• Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

  • N&PD Moderators: Skorpio | someguyontheinternet

Stimulants of the Future

Status
Not open for further replies.
nativenick said:
so do you think it would be possible to toy around with caffiene and make future analogues with more recreational potential
Click to expand...

Probably not, there have already been much stronger analogues of caffiene made, but they are not drugs of abuse. Caffiene just isn't that recreational, high doses cause anxiety rather than euphoria and with lots of nasty peripheral side effects.

It might well be possible to make a derivative of caffiene that was more fun to take, but this would involve significantly altering the activity profile. Simply producing a more potent analogue would confer little advantage.
 
Dondante said:
Thanks for the link. I have never doubted that DA was the primary determinant for reinforcing behavior, but what I'm saying is that other transporters might play a small role in modulating the reinforcement and psychomotor effects. Maybe I'm flat out wrong, I don't know.

Also, the goal here is not to create the most addictive molecule in history. There must be a reason that specific DAT inhibitors are not on the market. Stimulation is not synonymous with dopamine excess.

Here's a section of the abstract I posted:





So have we concluded that people wouldn't discriminate against serotonin? I think it's clear that it's not reinforcing itself, but that doesn't mean that it's not a useful pharmacological attribute. It seems to be in MDMA.



You really think someone has tried it? Maybe I underestimate the exploration that dedicated chemists do, but according to Shulgin, nobody ever brought it's cousin G-N (1,4-dimethoxynaphthyl-2-isopropylamine) above 2mg. At that level there were no signs of toxicity and no central effects.

I just realized that I missed 2C-G-N in Pihkal. Doesn't sound too pleasant. The one that hadn't been taken higher was G-N. Wonder what would happen if you took off those two methoxys, and maybe added a methyl to the nitrogen. It still might be interesting in the pyrovalerone analogue series.
Click to expand...

Abstract:
Monoamine transporter proteins are targets for many psychoactive compounds, including therapeutic and abused stimulant drugs. This paper reviews recent work from our laboratory investigating the interaction of stimulants with transporters in brain tissue. We illustrate how determining the precise mechanism of stimulant drug action (uptake inhibitor vs. substrate) can provide unique opportunities for medication discovery. An important lesson learned from this work is that drugs which display equipotent substrate activity at dopamine (DA) and serotonin (5-HT) transporters have minimal abuse liability and few stimulant side-effects, yet are able to suppress ongoing drug-seeking behavior. As a specific example, we describe the development of PAL-287 (α-methylnapthylethylamine), a dual DA/5-HT releasing agent that suppresses cocaine self-administration in rhesus monkeys, without the adverse effects associated with older phenylethylamine 5-HT releasers (e.g., fenfluramine) and DA releasers (e.g., amphetamine). Our findings demonstrate the feasibility of developing non-amphetamine releasing agents as potential treatments for substance abuse disorders and other psychiatric conditions.
 
An important lesson learned from this work is that drugs which display equipotent substrate activity at dopamine (DA) and serotonin (5-HT) transporters have minimal abuse liability and few stimulant side-effects, yet are able to suppress ongoing drug-seeking behavior. As a specific example, we describe the development of PAL-287 (α-methylnapthylethylamine), a dual DA/5-HT releasing agent that suppresses cocaine self-administration in rhesus monkeys
Click to expand...

That seems strange considering MDA, MDMA and methamphetamine all cause a large increase of 5HT & dopamine in their respective synaptic clefts and are noted for their abuse potential
 
Helios. said:
1-(3-chlorophenyl)-2-pyrrolidinylpropane HCl.
1-(3,4-methylenedioxyphenyl)-2-pyrrolidinylpropane HCl.
Click to expand...

IUPAC tourettes strikes helios again....
 
it's not how you spell it, it's what it feels like when you take it. that's what's important. get it? :o

should by dyl instead of dinyl?
WHO GIVES A F***
 
fastandbulbous said:
That seems strange considering MDA, MDMA and methamphetamine all cause a large increase of 5HT & dopamine in their respective synaptic clefts and are noted for their abuse potential
Click to expand...

Quickly reading the paper indicates that there might be other effects of PAL 287 which are confusing things, the authors mention that 4-methyl ampetamine has identical activity profile and yet was a reinforcer. PAL 287 has partial agonist activity at 5HT 2c receptors, this would certainly alter the stimulant effect of massive dopamine release/ uptake inhibition. the authors hint at the problems when they suggest that PAL 287 was preventing the critters from pressing the levers even if the wanted to:
The significant decreases in food-maintained responding suggest that decreases in cocaine self-administration may have resulted, at least in part, from nonselective effects of PAL-287
Click to expand...

This is what Nichols tends to write off as disruption, especially when it doesn't agree with the current theory.
The earlier work of these authors correlated NE release reuptake inhiition with self administration and reinforcement.

I remember reading something about the pyretic activity of a napthylamine maybe napthylethylamine something along the lines of it being one of the most potent pyretics discovered. I don't have the book any more, if anyone has Paul Karrers Organic Chemistry from 1940 something its in there.

"All the monkeys had histories of cocaine self-administration."
Click to expand...
damn those primates, stealing the stash.
 
meta-chlorobenzylpiperazine, not sure if that one's been done yet or not.
meta-chloro-des-(CO2CH3)-methylphenidate.
 
Rather than go for 2-benzylpiperidine, the logical target should be 3-benzylmorpholine as of the the diphenylmethyl substituted heterocyclic compounds, the original paper reported the morpholine derivative to be by far the most potent locomotor stimulant in trials.

This has the extra advantage of being a few easy staps from phenylalanine (via phenylalaninol) rather than having to fuck around with expensive things like pipecolic acid & nast organometallic compounds (Grignard or organolithium)

BTW 3-benzylmorpholine has the same phenethylamine skeleton as 2-benzylpiperidine, it's just the numbering starts from a different place due to the heterocyclic oxygen atom
 
namely,
3-benzylmorpholine.
3-piperonylmorpholine.
3-(meta-chlorobenzyl)morpholine.
3-(3,4-dichlorobenzyl)morpholine.
3-(3-indolyzyl)morpholine.
and so forth?
 
So...phenmetrazine derivatives. Why on Earth did methylone come before 3-methyl-2-(3,4-methylenedioxy)-phenylmorpholine? I wonder if the activity is closer to MDA. Para-methoxy-phenmetrazine? Hmm.. I'm guessing there's a good reason I don't know why these never happened.
 
Status
Not open for further replies.
Top