphoric, stimulant and enjoyable, the other is stressful, disphoric and makes you tired.


There's already a thread for this kind of speculation, please take your discussion there.


----------



## sekio

3,4 MDMA and 4,5 MDMA are actually the same molecule. Playing with molecular models should establish that.





These two MDMA molecules were each made by a different synthesis, can you tell which?


----------



## Gaffy

Does the angular curve inbetween the carbons then explain the difference between MDMA made from MDP2P and MDMA made from safrole? Just like Meth made from Ephedrine being like 10x times better than meth made from p2p. 

Any idea for another M1-4 compound? Different structure?


----------



## Gaffy

When is Nagelfar becoming moderator?? :-D


----------



## sekio

> Does the angular curve inbetween the carbons then explain the difference between MDMA made from MDP2P and MDMA made from safrole?



No. You seem to forget that most MDP2P is made from safrole. In any case, racemic MDMA is racemic MDMA. It would do you good to learn about the 3d structures of organic chemicals: the little line drawings are not 1:1 representations of how these compounds exist in space.



> Just like Meth made from Ephedrine being like 10x times better than meth made from p2p.


Ephedrine is a chirally pure natural product, so meth produced from it is 95% dextro-methamphetamine. Methamphetamine from P2P is only 50% as it's racemic.



> Any idea for another M1-4 compound?



Why, do you like salivation? The effects of muscarinics are not known to be very pleasant.

I suspect your compound is actually an antimuscarinic, i.e. atropine-like. Those are not known to be pleasant. Compare the structure of BZ and others. The dudes at Edgewood Arsenal pretty much beat you to the punch for antimuscarinics.


----------



## Gaffy

sekio said:


> I suspect your compound is actually an antimuscarinic, i.e. atropine-like. Those are not known to be pleasant. Compare the structure of BZ and others. The dudes at Edgewood Arsenal pretty much beat you to the punch for antimuscarinics.



Do you have an example?


----------



## sekio

I am suprised you aren't familiar with atropine-like deleriants? The muscarinic antagonism is part of what produces the CNS deleriant properties.
Some antimuscarinics are are useful agents to stop things like excess salivation but must be carefully dosed to avoid strange hallucinogenic effects.
BZ was developed as an incapacitating agent for that reason; a dose is measured in the low milligrams and will lead to a 2-3 day long delerious fugue state.
Similar effects are noted in intoxication with solanaceous plants like henbane, datura, brugmansia, etc. and also from drugs with anticholinergic acitivity like diphenhydramine.





Funny enough, one of the "antidotes" to BZ toxicity is sarin or similar nerve gas in a very carefully measured dose... the idea being that the nerve gas will inactivate some of the acetylcholinesterase enzymes, increasing cholinergic signalling, and overcoming the blockade of muscarinic receptors by BZ. Obviously this is not clinically reccomended but...


----------



## Gaffy

I actually am familiar with atropine, and have been intoxicated not so long ago with what must have been in the same trend as what you posted.. Very not funny.. Anyway, I will delete my post then, I'm not into making poison


----------



## Gaffy

Could M1-4 antagonism to a small extent as with cocaine be a cause for the inhibition it produces?


----------



## yaesutom

Found a cool javascript chemdraw thing... used to have to pirate the software to get features like structure to name. Anyway smoked some a-pcyp and started thinking about modifications to it... its a very potent stimulant. One of the most potent ones i've tried, almost like MDPV..


----------



## Gaffy

Cool, we've tought of these already, this one should be the winner:


----------



## sekio

OK, as of today, no nore STP posts here, please. Take those to the molecular doodles thread.






Apparently this is active at 5HT2a?


----------



## Gaffy

Is just using STP to use ChemAxon ok? Like in my post above?
As for unlikely Psychedelics, here's one I drew some time ago:





Btw Sekio, is the IUPAC in my signature correct? If not can you name one please?


----------



## sekio

Chemdraw chokes on it, and it doesn't look like a valid IUPAC name, no.
Is this what you meant?




The 3 chiral centers are 2, 3, & 4. Usually if you have a racemic compound specifying (RS) is unneccesary - any unspecified chiral center is assumed to be racemic.

Also, I would prefer you stick to smaller images posted using the [‍img][‍/img] tag.


----------



## Gaffy

I meant the picture I committed to naming GAFFY in the Name-A-Molecule thread ^^ This one:







A-AVP






Alpha-AziridineValeroPhenone


Edit:I just realised the difference between pyrrolydine and pyridine.. I will update that asap!

Done


----------



## sekio

IUPAC for that is 8-methyl-7-phenyloctahydroindolizine. (the fused piperidine-pyrrolidine is known as indolizidine). Stereochemistry at 7, 8, 8a.




(7S,8S,8aR)-8-methyl-7-phenyloctahydroindolizine - just picked a random set of chirality to illustrate the 3 chiral centers.

A related compound: (+)-ipalbidine. No idea on its pharmacology, but it looks familar, no?





Also, aziridines are not the most stable things.


----------



## Gaffy

Thank you Sekio!  I will update my signature. 
Oh.. that's probably why I never came across any aziridine PEA..

Yes, it should be a metabolic compound of it?


----------



## polymath

Is that aziridine meant to bind irreversibly to your monoamine transporters and keep you tweaking for 4 days after one dose?


----------



## Gaffy

Nah just kidding.

I didn't know about the properties of aziridine..


----------



## Gaffy

sekio said:


> IUPAC for that is 8-methyl-7-phenyloctahydroindolizine. (the fused piperidine-pyrrolidine is known as indolizidine). Stereochemistry at 7, 8, 8a.
> 
> 
> 
> 
> (7S,8S,8aR)-8-methyl-7-phenyloctahydroindolizine - just picked a random set of chirality to illustrate the 3 chiral centers.
> 
> A related compound: (+)-ipalbidine. No idea on its pharmacology, but it looks familar, no?
> 
> 
> 
> 
> 
> Also, aziridines are not the most stable things.


It seems ipalbidine comes from a plant!  Could the ipalbidine be turned into 8-methyl-7-phenyloctahydroindolizine ? The phenyl version of ipalbidine could be good as well but just doesn't seem as good as the piperidine version.
Searching for it renders only one result from a book citing plant alkaloids. No other results.
Did you find it via STP? If so there must be a paper about it, maybe 8-methyl-7-phenyloctahydroindolizine has already been synthed and biotested as a derivative thereof.


----------



## sekio

> Could the ipalbidine be turned into 8-methyl-7-phenyloctahydroindolizine ?



Not easily: the phenyl group is on the "wrong" side of the indolizidine. It would yield 7-methyl-8-phenyloctahydroindolizine if you could hydrogenate it and somehow also pull the hydroxy off.



> Did you find it via STP?



Nope, googling for indolizine alkaloids. I only found a structure, no idea what the activity might be.


----------



## Gaffy

STP is taboo but I can tell you that my little finger told me it has mainly D2, D4, SER and overall DOPA action predicted by my little finger's best friend.

Efit: You're right, :'D, I didn't even pay attention to all the postioning that was going on.. My bad..


----------



## Gaffy

Ipalbidine reminds me of a molecule clubcard pointed out to me, McN-5652 





CMN-5662 would have been funnier..


----------



## sekio

Your 8-me-7-ph-indolizine (in what I view as an example of the "monkeys on typewriters" experiment) actually is one of the better performing compounds when put into STP. I don't know whether to congratulate you or accuse you of plagarism...  The "magic 8 ball" suggests it should be some sort of triple monoamine reuptake inhibitor, affinity for VMAT as well, sigma receptor affinity, and possibly D2 receptor binding as well. To me, that sounds like a potential recreational drug candidate.

Now, don't go crowd funding a synthesis quite yet though  If anything, try to come up with a synthetic route, from commercially availiable reagents if possible. Treat it like a retrosynthesis exam.





CHEMBL416959 and CHEMBL1743824, presumed serotonin transport inhibitors.

The similarity to McN5652 is well noted. The structure reminds me a bit of sertraline too.

(I will make a serious pharmacologist out of you yet!)


----------



## Gaffy

On another topic; My bike just got assaulted by two hash-junkies blasting rap, who entered my residency.. Backbrakes stolen along with the suspension's screws, I think they where going for the whole suspension (worth around 150 bucka on its own, Fox suspensions, best there is.) 
Lucky I live in a crowded residency where people are on the watch out, the thievers must've gotten spotted as they didn't get the whole set. Still, the brakes they stole are worth 50-100 bucks, they're hydrolic. I'll go to the cops to deposit a complaint tomorrow, as a good citizen, I'll have to check if my bike is insured.  There are probably cameras in my residency, at least there should be given they just spent around 800k on renovations. I'll make shure to ask the police to check for other residency cameras, maybe it's not their first go at it. I somehow suspect either my father (lol?) who once told me he was a thief, and warned me just two days ago to stash my bike, or my residency's guard, who has been (weirdky not these last few days) quite impolite and once even agressive with me (and arabian, just like the thiefs, which I sae from my balcony as they left). Anyway.. 
These might just be what are just speculations.

Next step is getting the Chinese to start pushing GAFFY and the likes, maybe 2025? When iHexen and other caths will have gone out! 
Can't wait to try it! :D 

At least, a worthwhile design; and guess how..  carrying my name !  
Heh!


----------



## Gaffy

Let's switch to opioids  I feel we've been  focused on stimulants for the past two weeks.


----------



## Gaffy

*Ethyl 2-(Piperidino)-1-3'-hydroxyphenylcyclohex-3-ene-1-carboxylate*

I also like this one. Can't post STP results but it seems lile a winner.


----------



## sekio

TCS1205. A GABA-A subtype a1 partial agonist wirh anxiolytic effects.


----------



## Gaffy

Subunit 5 and 1 GABA
Thanks for the inspiration















The last two wouldn't pass trough STP, no known similar compoumds.


----------



## sekio

maybe because you are missing the hydrogen atom on that lonely alcohol group in the middle.


----------



## Gaffy

Nonono, the molecule drawn in STP wouldn't pass so I drew it in Pubchem

@sekio

I've drank eay too much but don't even feel drunk, I'm going to bed. 
Gn


----------



## Gaffy

8-Ethyl-7-PHenYLoctahydrOIndoliziNE





EPHYLONE


----------



## clubcard

I THINK you need a ketone next to that N. Tertiary amines only seem to be active due to the interaction of  & N:

Who knows if that Tocris ligand is any fun at all. Back in the day I had to tell someone to dump 10kg of 4-MTA that they accepted to clear a debt. I told him how dangerous it was and would he want his kids taking it... it was dumped.

Now, I DID do a deal of work into aminorex series and I am prepared to bet that the p-Me analogue of the McN compound will have potent SRI activity and thus won'tbe fun alone. a 2:1 mixture of p-Me & m-Me is likely good with or without 4-Me.

It's important to see how this class evolved and how a rigid analogue was developed. AFAIK it has yet to be tested in man. As long as Me oxidation is the overriding metabolic path, I would be dubious. For those looking for a high potency I would suggest that the (thiomorpholine analogue of desoxypipradrol is worth looking act. If I wanted it to be complicated, I would demand a p- or m- Me on them at least to begin with but I think the S will result in redistribution.... but I don't know, I am just giving an opinion. We didn't go down this path because (drum roll) it was too complex for the French.... and how many times have I had to say that!


----------



## Gaffy

clubcard you should really slow down, it seems to me you're in some sort of psychosis when I read your messages. Wish you the best


----------



## Gaffy

clubcard said:


> I THINK you need a ketone next to that N. Tertiary amines only seem to be active due to the interaction of  & N:
> 
> Who knows if that Tocris ligand is any fun at all. Back in the day I had to tell someone to dump 10kg of 4-MTA that they accepted to clear a debt. I told him how dangerous it was and would he want his kids taking it... it was dumped.
> 
> Now, I DID do a deal of work into aminorex series and I am prepared to bet that the p-Me analogue of the McN compound will have potent SRI activity and thus won'tbe fun alone. a 2:1 mixture of p-Me & m-Me is likely good with or without 4-Me.
> 
> It's important to see how this class evolved and how a rigid analogue was developed. AFAIK it has yet to be tested in man. As long as Me oxidation is the overriding metabolic path, I would be dubious. For those looking for a high potency I would suggest that the (thiomorpholine analogue of desoxypipradrol is worth looking act. If I wanted it to be complicated, I would demand a p- or m- Me on them at least to begin with but I think the S will result in redistribution.... but I don't know, I am just giving an opinion. We didn't go down this path because (drum roll) it was too complex for the French.... and how many times have I had to say that!



You do that, (ketone) , I'll keep it as it is


----------



## clubcard

Fine.


----------



## S.J.B.

I was surprised to see that there are no data on a methylphenidate/methamphetamine hybrid:


----------



## paracelsius

^ beta amino phenylacetates are unstable. tend to eliminate ammonia (or amine) very easily (even at ambient temperature) to give the styrene and amine. had a hard time isolating similar compounds in the past.unlike the phenydates tho!? but who knows with this particular compound?


----------



## polymath

The other possibility is that everyone assumes someone has already tested that compound in the 1950s or so, and found it useless. I couldn't find any original publication by the guy who made methylphenidate first time back then (and used his wife and himself as a guinea pig).


----------



## Rectify

antihistamine?


----------



## sekio

Irgacure 907, a UV photo-initiator for radical cross linking reactions. Looks like it'd be a cathinone stimulant of sorts if ingested.


----------



## polymath

sekio said:


> Irgacure 907, a UV photo-initiator for radical cross linking reactions. Looks like it'd be a cathinone stimulant of sorts if ingested.



4-methylthioamphetamine is a selective serotonin releaser according to Wikipedia. It could be that this compound doesn't release dopamine either. For some reason the STP online app thinks it could also bind to the GABA-A receptor. Some known direct GABA-A ligands have a heterocyclic ring with both a nitrogen and oxygen atom, maybe that's the reason.


----------



## blueberries

Dioxetamine

Since we're no longer allowed STPs, I should say it's an opioid with NMDA antagonism with high D2 and sigma agonism.


----------



## Rectify

ELIZABETH
2-nitro-5-(2-ethylaminopropyl)-pyridine


----------



## polymath

Piperonyl butoxide, a pesticide that looks like an MDMA precursor






But if you try to halogenate it, the halogen will first go to the benzylic carbon, and you probably can't cleave the long ether tail without destroying the methylenedioxy structure in the process.


----------



## polymath

Fenazoxine, a cyclized derivative of orphenadrine, is said to be a stimulant and monoamine reuptake inhibitor without anticholinergic side-effects.






https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1969.tb09523.x


----------



## sekio

Isn't that nefopam?


----------



## sekio

R-desmethyl-sibutramine reuptake inhibitor, 4nM at NET, 12 nM at DAT, 44 nM at SERT
R-didesmethyl-sibutramine, its metabolite,  13 nM NET, 8.9 nM DAT, 140 nM SERT	

possible cocaine/methylphenidate type stimulant drug?


----------



## jose ribas da silva

sekio said:


> R-desmethyl-sibutramine reuptake inhibitor, 4nM at NET, 12 nM at DAT, 44 nM at SERT
> R-didesmethyl-sibutramine, its metabolite,  13 nM NET, 8.9 nM DAT, 140 nM SERT
> 
> possible cocaine/methylphenidate type stimulant drug?




what the fuck is that a carbonic structure constrained by 90 degrees?


----------



## polymath

sekio said:


> Isn't that nefopam?



Oh, it has a new name. That structure also made me think of an orphenadrine with one of the N-methyls removed. It could be less of an anticholinergic compared to monoamine reuptake inhibition.


----------



## polymath

jose ribas da silva said:


> what the fuck is that a carbonic structure constrained by 90 degrees?



It's a cyclobutane ring.


----------



## blueberries

PC-Adamantane (PCAd)

I have no idea how it would act though as STP hasn't got that far in it's capacity to understand it though...any ideas?


Or....





Ohhh; HOLY CRAP
I know we aren't allowed STP's here but oh my word:


----------



## clubcard

sekio said:


> R-desmethyl-sibutramine reuptake inhibitor, 4nM at NET, 12 nM at DAT, 44 nM at SERT
> R-didesmethyl-sibutramine, its metabolite,  13 nM NET, 8.9 nM DAT, 140 nM SERT
> 
> possible cocaine/methylphenidate type stimulant drug?



The cyclobutyl moiety interested me to the extent that I wanted to add it to the MDMA scaffold - I believe they overlay well. Sibutramine itself has been taken off the market, hasn't it?


----------



## polymath

How small can you make the cycloalkyl ring in propylhexedrine and still retain activity? In some organic chemistry textbook I saw a cyclopentyl derivative that was said to be a stimulant, but I don't have that book anymore.











This was a good example of how the STP online app can produce misleading results. It thinks that cyclopentyl compound is mainly a nicotine receptor ligand and cholinesterase inhibitor, and only secondarily a dopamine reuptake inhibitor (it doesn't have this compound in the database as a known DAT ligand).


----------



## sekio

> How small can you make the cycloalkyl ring in propylhexedrine and still retain activity?







2-aminoheptane is a sympathomimetic, and you cannot really get any simpler than that, I don't think.


----------



## polymath

It's quite surprising that these aliphatic sympathomimetics can produce a cocaine like discriminative stimulus in experiments









						Abuse Liability of the Dietary Supplement Dimethylamylamine
					

Dimethylamylamine (DMAA) is a component of many dietary supplements and has recently been associated with numerous adverse effects, prompting the US military and World Anti-Doping Agency to ban its use as a supplement. The current study aimed to elucidate ...




					www.ncbi.nlm.nih.gov
				





> In the present study, DMAA produced locomotor depression, fully substituted for the discriminative stimulus effects of cocaine, produced partial substitution for methamphetamine (77% drug-appropriate responding), and produced a conditioned place preference. The potency of DMAA was comparable in all three assays (between 2.3–3.3 mg/kg). These results indicate that DMAA produces reward-like effects and may produce subjective effects similar to that of abused psychostimulants, and therefore has potential for abuse.



But ephedrine does, too, so it doesn't mean it's any good as a drug.


----------



## sekio

Solution: Ban all aliphatic amines.


----------



## blueberries

OK, so I was looking through UWA-001 and realised something... it's similarity to two other compounds, namely; Lefetamine and Ephenidine. So I decided to create the most fair balance between all three in an attempt to create an NMDA ant., an opioid and an SDRA all in one. 
I reckon I came fairly close but it can definitely be improved. Anyone want to try? 




Oh and sorry for not clipping it down, I've been working on this for hours now... on a phone. I've got about 8 scraps of paper strewn around with structures, names and values for NMDA, SDRA, HT2x and opioid values, it's a mess and I've had enough. 
Ttyt

PS: if you want the STPs, message me. It does work but it's... unnatural. Oh and the name took me a good 5 minutes to work out and it's still wrong. So I named it Trish (aka three shit chems in one).


----------



## Gaffy

I'm back! Now I just need to read up on 2 months posts


----------



## Gaffy

Would There be the same difference between 8-ethyl-7-phenyloctahydroindolizine and 8-ethyl-7-naphtyloctahydroindolizine as between méthamphétamine and méthamnétamine.


----------



## Gaffy

Or is it more like naphyrone?


----------



## Rectify

<random fluff deleted -polymath>


----------



## Gaffy

Do you know about 3-Methoxy-4-Hydroxy-(Methyl)Amphetamine? Since eugenol is so widely available


----------



## Rectify

Yes.  It is 1/50th as potent as MDMA.


----------



## Gaffy

How comme?


----------



## sekio

because the free phenol makes it too polar to cross bbb very well


----------



## Gaffy

So how come PCP is as potent as 3-OH ?


----------



## clubcard

https://upload.wikimedia.org/wikipedia/commons/thumb/8/8f/Octanitrocubane.svg/220px-Octanitrocubane.svg.png
		




			https://upload.wikimedia.org/wikipedia/commons/3/34/C2N14.png
		


Make a mistake with this and you get to leave the party early.


----------



## Gaffy

IDRA 21, said to reverse memory loss and help with post-traumatic injury brain deficiency, and functions trough Ampakine receptors







I also like this one: CX614






One of my own invention.


----------



## Gaffy

It seems I invented nothing at all with MEPHOZINE, take a look at this : https://en.m.wikipedia.org/wiki/1-Methyl-3-propyl-4-(p-chlorophenyl)piperidine

Still, I rediscovered something on my own, which I can still be quite proud of.!


----------



## Gaffy

Sorry for STP results but I had to post this. Maybe the Best antidepressant? Look at that SERT pbblty! total random discovery!

Original compound
With DOPA
Like polymath's


----------



## sekio

stp results mean dick all


----------



## polymath

No one has put a ketone group at a non-beta position of an alpha-alkylphenethylamine






You can produce something like that from ar-turmerone.


----------



## Shady's Fox

is dresden still around?


----------



## Nervewing

So I've developed a hypothesis-
Going off the structures of the NBOMe's and the NDEPA's (the lovely phenethylamines researched by Hans Meyer in a thread here, they look like lysergamides with all the rings broken and the DOM-NDEPA analogue seems to be a very potent psychedelic), it appears that having some sort of oxygenated group on the 3rd carbon from the nitrogen (i guess gamma substituted) (if you're doing some long N-substituted side chain) may conserve psychedelic effects, if the base phenethylamine structure is a known psychedelic. So what if we retained that structure but cut out all the excess?
I haven't exactly brushed up on my nomenclature so here's a picture of it (as a DOM analogue, and a methoxy group on the gamma position)







Or perhaps retaining the ketone group seen in NDEPA's or lysergamides





Or if you'd prefer a DOB analogue





I was also wondering what sort of impact adding a nitrogen to to the gamma carbon would have





I would imagine a hyroxy group on the gamma carbon would also have a similar effect to the molecules pictured here, whatever that wold be. I would also guess if these ended up being psychedelic they would be extremely potent, along the line of the other long chain N-substituted phenethylamines. And that the DOM version would probably be less potent than a halogenated homologue. Though I am also basing this pattern off of just 2 examples- Is there anything that really stands out that anyone sees that would render this inactive? It may perhaps be a pared down version of our familiar N-substituted structures

EDIT:
Here's a thiomethoxy variation and a tetrahydrofuran too. Wonder what effects those may have? IIRC Hans Meyer found an N-methylthiolane to active. It it follows the gamma-linked oxygen or sulfur pattern then both a tetrahydrofuran and a methyltetrahydrofuran may conserve the same effects, if arranged accordingly (as would their thio- homologues) Thoughts?


----------



## izo

here are some amphetamine/amt hybrids:









						Clipboard01
					

Image Clipboard01 hosted in ImgBB




					ibb.co


----------



## Gaffy

izo said:


> here are some amphetamine/amt hybrids:
> 
> 
> 
> 
> 
> 
> 
> 
> 
> Clipboard01
> 
> 
> Image Clipboard01 hosted in ImgBB
> 
> 
> 
> 
> ibb.co


Shorten thé amphétamine by one carbon and you'll have PCP like tryptamines. Your Idea wasn't Bad they're just inactive


----------



## izo

you mean ala diphenidine?

there have also been made some indole ndma antagonists by parke davis:

1962 - Saturated quinoline and indole derivatives US3035059

turn out that these have more in common with arylcyclohexylamines beeing a cyclizized version of it.


----------



## blueberries

Ooh got a great one today,  even STP doesn't know what the fuck to do with it!

Tellacyclidone or for casual users; Serpente Pyrastaphen



Just an FYI; please kids, don't make this at home!
I was thinking of adding Oganesson on the other side of the Oxo (so still 2). What do you think?


----------



## sekio

texas carbons don't exist


----------



## blueberries

DW I know it's completely impossible, I mean astatine only lasts..what 7hrs at RT?! Still though, looks pretty!
Regardless, what do you mean by texas carbons, is that the DNA shape inside the cyclohexyl?
If so it's unfortunate as they look really fun but yeh; impossible cos electrons.
Well, it could exist as a single carbon ring, right, completely disconnected? Like memantine...sort of!?


----------



## polymath

sekio said:


> texas carbons don't exist



I guess that's why the molecule drawing app has placed red squares around those C atoms.


----------



## clubcard

brijtpip
					

Image brijtpip hosted in ImgBB




					ibb.co
				




Britjepip

Apparently it's getting harder to smuggle methaqualone from India to South Africa so 2-Methyl-3-_o_-nitro-p-methyl-4(3_H_)-quinazolinone is turning up. I mean, it is some x15 methaqualone but SOMEONE is making cheap precursors and as for people putting this stuff into 'witpijp' must be bad news.

I know I keep saying it but all of those synthetic CB1 (or unselective CB ligands) are messed up. I must have seen over 100 GC-MS results an of the 100, 92 had dimers, trimers and polymers were present. Now, those HEAVY (large MW) compounds will not vapourize. They will be pyrolyzed and I really cannot see a good outcome in the long term. I predict a cancer spike in users.


----------



## Gaffy

I know 5-Methoxy LSD exists ,what about this? I suspect it would have some antihistaminic effects as with chlorpheniramine. It should be An imine with a benzene ring, Didn't go trough on the drawer


----------



## sekio

> It should be An imine with a benzene ring, Didn't go trough on the drawer


that would put a positive charge on the nitrogen


----------



## Gaffy

Dopaminergic cannabinoid, shares androgen and estrogen liability. Should be euphoric.




__





						SwissTargetPrediction
					






					swisstargetprediction.ch
				



Now let'd take the above and make it a bit more expensive, to get pretty much similar effects.. As of yet, a gold holding dopamine agonist etc etc


----------



## sekio

> Dopaminergic cannabinoid, shares androgen and estrogen liability. Should be euphoric.


I would bet money that it lacks any central nervous activity at all.
*You can't just plug a random compound into STP and read the top 5 predictions off as the gospel truth.* Especially when the predicted match probabilities are all super low.
If you stopped to do some critical thinking about your structures then people may actually take you seriously as a drug chemist. Not only computable metrics like the Rule of 5, LogP etc, but also structural homology to known active drugs & adherence to known SAR. Just as a start, a hydrocarbon with 1 heteroatom is going to have solubility/kinetic problems...



> As of yet, a gold holding dopamine agonist etc etc


This reminds me of when I was like 7 years old and would draw hilariously complex "molecules" with heteroatoms everywhere, then ask my dad what it would do. 
with respect to organogold compounds wiki sez: _Gold(III) complexes are 4 coordinate, square planar, diamagnetic, toxic, 16 electron species. _
doesn't sound to me like you can make that freaky gold-in-the-middle cyclohexane


----------



## Gaffy

Gaffy said:


> Ipalbidine reminds me of a molecule clubcard pointed out to me, McN-5652
> 
> 
> 
> 
> 
> CMN-5662 would have been funnier..


Semen... Get it??


----------



## clubcard

image-2020-10-23-234838
					

Image image-2020-10-23-234838 hosted in ImgBB




					ibb.co
				




Rigid analogue of nortilidine. Sadly, I do not think it possible to produce just the 1 isomers. I came across it when I learnt that fencamfamine has opioid properties. Well, Camfentamine had more pronounced opioid properties so I guessed that the ester/reversed ester was a structural requirement as it overlays the 4,5 ether bridge of morphine and what have you.

When designing a new RC, remember that the simplicity of the synthesis is vital. U-47700 could be made in 1 step from 2 commercially available chemicals. I am presuming that fentanyl has clung on because 'cooks' know how to make it but for my money, a morphinan some x80M is a much better option. For a start, it's effects last for 6-8 hours... it's a butorphanol analogue, but not one that a junkie would touch.


----------



## paracelsius

^ I doubt this compound is going be stable. especially in that trans configuration. the secondary amine might easily attack the (already reactive) benzylic carbon to give an aziridine with propionate as leaving group.  the aziridine might then get ring opened/hydrolyzed easily (cf anchimeric assistance ie neighboring group participation).  at least with the free base in aqueous solution, something to worry about!.but who knows unless you actually make it and see! (notice that wont happen with nortilidine tho!)


----------



## sekio

aziridines are not particularly stable, I know for instance that the acetate ester of ephedrine is stable so this should be too


----------



## xen2xen

Allyloxetamine - AXE





Ethylthioetamine - TXE-2


----------



## Gaffy

4F-DMC




4F-DMC


----------



## sekio

benzonatate, a sodium channel blocker/local anestehtic used as a ... cough supressant? and if you puncture or chew the gelcaps it can cause such profound numbness in the mouth that it can prevent effective breathing ro cause you to choke on your tongue or whatever?
look at those polyethylene glycols tho
reminds me of naloxegol (the opioid antagonist version of immodium - doesn't cross BBB)


----------



## Gaffy

sekio said:


> benzonatate, a sodium channel blocker/local anestehtic used as a ... cough supressant? and if you puncture or chew the gelcaps it can cause such profound numbness in the mouth that it can prevent effective breathing ro cause you to choke on your tongue or whatever?
> look at those polyethylene glycols tho
> reminds me of naloxegol (the opioid antagonist version of immodium - doesn't cross BBB)


Is that what caused me to be unable to drink for 24h, let alone eat, after getting my wisdom teeth removed? Dmn the length of these


----------



## Gaffy

@sekio, I'm asking you the permission to post the two molecules I posted in Dresden's thread, to discuss the stp results where the chloro one has HERG but not the fluro one according to STP, and because I think these chems deserve to be posted here, or else I'll feel like this tread is dying


----------



## Gaffy

Check them results Methylphenidate alternate?


----------



## klfiend

SwissTargetPrediction
					






					swisstargetprediction.ch
				




idk if I drew this right but ketamine without the ketone, or double bonded oxygen. 2-chloro-pcm?






						SwissTargetPrediction
					






					swisstargetprediction.ch
				




2-chloro-pce?


----------



## Gaffy

klfiend said:


> SwissTargetPrediction
> 
> 
> 
> 
> 
> 
> 
> swisstargetprediction.ch
> 
> 
> 
> 
> 
> idk if I drew this right but ketamine without the ketone, or double bonded oxygen. 2-chloro-pcm?
> 
> 
> 
> 
> 
> 
> SwissTargetPrediction
> 
> 
> 
> 
> 
> 
> 
> swisstargetprediction.ch
> 
> 
> 
> 
> 
> 2-chloro-pce?


You should go for ketone when there are substitutions on the 2' position





If you want legal ketamine, this is the closest you'll get to 






						SwissTargetPrediction
					






					swisstargetprediction.ch


----------



## sekio

> Is that what caused me to be unable to drink for 24h, let alone eat, after getting my wisdom teeth removed?


I don't think these are used in dentistry. Usually it's lidocaine and epinephrine, or maybe procaine used as anesthetics. But the more likely explanation is just inflammation from the trauma of a major dental surgery. I know when I had my wisdom teeth out the swelling and pain were very intense. They only gave me ketorolac too, which wasn't enough, let's just say....



> You should go for ketone when there are substitutions on the 2' position


reasoning? the ketone is not required for activity, if anything it reduces the potency somewhat and shortens the half life, PCE has similar half life to PCP (super long) but methoxetamine and ketamine have much shorter ones
"desoxy ketamine" should indeed be active, probably less than 2-Cl-PCE though.



> I'm asking you the permission to post the two molecules I posted in Dresden's thread, to discuss the stp results where the chloro one has HERG but not the fluro one according to STP, and because I think these chems deserve to be posted here, or else I'll feel like this tread is dying



post all the molecules you want. Just maybe don't focus on the STP results. Pretend you're a pharmacologist in 1985 and use your brain for once.
actually, fun fact, STP can tell you what *known active* molecules are the closest to your query, click the numbers under "Known Actives"









triple reuptake inhibitor, US-2008261967-A1





pKi SERT 9.50  NET 8.40  DAT 7.90 -- ref


----------



## Gaffy

I came up with this one (before sekio posted his analogue^^) by using my brain, of course STP helps to insure it's at least active.. And it overlays troparil just fine, as well as another drug that I saw on wikipedia, which I did reinvent myself, with a simple piperidine ring and a carbomethoxy instead of the ethyl, the one on wikipedia comes with a 4-Chloro sub. Now when I invented Blaezocaine (using my head) I then realised the pyrroline could be added to the N-Moeity as it overlays just fine.  All with my brain  The fun thing is it can be named Fluoro-Ephedrone or Fluoro-Ephylone, as in 4-Fluoro-7-Ethyl-8PHenYLOctahydroiNdolizinE 4-Fluoro-7-Ethyl-8PHEnyloctahyDROindoliziNE.
But I prefer to name it  FLUORO-EPHOZINE


----------



## sekio

> STP helps to insure it's at least active.


If I meet you in person I'm going to bonk you on the head with a rolled up newspaper. *STP IS NOT AN ACCURATE PREDICTOR OF DRUG ACTIVITY*. All it does is compare structures with known active compounds, there is no docking simulation of any sort done.



> . And it overlays troparil just fine,


How are you overlaying the structures? The only way that makes any sense is by comparing 3D structures (preferably in the active binding conformation, failing that, in energy minimized conformation). "Overlaying" 2d structures doesn't work too well because in reality, most molecules are not perfectly flat and planar.



> as it overlays just fine


There's 3 chiral centres there, so 8 total isomers. Just something to consider. Cocaine has the same issue - of the 8 possible isomers only one is an effective stimulant.
Here's a test for you: 
easy q: where are the 3 chiral centres?
harder q: which do you think is the active conformation?



> Fluoro-Ephedrone or Fluoro-Ephylone


Given that "fluoro-ephedrone" already refers to 4-fluoromethcathinone, and likewise "ephylone" already refers to N-ethylpentedrone, I don't think those are good names.
The IUPAC is actually 7-ethyl-8-(4-fluorophenyl)octahydroindolizine btw - the (4-fluoro) goes on the phenyl ring, not on the 4-position of the indolizine ring )which happens to be the N).


----------



## Gaffy

Thanks for the answer, the thing is I can't seem o understand your questions.. R-S most active? If you could explain it I'll learn from it, please?


----------



## Gaffy

Tnks


----------



## Ketamania

I don't know much about chemistry yet, middle way through college but here's my drawing. The two main peptides responsible for the high users feel from Kambo sticks. The experience is described as opiate like.


----------



## Rectify

Gaffy said:


> Dopaminergic cannabinoid, shares androgen and estrogen liability. Should be euphoric.
> 
> 
> 
> 
> 
> SwissTargetPrediction
> 
> 
> 
> 
> 
> 
> 
> swisstargetprediction.ch
> 
> 
> 
> 
> Now let'd take the above and make it a bit more expensive, to get pretty much similar effects.. As of yet, a gold holding dopamine agonist etc etc


 I don't mean to be negative, but these two molecules do not look promising.


----------



## Gaffy

Rectify said:


> I don't mean to be negative, but these two molecules do not look promising.


No they aren't


----------



## sekio

> here's my drawing.


I like the froggy. Just one little nitpick, the hashed bonds you draw should take the same shape as the wedges, and they should not have a gap at the end









The other way you can draw those bonds is as an unfilled version of the wedge bond, like this:







> The experience is described as opiate like.


From what i've read it is anything but opioid like. I think Hamilton Morris did an episode where he took sapo, let's just say there was not a lot of blissful nodding off.



> Thanks for the answer, the thing is I can't seem o understand your questions.. R-S most active? If you could explain it I'll learn from it, please?


What don't you understand? These aren't too difficult to answer I don't think.
Question 1, Are you "overlaying" structures by making 3D models of them, or are you "overlaying" the 2D skeletal drawings?
Question 2. Can you point out which carbon atoms are chiral centers on your indolizine? A chiral center is a carbon atom that has 4 different groups bonded to it.

(answer to question 2)

*NSFW*: 







Chiral centers are marked: there are 3 sites - carbons 7, 8, and 8a


----------



## Gaffy

sekio said:


> I like the froggy. Just one little nitpick, the hashed bonds you draw should take the same shape as the wedges, and they should not have a gap at the end
> 
> 
> 
> 
> 
> 
> 
> 
> 
> The other way you can draw those bonds is as an unfilled version of the wedge bond, like this:
> 
> 
> 
> 
> 
> 
> From what i've read it is anything but opioid like. I think Hamilton Morris did an episode where he took sapo, let's just say there was not a lot of blissful nodding off.
> 
> 
> What don't you understand? These aren't too difficult to answer I don't think.
> Question 1, Are you "overlaying" structures by making 3D models of them, or are you "overlaying" the 2D skeletal drawings?
> Question 2. Can you point out which carbon atoms are chiral centers on your indolizine? A chiral center is a carbon atom that has 4 different groups bonded to it.
> 
> (answer to question 2)
> 
> *NSFW*:
> 
> 
> 
> 
> 
> 
> 
> Chiral centers are marked: there are 3 sites - carbons 7, 8, and 8a


Ît overlays troparil by the piperidine and tropane nd phenyl position in 2d


----------



## sekio

See, the thing is, the 2D structural drawings we use to depict molecular structures aren't actually accurate at representing the true 3D shape of the compounds in question.
If you want to determine similarity, the way to do that is by building 3D molecular models of the compounds, and comparing those instead.


----------



## Ketamania

sekio said:


> I like the froggy. Just one little nitpick, the hashed bonds you draw should take the same shape as the wedges, and they should not have a gap at the end
> 
> 
> 
> 
> 
> 
> 
> 
> 
> The other way you can draw those bonds is as an unfilled version of the wedge bond, like this:
> 
> 
> 
> 
> 
> 
> From what i've read it is anything but opioid like. I think Hamilton Morris did an episode where he took sapo, let's just say there was not a lot of blissful nodding off.


yeah I actually watched that episode! I like Hamilton's episodes. Yeah it doesn't look to pleasant. But I'm a connoisseur.. haha. Thank you for pointing out what I could do better (I haven't taken orgo yet...).


----------



## sekio

> (I haven't taken orgo yet...).


That's OK, neither have I. (seriously)



> But I'm a connoisseur.. haha.


I'm a connoisseur of nicely drawn structures  I have to say, you have better penmanship than some of my former coworkers...


----------



## Gaffy

I made a little drawing to represent the overlaying, but I can't seem to find a way to upload the image , so here's the link:https://i.ibb.co/1QV2cb6/Exif-JPEG-420.jpg


----------



## Gaffy

This one has a good D1 activity when balanced with the rest of the analogues. It has more serotonin receptor activity aswell.. Legal MDMA??


----------



## Nagelfar

↑Somebody probably has done this. It's a Demerol–phencyclidine intermediate.


----------



## Gaffy

Long time no see nagelfar  how you doin?


----------



## Nagelfar

Gaffy said:


> Long time no see nagelfar  how you doin?


↑I've been around, just not in this thread.

The more I learn about chemistry the less I see my doodles have any significance, unless there's something very specific going on where I'm informed of the angstrom length of a binding pocket and another drug of some length elsewhere or similar.






↑on that note, (4′-)para-cis-propenyl-phenyl-N-methylamphetamine is something I'd really like to see. Doubtful it would have the same selectivity as the phenyltropane but would be interesting nonetheless. Just a basic MDMA clone? - or something more? How would affinity as a DAT releaser be affected?


----------



## Gaffy

Nagelfar said:


> ↑I've been around, just not in this thread.
> 
> The more I learn about chemistry the less I see my doodles have any significance, unless there's something very specific going on where I'm informed of the angstrom length of a binding pocket and another drug of some length elsewhere or similar.
> 
> 
> 
> 
> 
> 
> ↑on that note, (4′-)para-cis-propenyl-phenyl-N-methylamphetamine is something I'd really like to see. Doubtful it would have the same selectivity as the phenyltropane but would be interesting nonetheless. Just a basic MDMA clone? - or something more? How would affinity as a DAT releaser be affected?


Cool to have you around. What do you think of my ephozine derivatives?


----------



## Nagelfar

↑How far back are they?







↑Bet you could never tell this was Effexor (venlafaxine) with only 1 extra bond, could you?


----------



## sekio

Gaffy's thing. I think this is the active isomer. maybe.


----------



## Gaffy

Thanks a lot Sekio :D


----------



## sekio

that's only 1 of 8 possible conformations, it's my attempt at making it overlay natural (-)cocaine, though structurally speaking I think phendimetrazine may be a closer match


----------



## Nagelfar

Interesting, wonder if it'd be improved with a para-arene substitution. From what I understand cocaine analogs are often inproved but not phenmetrazine.


----------



## Gaffy

Drawn with the composition you published it as,
@sekio , it becomes this on STP , which is a switch in isomers right? STP doesn't seem to accept it the way you drew it.. anyway, the stats are a better resulting matches than with the original, with sigma and some others added to the dopamine and serotonine matches. I'm going to call it matching now, nothing else, so there won't be any persuasive convertion of results.


----------



## Gaffy

I really have high hopes for this molecule. Same for the carbomethoxy ones


----------



## sekio

> @sekio , it becomes this on STP , which is a switch in isomers right?


It's the same stereochemistry except for the 7 position.


----------



## Nagelfar

A cross between a constituent from the 'Euphorbia resinifera' "cactus" which is related to capsaicin & LSD. Kind of a hot tamale peyote Frankenstein.






↑Anyone else with a better (or even *some*, unlike myself) knowledge of the ligand binding structure care to take a crack a THC/Phenmetrazine intermediate?

Perhaps just putting a nitrogen on a THC analogue such as "O-1918"?





Crude rendition of what LSD & morphine might look like together. The isomerism of the 14 position isn't correct for LSD, but then again the whole nitrogen bridge probably interferes.




↑Inspired by direct dopamine agonists & serotonin.





↑would this even qualify as a Xanthine?




↑I still love how convoluted this one looks and yet is probably the most likely to be active and improved, keeping the 3β-styrene alkylphenyl and the 2’(–ortho)-acetyloxy (2.10 ± 0.04 & 70 ± 1 for DAT respectively) and the C1 phenyl (32.3 ± 5.7), I also inverted 2β-carbmethoxy to an acetyloxy which should help penetration. This one, as an admirer of cocaine analogs, is pure beauty.


----------



## Smyth2

As Part of a collaboration between Abbott & GSK: Paroxetine + Tebanicline = Paroxnicline.







Wormin & Dettol are other alcohols instead of the Sesamol. Get Wormaxil & Dettoxil, respectively.
Please indicate if you would like my idea.


----------



## Smyth2

Nagelfar said:


> ↑Somebody probably has done this. It's a Demerol–phencyclidine intermediate.



[36882-04-9]

It would be close to MPTP intermediate depending on the route taken.


----------



## Nagelfar

Smyth2 said:


> [36882-04-9]
> 
> It would be close to MPTP intermediate depending on the route taken.


Really? I am certainly not well versed in metabolic pathways, or even what is stable. I suppose by "close" you mean without the bond in the cyclohexane, and still convert into an arene?

(It would be quite useful to laymen if there was an online ChemDraw / MolView etc. program, using basic rules and formula, that showed you what a compound would transition into given normal circumstances, room temperature, or human metabolic lability)

I figured it wasn't too different from what factors contribute to the action of Desmethylprodine. Alas, the folly of assumption to those not schooled in the particulars of a science is legendary.


----------



## Smyth2

I don't have any literature in front of me, but in terms of what you need:

 1-Methyl-4-phenylpiperidin-4-ol [4972-68-3]

You need FGI of the alcohol to a leaving group, then displace with piperidine would work.

A triflate would be the most facile lg.

The actual commerically tried & trusted drug itself is obviously Parkinsan (Budipine).


----------



## Smyth2

On a second note, the Ritter reaction on 1-Methyl-4-phenylpiperidin-4-ol [4972-68-3], hydrolysis of the amide, and base alkylation with pentyl-1,5-dihalide might also be viable.

This second method is actually congruent with the protocol that had been used for Osanetant.


----------



## Gaffy




----------



## Gaffy

Game changer


----------



## Gaffy

Some BS and some good:










What you see here is the métabolite (theoretical) of PYROFAN


----------



## Gaffy

@sekio @clubcard @Nagelfar


----------



## Nagelfar

↑Looks interesting. I never really used these predictive chemical utilities: what does it mean 'being a target' of ‘brain tumor-like protein'? Just ligand? Having no function for better or worse necessarily?


----------



## Gaffy

Stay on coke analogs, be better than that


----------



## Gaffy

Sorry for yesterday, I was drunk and suffering from rebound (loxapac ceased) and was quite unkind. On the tonic, @Nagelfar, I don't really know either.


----------



## Nagelfar

No worries.


----------



## Gaffy

@clubcard , can  you run this one on tour computer? Thank
I'm searching for an everyday drug that isn't too toxic and that can be taken up to 10 Times the minimum dose without toxicity and that can Be taken together with speed/opiates/hash without Being psychotic, and that doesn't disturbs the sleep too much. We on it


----------



## Gaffy




----------



## Gaffy

Gaffy said:


> ATTENTION.


Same for fentanyl. Something to sorry about?


----------



## Gaffy

I got a bit tired of inventing party and euphoric drugs so I took a new path, discovering new femal hormones, lets just say the equivalent of cialis or viagra (sorry for the brand names). Its essentially very simple molecules that are made out of carbom, hydrogen and oxygen, and ressemble dopaminergic drugs but without nitrogen. ?.
Here's what I came up with.
Happy happy


(Give me 5 minutes to post with stp results)


----------



## Gaffy

@sekio, Ill leave you the honor of naming them
The ones without benzene have a smell that ressembles pheromones and create attractiveness and libido. Watch out, some might be cytotoxic or bad for the vagina's flora, research is being done just as with almost all of my inventions..


----------



## Gaffy

It's proof olfaction plays a very big role in libido and attractiveness.


----------



## Gaffy

Is this thread dead?


----------



## Gaffy

Gaffy said:


> And the best one, ever.


----------



## ibtisam midlet

can you give us the smiles of the drugs structure


----------



## Gaffy

You??


----------



## MsDiz

Gaffy said:


> It's proof olfaction plays a very big role in libido and attractiveness.


This has always been known.


----------



## Gaffy

Indeed


----------



## Gaffy

Hey Chinese people, instead of killing sharks, why don't you just try taking this? Or breed them ecologically and put this in their food, even better! Chili wang fang chi wang


----------



## Rectify

"Molecular Structure Is The Key To Understanding."--Transformer Proverb.


----------



## xen2xen

Trifluoromethoxetamine - TFMXE


----------



## Gaffy

Very toxic


xen2xen said:


> Trifluoromethoxetamine - TFMXE


----------



## xen2xen

Gaffy said:


> Very toxic


Can you expand on why you think that is?


----------



## Gaffy

Nope


----------



## xen2xen

TTFM


----------



## Smyth2

xen2xen said:


> TTFM


Did you hear of a compound called *FAZ: *1-[2-(3,4,5-trimethoxyphenyl)ethyl]aziridine [36266-37-2]








						Effects of mescaline and its derivative N-[3,4,5-trimethoxyphenylethyl]-aziridine on the spatial orientation of rats in a T-maze - PubMed
					

The central effect of mescaline and of its derivative N-[3,4,5- trimethoxyphenylethyl]-aziridine (FAZ) after their stereotaxic administration into the lateral ventricle of the brain was studied in behavioural experiments on rats. The effect of the two substances was tested by a method studying...




					pubmed.ncbi.nlm.nih.gov
				



Raj K Razdan, US3889600 (1975 to Us Army).


----------



## Gaffy

Sert antagonist against sérotonine syndrome?


----------



## Gaffy




----------



## Nagelfar

quinisocaine + pramipexole


----------



## Gaffy

Nagelfar said:


> quinisocaine + pramipexole


Intersting..  
What pharmacologue would you expect from it? 
BTW, where thé f is Sekio. Hospital again?


----------



## Gaffy

Gaffy said:


> @clubcard , can  you run this one on tour computer? Thank
> I'm searching for an everyday drug that isn't too toxic and that can be taken up to 10 Times the minimum dose without toxicity and that can Be taken together with speed/opiates/hash without Being psychotic, and that doesn't disturbs the sleep too much. We on it



Noddy on low doses (2-4)mg and stimulating but a.bit off at 10-15mg. Adaptoguinny


----------



## Nagelfar

Gaffy said:


> Intersting..
> What pharmacologue would you expect from it?
> BTW, where thé f is Sekio. Hospital again?


Not sure about Sekio or my compound. I just found the chemistry interesting because of how much the sodium channel blocker overlays the dopamine agonist. Thought it notable.


----------



## Gaffy

Overlaying drugs like you did with phendimetrazine and nicotine doesn't really work buddy.


----------



## Nagelfar

Gaffy said:


> Overlaying drugs like you did with phendimetrazine and nicotine doesn't really work buddy.


Could you cite which one you are referring to? (perhaps by quoting it, I assume you mean me).

I don't know what you mean by "work", did I claim otherwise? I wouldn't expect even a forth of these imaginary compounds to be active. This is mainly 'aesthetic' outlet for shapes, predominantly in a 2D visual context.


----------



## Gaffy

.. ... .. ....... .. ...


----------



## Gaffy

.... .,... .... ..,..... ...,... .......,...... .......,..,. Niiiiice. 








						Screenshot-20210529-015230
					

Image Screenshot-20210529-015230 hosted in ImgBB




					ibb.co
				






@Dresden


----------



## Gaffy

Screenshot-20210529-165116
					

Image Screenshot-20210529-165116 hosted in ImgBB




					ibb.co
				




.... .. .... .. . ... ... .  ....... ... ....... .. ..
Keep a secret.

KIEFER


----------



## Gaffy

And thé most euphoric opioid I trust: 








						Screenshot-20210529-191954
					

Image Screenshot-20210529-191954 hosted in ImgBB




					ibb.co
				




It's a secret, but it creates 3 drugs when métabolisés. .. ... .. .. ... ... . ... .... ... . . .. .. .... .  ... ... .. .. ... ...... ........ .. ......... .... .top much info


----------



## Gaffy

It's z testastrial drug


----------



## Gaffy

Gaffy said:


>


Cinical indirect agonism to protec from htp or just a drug that make you tired and then very stimy


----------



## Gaffy

... ... ..... ..... .. ..... .... ....... ..... ... ... .


----------



## raio

hey; i should have maybe been posting some here; i’ve been looking at a lot of compounds with iSpartan. i was also using mo-cubed beforehand. and now i see there is a target predictor. not sure if it’s really accurate, but it sure is a step up from what i knew.


----------



## raio

i ran this http://www.swisstargetprediction.ch/result.php?job=1111680286&organism=Homo_sapiens

for https://molview.org/?smiles=C12OCOC=1C1CC(N)CC=1S2

it’s a bummer and cool that i’m actually getting feedback to learn from.


----------



## raio

i like this one but it doesn’t show MGluR2 (MGlu2) listed. but a lot of classical psychedelics aren't showing that receptor on the predictor (cogener with 5HT2A actually. some list the 5HT2A and the MGluR2 separately and as predicted targets in known compounds) either.


C(C(F)(F)F)1=C2C(F)(F)C(F)(F)OC2=C(CCN)C=C1OC





__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				




https://molview.org/?smiles=C(C(F)(F)F)1=C2C(F)(F)C(F)(F)OC2=C(CCN)C=C1OC










this one too

C1(C(OC)=CC(CCN([H])[H])=C2C=1C(CO2)(F)F)C(F)(F)F






__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				










__





						MolView
					






					molview.org
				





https://molview.org/?smiles=C1(C(OC)=CC(CCN([H])[H])=C2C=1C(CO2)(F)F)C(F)(F)F


----------



## raio

and....haha there’s this one



C12C(F)(F)C(F)(F)OC1=C(CCN)C=C1OC(F)(F)C(F)(F)C1=2





__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				









__





						MolView
					






					molview.org
				











then there’s this..........






C12=C3C(OC(C3(F)F)(F)F)=CC(CC(C)N([H])CCC(N(CC)CC)=O)=C1OC(F)(F)C2(F)F






__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				









__





						MolView
					






					molview.org
				





this one  pulled up three things that worry me which worry me about all experimental/investigational psychedelics; thrombosis . i don’t really know what i’m doing (i like the supposed einstein quote on that really , because some people who are very educated in sciences; and given lots of access , can be snobs)
but i like to keep thinking and rolling with it and re approaching; not fully disgarding slight possibilities but wising up to knowledge from people more knowledgeable than myself. there’s a lot to learn; some things i think about are the affinity to the serotonin 2a compared to the complex  it makes with the metabotropic glutamate r2 receptor. (i was wondering if a specific 2C receptor antagonist that didn’t effect 2A could drive some psychedelic to be experienced different because it couldn’t displace the antagonist at 2C and instead went to 2A more than normal; or to the 5HT2A*MGluR2 complex more than it would. i guess they probably thought and looked or didn’t because they thought it wasn’t important; or can’t because there isn’t a selective and potent enough 2C antagonist . idk. but there seems to be safe psychedelics and unsafe ones and the effects are all different in actual experience; so i’m just wondering where the gold is and what makes a psychedelic really good to take; compared to merely potent and possibly deadly

i didn’t run the alpha methyl because of how 2c-b fly turned to bromo dragonfly was seemingly giving much more thrombosis. i’m not sure if that is at equivalent doses or because of potency issues in overdose, but even DOI seems to have thrombosis.  heroic levels of 2C-I don’t seem to be reported much; i’m just incomplete on my knowledge here. what i’ve gathered is that highly potent stuff seems to be real directed at 5HT2A but the affinity for the 5HT2A * MGluR2 cogener is not reported. usually it’s a 2C/2A comparison. the 2B is similar but not identical to the 2A but i don’t know if it is also a thing that varies depending.

but the potent stuff doesn’t seem to be better; if anything worse.

i was just wondering if the unique effect of flourine gives it “color” but also makes it famn near impervious to attack. also though it seems to be one of the most electron withdrawing things i could model on “mo-cubed” which while likely very inaccurate, has a quantum computation function and i will post the one where it has a 2-SMe too because that was rad to look at (well, if it shows up ok on the target predictor maybe)
but i was thinking maybe an NDEPA would make it less potent ironically, because i think they are less potent than NBOMe compounds “normally”, from what i read from hans meyer. so i’m wondering if the crazy flourine molecule had some problems like the bromo dragonfly (but it isn’t a modified  aromatic so it’s a plain benzene , and hopefully it’s different..) then being a regular PEA seemed the first best test; and then skipping straight over the alpha methyl; to the alpha methyl n diethyl propan amide. maybe

but the target predictor gives no targets as percentages: 100 though: and in an order that j am unsure of regarding priority;

my main concerns and hopes that it doesn’t touch upon at all are


•Coagulation Factor VII     





__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				





•Thrombin and Coagulation Factor X





__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				






•Thrombin





__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				





•Corticotropin releasing factor receptor 1





__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				






i see the first is 5HT2A (no actual percent likelyness given)
but also, very far down is the 5HT2B, so that’s what i mean by this not being maybe very accurate; but i’ve learned to take what i can get to educate myself; from mol view to mo-cubed to iSpartan to now this;

it’s cool to see i have a lot more to learn and reach for in biochemical receptors, biopharmacology etc, when at least the data seems accessible

ok well idk


----------



## raio

whaaat ......? no percentages but only three listed receptors


Serotonin 2a (5-HT2a) receptor _(by homology) _HTR2A​P28223​CHEMBL224​Family A G protein-coupled receptor​0.0


0 / 4   

​Androgen ReceptorAR​P10275​CHEMBL1871​Nuclear receptor​0.0


3 / 0   

​Proto-oncogene c-JUNJUN​P05412​CHEMBL4977​Transcription factor​0.0


1 / 0   





Showing 1 to 3 of 3 entries





C12C(F)(F)C(F)(F)OC1=C(CCN([H])[H])C(SC)=C1OC(F)(F)C(F)(F)C=21





__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				








__





						MolView
					






					molview.org
				












haha; this thing looks nuts on the android app mo-cubed, with the quantum computation of electrostatic potential !





just throwing this one in. it has the first two as estrogens


C12C(F)(F)C(F)(F)OC1=C(CC(N(CCC(N(CC)CC)=O)[H])C)C(SC)=C1OC(F)(F)C(F)(F)C=21





__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				









__





						MolView
					






					molview.org


----------



## raio

but anyway, so that’s all nice even if not besides the three ones that are maybe likely; all those flourines seem really difficult to get on there. so while i hope i run into some chemists on some other forums who have the secret knowledges haha

i’m more realistically interested in this








__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				







Canononical SMILES
(CC)C(=O)C1CN(C)C2Cc3cnc4ccccc(C2=C1)c34

Isomeric SMILES
O=C(N(CC)CC)C1CN(C)C2C(/C3/C4=C(C2)C=N/C/4=C/C=C\C=3)=C1

inchi key
SRWNBOCIPZBNRE-UHFFFAOYSA-N

inchi
InChI=1S/C21H25N3O/c1-4-24(5-2)21(25)15-10-17-16-8-6-7-9-18-20(16)14(12-22-18)11-19(17)23(3)13-15/h6-10,12,15,19H,4-5,11,13H2,1-3H3





__





						MolView
					






					molview.org
				








__





						MolView
					






					molview.org
				





i wasn’t even sure if i should have posted it really. not sure the best approach when it comes to it. lose it all in the light or keep it secret and spread around like a secret society wink wink you know.













and this





__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch
				









Canononical SMILES
CN(C)CCc1c[nH]c2cccc3ccnc3c12

Isomeric SMILES
C12=NC=C/C/1=C/C=C\C1NC=C(CCN(C)C)C=12

inchi key
TXWVQLPDEKNAAD-UHFFFAOYSA-N

inchi
InChI=1S/C15H17N3/c1-18(2)9-7-12-10-17-13-5-3-4-11-6-8-16-15(11)14(12)13/h3-6,8,10,17H,7,9H2,1-2H3



i bet they’re nice colors at least.
and highly fragile


----------



## Gaffy

New LSD


----------



## Gaffy

Please enter a validé message


----------



## raio

me ? i don’t know. but that doesn’t look like LSD lysergic acid diethylamide LSD; it is “lysine specific demethylase” and stuff about that. i typed it in on google.


----------



## Gaffy

Lolz


----------



## Gaffy

LSD 1 CORREST DANGER. Hhah


----------



## Gaffy

Music : .. ... ... .... ... . ... ... . . .. ... . .... ... ... ..... ... ..,,
62,41,26


----------



## Rectify

I See Dead People.  And Robots.  And Robots.

Turns out I'l allergic to Gaffy.


----------



## sekio

swiss target prediction is a guessing tool not a reliable affinity predictor.


----------



## polymath

I just inserted the structure of clotrimazole (an antifungal medication) in Swiss target prediction today and found out that a toxicology database says it binds to mu receptor with affinity 700-800 nM and to delta and kappa with slightly less affinity. Almost all other receptor affinities were much weaker. Not that anyone would take enough of a compound meant for women's yeast infection to cause effects at that affinity level, and it's not clear if it's even an agonist, but it's an example that well known substances can have unexpected effects at some concentration level. An acute toxicity test showed it caused "abnormal swimming behavior in fish", .


----------



## raio

this one i forgot to link, with the lysergide one that uses the azulene as well

https://molview.org/?smiles=C1/C=C\C2=NC=C(CCN(C)C)\C\2=C\C=1

@sekio it looked like it showed dopamine activity in that swiss site. i didn’t look at the swiss docking part yet; i know it’s not a really reliable way to look at anything,  but this one really interests me . smoking would seemingly be out of the question, but nebulizing would maybe be the ticket.


?





edit: also, is there any info on this (from the arecoline cocaine analog thread) yet ? https://opsin.ch.cam.ac.uk/opsin/ 1-methyl-3-carbomethoxy-4-(phenyloxy)piperidine.png


----------



## raio

Rectify said:


> I See Dead People.  And Robots.  And Robots.
> 
> Turns out I'l allergic to Gaffy.


do you think this would only be serotonergic , not psychedelic;

not sure that it is dopaminergic.

what say all ?


----------



## izo

id say similar to the known phenylpiperazines, so serotonergic but not psychedelic in the classical sense.


----------



## polymath

raio said:


> do you think this would only be serotonergic , not psychedelic;
> 
> not sure that it is dopaminergic.
> 
> what say all ?











						2C-B-PP - Wikipedia
					






					en.wikipedia.org


----------



## raio

that’s cool . i was mistaken, thinking of the type with a carbon between the group and wrongly assumed it was inactive. ie: https://en.wikipedia.org/wiki/2C-B-BZP

apparently it says 2c—aminirex is psychedelic, i was wondering about that ! https://en.wikipedia.org/wiki/2C-B-aminorex

i wonder what that’s about, and what a methyl does to it. interested in the mescaline ones too but shulgin seemed to note that TMA wasn’t the same. maybe it would be diffirent. the 3,4,5 things interest me even though not much ever panned out from them. i still haven’t seen info on  the alpha methyl of TB (thiobuscaline) ; i wonder what the aminorex and methyl aminorex ones would be like.


----------



## raio

can anyone familiar with arylcyclohexamines weigh in on these things i drew up, especially the attempt to bypass ketamine’s bad metabolites.

i was hoping maybe that scheme would work towards other things like mxe etc.

but what about 2,3 substitutions where halogen is at 2 and oh at 3.

nitrile in place of nitrile at 2

and A) benzofurans/thiobenzofurans

B) 1,2-benzisoxazole/1,2-benzisothiazole

hydroxide,  halogen or nitrile on points ( 2 or 3 position relative A, 3 position relative to B)

thiocyanate is something else i wonder about because maybe it reacts in receptor or stays protected intact and has effectively electronic effects ?

please share wisdom so i can understand more clearly.

thanks

what is a better site to use for structure pictures ?


----------



## raio

when i enter them into iSpartan, the orientation shifts around (not just the isomer) and even though that program isn’t really known as accurate (can’t run a “real” calculation in it)
i like to use it as one look at it

mo-cubed in android can give another look.

i hope to get a real molecular simulator; and molview isn’t realistic, it only gives data like CID# CAS#, SMILES etc, and a linkable model that shows the idea

but




i just guess that a lot is physical orientation and the other part is quantum electrical features


i’m a novice but need guidance in clearing up my hypothetical dream/imagine/brainstorm/research vision


----------



## raio

i gather that OH is best at 3 for effects, OMe is mixed and active but then why not try for a dihydrofuran using that approach, if it isn’t a drug and prodrug to the OH and an overlap of effects ? and then maybe shifting(?) aromaticity and making it a bit larger in area with an aromatic benzofuran, would give a modified result for a “2” halogen or a “3” OH or OMe (or Methyl, whatever though idk) (CN ?) with the calcogen at the appropriate area to simulate a 2 or 3 (phenyl) positioned atom with modified electronic effect. mo-cubed always showed a positive electrostatic potential in Sulphur when using the “quantum calculations”  in thio-dibenzofurans, especially so when they were aromatic thiobenzofurans . i tried to see how to modify 2-TOX and 5-TOX in shulgin’s p.i.h.k.a.l . i could run calculations on anything at or under 50 atoms.

so i wonder if that would be effective here. the effects of thiofuran in Tiletamine are heavy dissociative; but in the methamphetamine version; it isn’t; so i’m wondering that a thiobenzofuran with the 1-S at what would be 2-Phenyl; would not be like Tiletamine

and then maybe the potency and psychoactive effect could be increased by a “3-phenyl” attempt at something like OH, OMe, Halogen, Nitrile ? at the 2 or 3 thiobenzofuran position ?


my investigatory logic needs experiential real world feedback to see clearer


edit; also i was wondering about this compound being trialed, or the OMe, Cl version

5-OH-Tiletamine





						MolView
					






					molview.org
				




and the same with this

4-OH-Tiletamine





						MolView
					






					molview.org
				




and lastly i guess...... ..........

Isothiazole of Tiletamine (doesn’t look great on iSpartan ? idk)





						MolView
					






					molview.org
				




Thiazole (N at 3 where 1 is methamine ligand and group OR if tou number it as a thiozole https://en.m.wikipedia.org/wiki/Thiazole then the S is one, the branch of ligand is at 5 and the N is at 3) (looks ok on iSpartan; where are the papers on this stuff, people must have looked into this sometime on the cutting floor,!wtf)





						MolView
					






					molview.org
				







Tiletamine seems like crap but i really don’t know personally i’m just wondering how tinkering affects the molecules and effects at the target

thanks


----------



## raio

also on my mind today; because p.i.h.k.a.l entry seems to shiw MMDA-3b is unique; and so are the 2/5-TOM 2/5-TOET; 
some attemps to make them more active or altered in effect.......
swipe past MMDA-3b structure to 3D model and then succesive model comparisons ending with structure list photo


----------



## raio

is there anywhere i can get more help with structure design ?;

i know a certain place made of  a good deal of academic paper , i dunno, maybe wood and stuff; but it’s not as active as i require. there doesn’t seem to be much investigational compound research/discovery as there was in the progenitor that i was too “young”/unaware-and-less-knowledgeable to be a part of.


@sekio you know what i mean right ?

can you DM me ?


----------



## Gaffy

Smart druuug





__





						SwissTargetPrediction
					






					www.swisstargetprediction.ch


----------



## izo

YXO-15 like compounds have been made without the ketone and ring substitution. there is a patent by parke davis.


----------



## izo

2-(2,5-dimethylpyrrolidin-1-yl)-1-phenylpentan-1-one

could be toxic due to inhibited metabolism of the pyrrolidine ring, here you find the usual way it gets broken down by the body:









						2009 - New designer drug alpha-pyrrolidinovalerophenone (PVP).pdf
					






					drive.google.com


----------



## polymath

The sedative antihistamine cinnarizine (image) is said to bind to mu opioid receptor with a Ki of 922.0 nM, according to the ChEMBL database. Making it more fentanyl-like by replacing that N-(3-phenylallyl) group with an N-(2-phenylethyl) could possibly make the affinity better.


----------



## izo

i think especially the phenylally is needed for mu-binding, as in ap-237.


----------



## polymath

Or if you interpret the cinnarizine molecule as similar to MT-45, not AP-237, then you could just put an N-cyclohexyl in the place of the phenylallyl group.


----------



## Gaffy

I made this http://www.swisstargetprediction.ch/result.php?job=147426009&organism=Homo_sapiens out of ethyl ethylephedrine and this metabolic route saved someone from an overdose ! :D Quite euphoric


----------



## Gaffy

What are your metabolic routes to recycle benzoylecgonine? I just drink a monster with BENZOIC acid and am wired up again


----------



## Gaffy

Gaffy said:


> I made this http://www.swisstargetprediction.ch/result.php?job=147426009&organism=Homo_sapiens out of ethyl ethylephedrine and this metabolic route saved someone from an overdose ! :D Quite euphoric


Will probably be recycled into buphedrone in the liver  fr otc?


----------



## sekio

> i hope to get a real molecular simulator


ChemBio3D is good (part of ChemBioOffice). can run MMF94 optimizations on your molecules to orient them into their lowest energy conformation (i.e. the most likely structure). can even run "molecular dynamics" simulations and watch the atoms wiggle around due to thermal motion,

also has structure <-> name support. Draw a structure, get its IUPAC name. And type an IUPAC/common name in and it can give you a structure.



> is there anywhere i can get more help with structure design ?;


There is no real "structure design bible". Generally you need some knowledge of the "shape" of the binding site (i.e. early opioid chemistry mapped out the general shape of the mu opioid receptor well before its protien sequence was found) either by analysis of a large number of drugs and their potencies, or nowadays by direct "imaging" of the receptors with a high affinity ligand docked.
Once the binding site and its topology is known (which parts prefer positive charges, negative charges, aromatic rings, lipophilic groups etc) then ligands can be engineered not only for binding affinity but also for ADMET purposes (Absorbtion/Distribution/Metabolism/Excretion/Toxicology). Maybe the compound works well in cell culture but is poorly absorbed or rapidly metabolized. Maybe it produces some side effect that is undesirable. Also certain structures take more complicated reactions to produce so cost may be a factor to optimize. and so on....

Nowadays if you want to be an amateur drug designer (and not just gaffy, the equivalent of monkeys playing with a molecular model kit) I would suggest you get familiar with software like Chemdraw and then learn how to use protien docking software. You provide a receptor structure (many have been found nowadays) and it attempts to "fit" molecules into the binding site and predicts how well they will fit. better fit = better binding. (Figuring out whether it is an agonist or not isn't as easy tho)



> What are your metabolic routes to recycle benzoylecgonine? I just drink a monster with BENZOIC acid and am wired up again



1. the amount of benzoic acid consumed in drinks is negligible
2. monster has caffeine and sugar
3. benzoylecgonine needs to react with *methyl alcohol* to form cocaine not benzoic acid. if the benzoate splits from cocaine you get ecgonine methyl ester. so unless you drink wood alcohol on a regular basis, no cocaine is going to form.
4. there is always more water and cocaine present vs methanol and benzoylecgonine so the esterase enzymes will preferentially hydrolise cocaine rather than re-form it


----------



## simstim

Beta methoxy 4-methylmethamphetamine
Possibly less cardiotoxic than 4-MMC itself, should not produce the highly cardiotoxic 4-methylephedrine as a metabolite
Likely longer acting than 4-MMC.
Likely to be less neurotoxic to dopamine neurons similar to 4-MMC and 4MM (compared to Meth, Methcathinone, and MDMA)
BO4MM
(Beta methoxy per Shulgin BOx, 4MM the name given to 4-methylmethamphetamine in a recent research article about neurotoxicity)
After trying BOD recently I really believe in the potential of this one!


----------



## polymath

Beta-hydroxy and beta-keto versions of lefetamine and ephenidine look interesting, because they can be made from easily available benzoin, but there is not much info about their effects. Having the wrong stereoisomer present in the product could also cause problems.


----------



## blueberries

Ok, so I don't know how no-one spotted this before but this compound is something special. My god!

It's the DMT variant of AGH-192 I dubbed FIDMT












This is from doing the same to 4 and 5-CT


----------



## blueberries

Another I found using the skeleton of Delucemine; Methoxethlucemine


----------



## blueberries

Also just a quick one to show STP's legitimacy when it comes to complex compounds with little known pharmacological proof;

Efavirenz: 




From the wiki: "Some neuropsychiatric adverse effects may be mediated through cannabinoid receptors, or through activity at the  5-HT2A receptor, but efavirenz interacts with many CNS receptors, so this is not clear."

Note the CB1&2 and HT2a activity, not to mention NMDA, sigma and A2A activity also.


----------



## perpetualdawn

Any thoughts on NBOMe-MDMA, NBOMe-methamphetamine, NBOMe-amphetamine? Would those work, have they been synthed or tested? The idea of an ultra potent variant of MA on the street has been haunting me...


----------



## Bagseed

perpetualdawn said:


> Any thoughts on NBOMe-MDMA, NBOMe-methamphetamine, NBOMe-amphetamine? Would those work, have they been synthed or tested? The idea of an ultra potent variant of MA on the street has been haunting me...


I think the idea with the nbome phens is that the molecule including the bulky n-benzyl group takes a 3D-shape optimized for 5HT2A bonding in a similar way to LSD. seems unlikely that it would do any good for amphetamine pharmacology.


----------



## perpetualdawn

That makes a lot of sense @Bagseed, thanks.


----------



## Bagseed

perpetualdawn said:


> That makes a lot of sense @Bagseed, thanks.


don't quote me on that though. :D


----------



## simstim

Bagseed said:


> I think the idea with the nbome phens is that the molecule including the bulky n-benzyl group takes a 3D-shape optimized for 5HT2A bonding in a similar way to LSD. seems unlikely that it would do any good for amphetamine pharmacology.


Beta methoxy substituted MDMA or 4-methylmethamphetamine is another story though. Even beta methoxy methamphetamine. I wouldn't expect much good to come pharmacologicalically from NBOH or NBOMe substituted stimulants or entactogens though.


----------



## perpetualdawn

simstim said:


> Beta methoxy substituted MDMA or 4-methylmethamphetamine is another story though. Even beta methoxy methamphetamine. I wouldn't expect much good to come pharmacologicalically from NBOH or NBOMe substituted stimulants or entactogens though.


Is this what you mean by beta methoxy subbed MDMA: https://isomerdesign.com/PiHKAL/explore.php?domain=pk&id=2478


----------



## simstim

perpetualdawn said:


> Is this what you mean by beta methoxy subbed MDMA: https://isomerdesign.com/PiHKAL/explore.php?domain=pk&id=2478


Yes, that. 

Perhaps this is wishful thinking but after recently sampling BOD AKA beta methoxy 2c-d i have high hopes that beta methoxy MDMA and beta methoxy 4-Methylmethamphetamine will be more similar to bk-MDMA and 4-mmc than you could imagine.  This is partially based on my observation that the duration of BOB is more similar to bk-2c-b than 2c-b. Therefore i am anticipating the beta methoxy amphetamines being more similar to longer acting cathinones. The methyl group of beta methoxy likely solves the problem of beta keto phenethylamines turning into beta hydroxyl metabolites too. Which is likely to be a heart health benefit over cathinones.

Beta methoxy also would prevent the formation of a dimer in the case of primary amines which happens with cathinone and things like bk-2c-b. Opens up the possibility of things like beta methoxy amphetamine and beta methoxy 4-methylamphetamine as well. Also beta methoxy DOM, etc.


----------



## blueberries

Huh...I was just about to post beta-methyl-methamphetamine (bMMA).
Some synchronicity at work here!

So...what's the concensus as to if it's safe or not. I sadly can't remember much about the beta-xx-A's but if I'm not mistaken they work quite well (in the methyl and methoxy variant anyway). Also I just thought of N, a-cyclopropylphenethylamine, which, at best, would be at least 50mg for a fairly even, nice stimulant (that is, unless there's a rule about N, a-CPAs?).

You could put it on MD and 2C-B too!


----------



## simstim

blueberries said:


> Huh...I was just about to post beta-methyl-methamphetamine (bMMA).
> Some synchronicity at work here!
> 
> So...what's the concensus as to if it's safe or not. I sadly can't remember much about the beta-xx-A's but if I'm not mistaken they work quite well (in the methyl and methoxy variant anyway). Also I just thought of N, a-cyclopropylphenethylamine, which, at best, would be at least 50mg for a fairly even, nice stimulant (that is, unless there's a rule about N, a-CPAs?).
> 
> You could put it on MD and 2C-B too!


If you mean tranylcypromine, then you should know that it is a prescription maoi. There is some evidence of abuse potential with it though.



			https://upload.wikimedia.org/wikipedia/commons/thumb/9/91/Tranylcypromine.svg/1200px-Tranylcypromine.svg.png


----------



## izo

loosely based on CL-218,872:









						CL-218,872.jpg
					






					drive.google.com


----------



## izo

an idea from another user in blacklight:









						tryp.jpg
					






					drive.google.com


----------



## izo

noid.jpg
					






					drive.google.com


----------



## izo

Clipboard02.jpg
					






					drive.google.com


----------



## blueberries

I just got this from STP, I don't want to show the molecule due to fear of plagiarism or any number of things that can go wrong if you let the cat out of the bag because these results are incredible.

DOA-001

Please message me if you think there is a future in these results and have funding for the next step. Quite frankly...it's a bit of a miracle.


----------



## Rectify

Are you Bill Clinton?  Also, if we can't see the structure, wtf?


----------



## S.J.B.

blueberries said:


> I just got this from STP, I don't want to show the molecule due to fear of plagiarism or any number of things that can go wrong if you let the cat out of the bag because these results are incredible.
> 
> DOA-001
> 
> Please message me if you think there is a future in these results and have funding for the next step. Quite frankly...it's a bit of a miracle.





sekio said:


> stp results mean dick all


----------



## obviously_not_carl

I am sure this is the wrong thread, but I don't know where it else would be appropriate.... sorry!
And my apologies to the mod who probably will move this post somewhere, as well...

This is what makes me ponder for quite some time.
What I'd like to know is the activity of those analogues of, e.g. naphyrone, PAL-287/1046 and the like, but with the tiny little differences of the aromatic 6-MeO group.
A friend said, its likely that this is done to slow down CYPD metabolism.

But does nobody know if, or rather, in what regard this could change its course of action?
I would be really thankful for that information.
The switzer crystal ball is only of very little use at all.

These are the substances I am talking about, precursor in the middle, and yes I know that 6. is twice in there:


----------



## simstim

I'm sure other people have had the idea for this one, but I haven't heard it proposed yet myself so I whipped this up this morning.

bt-4MM
(Beta-thienoketone-4-methyl-methamphetamine)





EDIT
I actually just changed the name. 4-MM is the name given to 4-methylmethamphetamine in a research paper I read which was a neurotoxicity study. I chose to stick with it because it's the only paper I've seen which studied this chemical at all. Also, Shulgin already gave the name pMMA to 4-methoxy-methamphetamine.


----------



## simstim

This next one was inspired by finding a source online which claimed to have 2,5-dimethoxy-4'-methylaminorex which would be the direct precursor to...

2-C-B-MAR
(2,5-dimethoxy-4-bromo-4'-methylaminorex)


----------



## simstim

This next one is pretty far out there. As far as I know no one has ever added an oxygen to the alkyl side chain of a tryptamine. My thinking is that if we could get away with making a tryptamine alpha methyl then perhaps we could also get away with making it beta methoxy. This one is inspired by two different long acting psychedelics...BOD and aMT.

I call it...
b-MeO-T
(beta-methoxy-tryptamine)


----------



## izo

Clipboard01
					

Image Clipboard01 hosted in ImgBB




					ibb.co
				












						Clipboard02
					

Image Clipboard02 hosted in ImgBB




					ibb.co
				












						Clipboard03
					

Image Clipboard03 hosted in ImgBB




					ibb.co
				




some ideas of mine.


----------



## obviously_not_carl

@simstim, your thione-analogue of mephedrone is likely very unstable(also possibly of a deep-blue colour if it can be made).

The other compound, the BOB analogue of 3-(2-aminoacetyl)indole, thats likely not a psychedelic.
I heard anecdotal reports of a similar compound, the beta ketone of DMT, to be just a normal stimulant, and that it felt similar to methcathinone.
No psychedelic effects, surprisingly.
I would assume its the same for this compound, more likely inactive, given that tryptamine is inactive is well as parent compound.


----------



## izo

ok, sounds wierd.


----------



## roi




----------



## izo

Looks Good.


----------



## Feretile

H₂O


----------



## Feretile

CO₂


----------



## Feretile

CO


----------



## sekio

Xe


----------



## Feretile

sekio said:


> Xe



Now I know you too well Sekio... a monatomic gas is taking it to the next level 

How about NaH. Make the adamanzane implicit & you get Na− which I find spooky.

I looked to see if their is a chemists way to draw a Bose-Einstein condensate. I could not find on.


----------



## The Holy Quadruplty

https://www.quora.com/profile/Dripz...4&share=9cb57928&srid=uKYJAp&target_type=post 

I created a chemical structure and was wondering if anyone could tell me the receptor binding affinities of it, or anything like that at all? I tried to post the image itself, but it wouldn't let me so there's the link to it on one of my Quora posts. I was also wondering what you would call it? I called it Prodopalol. Lol


----------



## The Holy Quadruplty

Anyone got any input on this?


----------



## VerbalTruist

The Holy Quadruplty said:


> Anyone got any input on this?


I don't think that DC is the right place for this. Let me know if you want it moved to BDD or OD.


----------



## falsifiedhypothesi

I don't really see the point. I'm no chemist but I don't think you can just slap random atoms onto a molecule and call it something interesting. 

I was expecting the molecule to be in the shape of a dick or bird or something


----------



## arrall

The Holy Quadruplty said:


> I created a chemical structure and was wondering if anyone could tell me the receptor binding affinities of it, or anything like that at all?


I'm lazy, so send me the SMILES of it and I'll look it up for you.


----------



## thegreenhand

we’ve passed 250 pages on this one

new thread here


----------

