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Pemoline - what's up about the oxazolines?

dopamimetic

Bluelighter
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Mar 21, 2013
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Since I got diagnosed with inattentive ADD and tried the meds available as well talking with other patients, and being not satisfied with methylphenidate and d-amphetamine (or their side effects), I have thought about possible "better" treatment options.

Pemoline being the one that interests me at most. Wiki describes that it is not a sympathomimetic or NDRI / NDRA but instead working as a surrogate for dopamine, not affecting endogenous dopamine (reminds me of dopamine agonists, but they don't seem to be that effective at all.. outside of treating parkinsons') - requiring some time for effects to become evident, like with antidepressants, and not having sympathomimetic side effects of course. Then I've read that one could nevertheless stay up for two days or more with Pemoline. And of it having nootropic like effects, maybe especially in the magnesium salt form.

They say it has been pulled off the market due to some cases of liver damage. While this is serious of course, it wonders me how serious it really was since there are just around twenty cases out of millions of patients and I guess they did not have liver enzymes monitored, as that side effect was not known back then. Thinking of other, widely used pharms like sodium valporate (just as an example) or that nasty new Agomelatine that are known to be hard on the liver and get prescribed nevertheless.

Then there are of course the more or less related aminorex chemicals. I have done that 4,4'-dimethylaminorex many times in low dosage, and while its effects are heavily serotonergic, it has some distinctive "sharp-minded" clearness to it that 4-MAR is said to have as well - and regarding the (acute) subjective side effects, this category of chemicals seems interesting to me too.

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So, what I'm wondering about now is, has Pemoline really been such a top ADHD med / superior to what's available today or is it overhyped and comparable to the amphetamines? Could it be that the liver damage was not the only reason to pull it?

Are there papers on other oxazoline derivates that are dopaminergic like pemoline and possibly safer to the liver?


200px-Pemoline_structure_2.svg.png
200px-Aminorex-2D-skeletal.png

Pemoline (2-amino-5-phenyl-1,3-oxazol-4[5H]-one) and Aminorex (5-phenyl-4,5-dihydro-1,3-oxazol-2-amine)
 
Amphetamine is the gold standard for ADHD

I'm sure political ploys had something to do with it
 
I had some 4-MAR years ago and I remember it felt like it made my brain work better or smarter etc. Super clear headed focus.. that i can't get with amphetamines (i mean d-amp and d-methamp work good but often send me into the "ON" position but in a forced way.. 4-MAR seemed better like i could turn it ON or OFF at will)
 
I had some 4-MAR years ago and I remember it felt like it made my brain work better or smarter etc. Super clear headed focus.. that i can't get with amphetamines (i mean d-amp and d-methamp work good but often send me into the "ON" position but in a forced way.. 4-MAR seemed better like i could turn it ON or OFF at will)

Sounds like ampakines (among many things). Perhaps these things have some glutamatergic (or AMPA-specific) activity.
 
I was on Pemoline back in college many many years ago, before the put me on dexedrine. Pemoline did not possess stimulant effects that anyone here would be into, it lacks any 'CNS edge.' I have no opinion on it as a real ADHD medication but I can't say I found it helped at all for focus, which is why the moved me on to the good stuff. I never got try try 'U4Eah' or whatever they call (4-methylaminorex) but I do hear from trusted friends that that is to die for.

Since I got diagnosed with inattentive ADD and tried the meds available as well talking with other patients, and being not satisfied with methylphenidate and d-amphetamine (or their side effects), I have thought about possible "better" treatment options.

Pemoline being the one that interests me at most.
 
Having tested pemoline lately I tried 40mg oral.. Poor.. Then I tried intranasal dosing up to 60-80mg ala 20mg portions every few hours.. It's actually a strong stimulant.. Pretty euphoric but odd, no true crash. Apparently the Ki for the DAT is 0.5uM..

Various problems with pemoline exist the ring is not basic enough and does not form a true acidic salt... However it can form the magnesium salt.. Tautomerization can be a problem in some ring systems as the charge from ionization is not "handled" well as you would believe...

The removal of the ketone in pemoline would be great however.. Substituting the nitrogen leads to noradrenalinr and Dopamine releasing agents apparently.. I haven't found any info on n-methyl pemoline yet.. See thozalinone and fenozolone which were marketed in Eupore for a bit

Class had odd potential
Zedsdead
 
Wiki describes that it is not a sympathomimetic or NDRI / NDRA but instead working as a surrogate for dopamine, not affecting endogenous dopamine (reminds me of dopamine agonists, but they don't seem to be that effective at all.. outside of treating parkinsons') - requiring some time for effects to become evident, like with antidepressants, and not having sympathomimetic side effects of course.

By "wiki", do you mean Wikipedia (bluelight has a wiki, you know ;))? Well, whoever made that edit is mistaken, as the compound interacts strongly with DA and NE transporters, most likely reversing transport. It is really a "vanilla stimulant".

ebola
 
Sorry yes, I meant wikipedia. There it is written that pemoline's precice method of action is not yet known - but have to admit that I am too lazy often with searching for more precise sources (and requiring a subscription to read full papers is frustrating).

So then would it be correct to say that the main difference between pemoline and the aminorex family is the latter additionally affecting 5-HT (leading to, among others, a risk for pulmonary hypertension).

Zeds, do you think the ketone could be the reason for (metabolic?) liver toxicity? Aminorex seems not to be associated with liver injury, but I guess both dosage was lover as well as mean duration of treatment - yet long enough to cause p.h. on the other side. Thozalinone and fenozolone are interesting, too. Is anything known about their affinity to SERT? And could the double bound amine group they and the aminorex'es lack, be an issue too? (Well, remembers me that there is still so much I have to learn about biochemistry and all..)

Your experience with pemoline supports what I think of the capabilities this class probably has. Crash- and tolerance-wise smooth stimulants. I wonder why there has not been more research done, but today even a good stimulant would not get approved, so well..

Thanks for your answers!
 
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Dopamimetic-

The oxazolidone ring may not be the problem per say- the issue may be that pemoline (notably free amine) can be conjugated in a dangerous manner. Some hepatoxic conjugation reactions include the N-oxide of the ring nitrogen or the amine N-oxide.. I only mention these because the N-alkylated derivatives thozalinone and fenozolone do not appear to have stated toxicity however this may as well be due to poor pharmacokinetic studies performed as of late.
Regardless the ketone may be the toxicity reason as it withdraws electrons and gives the ring a tautomeric form allowing conjugation or formation of the n oxide.. (which are generally easy to deal with but the example of this on a tautomeric ring may be asking for trouble)..

These are fun drugs though if you ask me we should see what the nbome derivative or a the racetam derivative is like.. You can easily spacefit the ring into either structure.. Obviously many wouldn't think it could be psychedelic or nootropixs at first but in med Chem I am apt to believe anything can happen....

Zedsdead
 
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