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The Big & Bangin' Miscellaneous Chemistry/Pharmacology Odds N' Ends Thread: Part 3


Bluelight Crew
Sep 14, 2009
streets of simcity
The Big & Bangin' Miscellaneous Chemistry/Pharmacology Odds N' Ends Thread: Part 3

This is the place to discuss all your one-off questions and observations on the topics of pharmacology and drug chemistry.

Here's a link to the last page of the previous thread.
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You think the reason for dissociatives and psychedelics being different has to do with different affinities for slightly differing versions of the same receptors and different populations of those 'polymorphs' throughout the CNS, for different downstream pathways due to the conformational changes of the receptor being different (meaning that activation or no activation is definitely not the only factor in activity), both?

The differences I am talking about are for example: some dissociatives can be manic, immobilizing / anaesthetic, the dissociation can be more a mind-body thing or more purely cognitive, etc - for psychedelics: they have different tendencies regarding being friendly or sinister, some like DMT don't really produce tolerance.

I doubt that efficacy at additional 5HT receptor subtypes really covers a huge part of the picture, that doesn't seem to be the analogous case for dissociatives anyway.

Something like stimulants seems a little more straightforward. Maybe there are also 'special' pharmacodynamics possible there, but I do wonder if achieving the exact same levels of release and reuptake inhibition for all major 3 monoamines would usually give indistinguishable subjective experiences independent of how you achieve it. Then again, some compounds are considered much more magical as empathogen than others and I wouldn't be so quick to say it's merely because of synergy from that balance being *just* right.
I doubt that efficacy at additional 5HT receptor subtypes really covers a huge part of the picture, that doesn't seem to be the analogous case for dissociatives anyway.

There is a large range of action for dissociatives in terms of how effective they (1) produce direct and indirect effects on monoamine function, and (2) what other channels and receptors they act on. PCP can increase catecholamine activity directly, by blocking transporters, and indirectly by disinhibition. Ketamine inhibits Ih channels, PCP is a nicotinic antagonist, etc. There are also potentially effects of metabolites that may be different than the parent drug.
That's interesting and fair, do you know of any such action of significant efficacy that could explain the anaesthetic qualities? Still it seems strange though, something like 3-MeO-PCP is still anaesthetic I think but only at relatively high doses compared to ketamine which seems harder to give cognitive effects without anaesthesia, yet they can be separated by taking only one pure isomer: R-ketamine does not immobilize me even if I have lost absolutely all my marbles, S-ketamine anaesthesizes and feels narcotic rather than heavily psychedelic. I don't really know what pharmadynamical difference between them explains it.
I guess the 3-MeO-PCP or PCP difference *could* be explained by different relative efficacies for such secondary MOAs if that is it. Are there different anaesthetic qualities at play here: is there the extra anaesthesia from something like S-ketamine's secondary effects but also the anaesthetic effect that virtually every NMDA antagonist will eventually produce by dissociation in the cerebellum etc?

Another question:
Do classical surfactants with polar head and fatty tail mostly work when they have pretty big non-polar aliphatic chains and form micellar structures, or can shorter chained homologues be used to help dissolve for example 4-HO-DPT or other drugs with polar and non-polar regions that appear to be the source of aqueous solubility difficulties? So can very tiny localized pseudomicelles from shorter chained surfactants form around non-polar moieties?
Even though it isn't conventional nomenclature, wouldn't it be correct to call water (being H2O, according to the rules of chemistry and how other compounds are referred) "saturated oxygen"?
I think saturation is a term in organic chemistry referring to hydrocarbons and the presence of double or triple bonds vs. the saturation of all possible (aliphatic) positions by hydrogens. AFAIK involving say nitrogen-carbon bonds and the saturation of hydrogens bound to that nitrogen is already unusual as far as that term goes (but it might fly?), however water is not a hydrocarbon or even organic in that sense so it doesn't seem to apply. A chemist might know what you're talking about but doubt there is anything orthodox or correct about it, other than oxygen indeed having its maximum number of covalently bound hydrogens attached. Then again water is special and the bonds in it are also of a special kind.

'Oxidized hydrogen' on the other hand...?
Can someone explain how aspartame is excitotoxic?

Too much glutamategric activity would be too, I just don't know how. I know that ischemia triggers a lot of glutamate action (presumably functioning as an aid to get out whatever natural threat the primordial parts of our brain presume most be going on); so it some cases at least this would be unsafe, but my naivete on this subject is large. But I also know that it contirbutes heavily to beneficial brain plasticity, such as that seen through a successful mushroom trip.

Generally speaking, "GABA promoters" with long half-lives sometimes carry the side effect of depression. I would guess because this means less glutamatergic action. I forget which is ultimately used to metabolize into the other. It someone jumps off of 6mg of Ativan per day after being on it for years, inevitbale seizures would be largely caused by excessive glutatmatergic action, not nor/epinphrine, due to the structural similarity between glutmate and GABA, right? And because glutamate and GABA can work at the same ligand-gated ion channel. The monoamines work on signal proteins, by contrast.

Just musing...
Does it breakdown into aspartic acid and appreciably stimulate NMDA receptors?

And I was under the impression that a lot of the excitotoxicity seen with ischemia is due to failure of the ATP dependent sodium/potassium pumps (which can take up 2/3rds of a neurons energy expenditure), see for example https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3015038/ - "These findings imply that intracellular Na+ accumulation via decreased Na+/K+-ATPase exacerbate the Ca2+ overload cooperated by the increased NCX1 and NR2B-containing NMDA receptor which may play an important role in the pathogenesis of the penumbra."

It could also be that some of the inhibitory neurons are higher metabolism and/or are more sensitive to ischemia (parvalbumin positive GABA interneurons) so the inhibitory neurons are the first to stop functioning with ischemia.

But as I understand it the main issue with benzos is indeed glutamate. Although interestingly it seems like co-release is the rule rather than the exceptions these days (GABA neurons release glutamate as well, supposedly to perhaps sharpen the signal).
Can someone explain how aspartame is excitotoxic?

It's not, in vivo. Glutamate can be toxic but only in cell cultures - how many times have you heard of people ingesting MSG and that leading to seizures?
In college they told me glutamate and N-methyl-d-aspartate were so important as excitatory neurotransmitters. If that is so, why aren't there many drugs based on the structure like MDMA is to adrenaline, for example?
The highly polar nature coupled with the fact that both of the neurotransmitters are amino acids doesn't bode well for synthetic drugs. Also, both glutamate and NMDA are actually excitotoxic in vitro - somehow I suspect an analog that actually made it to the CNS would be along the lines of pentylenetetrazol - effectively a seizure induction compound for modelling epilepsy.
Why isn't this molecule a neurotransmitter?

It's epinine


If your question is why it doesn't also occur in humans besides certain animals and plants, I don't know whether that is a valid question. But more generally, it is a neurotransmitter.
Unsurprisingly, like other catecholamines it has cardiovascular action via adrenergic / dopaminergic pathways.

By the way, IMO you can find the NMDA structure roughly in many dissociatives, although there are rather aromatic groups instead of the carboxyls. And yeah apart from encitotoxicity and seizures, it seems like glutamatergic or NMDA agonistic agents would be quite unpleasant but that's just sort of speculation.

The GABA / glutamate system is very pervasive and master-switch like, non-specific excitation is something you probably don't want - it would have to be a carefully designed selective agent of some kind if anything. For example an ampakine. Maybe a good question is what ampakines are glutamate-like in structure. Possibly because glutamate-like compounds would tend to be not selective for AMPAr so it should be more AMPA-like.
Even then, AMPA agonists, AMPA-like in structure are also neurotoxic - it's the PAMs that are useful for us, and I guess that means the AMPA pharmacophore isn't involved anymore.
Have selective agents for GLUN1 and N2 and subtypes been explored? Or is that known to be a pointless exercise?

So those are reasons why you don't see drugs that are glutamate or NMDA like..

What I wonder is how far you could go with glycine agents, like a potent derivative of theanine?

There is a large range of action for dissociatives in terms of how effective they (1) produce direct and indirect effects on monoamine function, and (2) what other channels and receptors they act on. PCP can increase catecholamine activity directly, by blocking transporters, and indirectly by disinhibition. Ketamine inhibits Ih channels, PCP is a nicotinic antagonist, etc. There are also potentially effects of metabolites that may be different than the parent drug.

Turns out (apparently) that indeed a major difference I was talking about could be explained by Ih channel blocking:

The hypnotic effects of ketamine are caused by a combination of immediate channel blockade of NMDA and hyperpolarization-activated cation channels

Sleigh J, Harvey M, Voss L, Denny B. Ketamine-more mechanisms of action than just NMDA blockade. Trends Anaesth Crit Care.
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So those are reasons why you don't see drugs that are glutamate or NMDA like..

I think it could be really weird to have AMPA stimulation resulting in LTP that isn't associated with anything in particular (not like a synapse undergoing LTP to help you remember a location etc that has been paired with other cells that are firing meaningfully). Normally there needs to be significant AMPA activation post-synaptically across many different synapses on the same cell for NMDAr activation and induction of LTP, but with the Mg out of the pore it seems like any one pre-synaptic release of glutamate could build LTP really easily, and this should be a decrease in signal to noise ratio. A neuron with NMDA receptors may be receiving thousands of inputs but LTP will primarily be expressed at the synapses that are receiving input (the synapses that are meaningfully activated by endogenous activity, as opposed to a PAM activating non-selectively). There is a theory about the synapses with NMDAr that are activated being tagged specifically for proteins, instead of the LTP being cell-wide.

I think the Mg block is serving as a filter for noise in this scenario and overstimulation of AMPA would negate that effect (even though there might be scenarios where AMPA/NMDAr stimulation is desired, and ketamine's HNK does modulate AMPA and this could be responsible for its efficacy for MDD). But one short term mechanism of LTP is that AMPA stimulation leads to NMDA activation which leads to trafficking of AMPA receptors to the synapse, which strengthens the synapse but seems like it could be a recipe for disaster in terms of excitotoxcity, coincidence detection going out the window notwithstanding.

But D-cycloserine is an NMDA partial agonist that may be helpful in treating PTSD by promoting reconsolidation of memories. AMPA ligands with affinity for different AMPAr's could have very different functional consequences, seeing as for example GluA2-lacking AMPA (commonly found on GABAergic interneurons) are permeable to Ca2+, and this is probably especially important for the few cells that don't express NMDAr, while apparently the calcium impermeable AMPAr are expressed in most other cells.
I have a question; maybe this is the right place for it. Why is there (as far as I can see) absolutely NO info about N- ethylamphetamine? It's such an obvious molecule to make (and if meth is anything to go by, it would be incredible drug) yet basically all I've found is a wiki article with no useful information and a bluelight thread from years ago that's similarly useless.

I expect it would be awesome drug, and it's such an obvious structure, I don't understand why there is so little info about it.
The Goutarel's Hypothesis of the anti-addictive effect of Ibogaine

I have been researching this remarkable molecule for some time now. The more one digs, the more fascinating it is. How does Ibogaine (often after a single dose) completely "reset" the addicted (AND the non-addicted) brain? The "non-addicted" like anectodal PTSD subjects that "fully recovered" following Ibogaine treatment. Plus not only to opiates, but also nicotine, alcohol, stimulants (even benzos it now appears) addiction. probably even in gambling, sex and other

One intriguing hypothesis the Goutarel's Hypothesis of the anti-addictive effect of Ibogaine by the French chemist Robert D Goutarel is rather interesting: I'll like to share it you guys (sorry kind of long post but it is worth the time..

The French chemist Robert Goutarel (14) hypothesized that ibogaine treatment involves a state with functional aspects shared by the brain states of REM sleep, with important effects on learning and memory. During the REM state, there is believed to be reconsolidation of learned information in a state of heightened neural plasticity, with the reprocessing of previously learned information and the formation of new associations (192,193). Goutarel suggested that a REM-like state may be induced by ibogaine, which corresponds to a window of heightened neural plasticity, during which there may be weakening of the pathological linkages between cues and representations of the drug incentive and the motiva- tional states with which they have become paired (14). Analogous to the reconsolidation of learned information that is thought to occur during the REM state (192,193), Goutarel theorized that the pathological learning of addiction was modified during ibogaine treatment. He appears to have based his theoretical formulation mainly on reports of the phenomenological experiences of awake ibogaine-treated subjects that share features in common with dreams. Goutarel’s hypothesis is speculative, but nonetheless has an interesting apparent consistency with the literature on the relationship of learning and addiction and the physiologic function of the REM EEG state with regard to the consolidation of learned information.

There is some evidence that may be viewed as consistent with Goutarel’s hypothesis. Goutarel’s belief in a relationship of the ibogaine-treated EEG state to that of REM is supported by studies in animals treated with ibogaine that report an apparently activated or desynchronized EEG state consistent with arousal, vigilance, or REM sleep (90,191). The observation that ibogaine enhanced an atropine-sensitive theta frequency rhythm (191) suggests the possible involvement of ascending cholinergic input, which is an essential determinant of EEG desynchronization during REM sleep (192). The possible reconsolidation of learned information due to heightened plasticity during both the REM and ibogaine-induced desynchronized EEG states is suggested by the observation that EEG dyssynchrony is associated with an increased facilitation of Hebbian covariance (194), which is believed to be an important determinant of the neural plasticity involved in consolidation of learning and memory. Also, with regard to a possible analogy of the REM and ibogaine induced brain states, some ibogaine treatment guides have anecdotally mentioned that they have observed REM-like eye movements in awake patients during treatments (195,196).

That Ibogaine actually induces REM like states while awake and LPT taking place during that state seems plausible since REM sleep is thought to be a period of lots of brain activity (hence paradoxical sleep) such as memory consolidation where the brain sorting and making sense of sensory inputs experienced during the day (activities aka Dreaming!). Note that mostly Cholinergic activity is taking place during REM with virtual complete shut-off of all other neurotransmission like NE DA or Serotonergic..

Ibogaine is selective brain α3β4 nicotinic acetylcholine receptors antagonist. Could that be the mechanism behind the induction of awake REM-sleep like state by Iboagine. If that was the case, then other α3β4 drugs should be able to provide same anti-addiction effect as IBG potentially without its other side-effects like cardiac arrhythmia and such. Also, if REM sleep induction is the basis for the drug effect, then other drugs that can induce REM sleep while awake (IF such other drugs exist) should be able to have similar effect than Ibogaine!
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edit or rather addition to ^: the drug Mecamylamine a prescription anti-hypertensive is actually a α3β4 nicotinic acetylcholine receptors antagonist but is rather non-selective. It is used off-label to treat nicotine smoking cessation. Does anybody know more about this drug?
So a while ago I decided I wanted to get a proper understanding of drug science. Parallelly to my browsing of the stickied "resources for self-studying" thread I would like to express something here to see if anyone has any comments:

I figured to get a solid understanding I had to start from the very basics. Forget serotonin receptors we would begin with plain organic chemistry and only later get to those. I picked up Janice's Organic Chemistry. Went over the first chapters religiously, doing exercises and all that jazz. Structure and bonding, acids and bases, the idea of functional groups, alkanes and their conformations, stereochemistry, the basics of reactions — entropy, enthalpy, orders of kinetics, mechanisms... Then things start to get real with alkyl halides and nucleophilic substitution, elimination; alkenes, -ynes and addition; reduction & oxidation... By now and from here on, the book seems to consist basically of functional groups and the reactions they undergo — so many of them by the way whoa, unfortunately I really don't get along with memorisation.

And here's the thing, in "fn groups and the reactions they undergo", the "reactions" seen are the ones that would take place inside a flask, not the body — hydrogenation with palladium catalyst, reduction with LiAlH_4? As in, the book is perhaps aimed as someone that at some point would actually carry out those reactions. I would be more interested in chemistry in the context of a biological systems, seeing my ultimate goal.

So does anyone has any suggestions for me? Or alternatively the above is knowledge required before moving onto the chemistry of the body? — e.g. aminoacids do show up in Janice's book however only at the very last chapters...
Thanks sekio, I'll check it out. Does it really get down to the nuts and bolts of cells or is it just like high school biology where one has to plain rotely memorise the names of the organelles and their functions for example? (Mm perhaps that is impossible currently?, to understand cells from the level of individual molecules, without any leaps between the micro and the macro?, given that perhaps we just don't know enough yet or things just get too damn complex?...)