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Stimulants of the Future

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1-Naphthalen-2-yl-2-pyrrolidin-1-yl-pentan-1-one looks interesting. Might be a little too good at binding all those monoamine transporters.

Also, does it make sense to assume that the 3,4-methylenedioxy analogue (MDPV) would be similar to the 3,4-dihydroxy shown in the paper Nuke posted? Looks like a farily similar profile to methylphenidate except 5x as potent (3-5x as potent on dopamine reuptake and DAT; 6-8x as potent on norepinephrine reuptake and NET; no SERT inhibition). Makes sense from initial reports suggesting 5 mg MDPV.

It's odd that the naphthyl analogue affects SERT and serotonin reuptake so strongly when most of the others have a negligible effect. Hmmm ... how about adding that naphthyl to some phenethylamines? 1-Naphthalen-2-aminopropane? Any thoughts?
 
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2C-G5 looks cool. The thing is, I thought the general code of conduct is that people try and discriminate against serotonin and not in favor of it. I may be wrong though. A similar result was also uncovered when dealing with methylnaphylate (c.f. methylphenidate) isomers. <- That is, the buck of the naphthyl compounds toward 5-HT did not fit-in with the general trend and was out of character.
1-Naphthalen-2-aminopropane? Any thoughts?
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Im sure people have tried it only it wasnt very popular and has subsequently never established any sort of reputation. Still, i'd like to hear any accounts on this compound also - even negative ones, just to try and find out what the crack is wit this shit.
 
2C-G-N is 1,4-dimethoxynaphthyl-2-ethylamine, but Shulgin never brougt it up to active levels. (Edit: oops, I guess he did) I think the aromatic naphthyl would make it significantly different from 2C-G-5 or 2C-G-3 just because of those free electrons. Sorry, I'm getting off topic since these are almost certainly not going to be "stimulants of the future" in the meaning of this thread.

I do wonder what Shulgin's 2C-G-N would be like, but I'd almost rather take off the 1,4-dimethoxy and see what happens. One can only wonder.

Smyth said:
2C-G5 looks cool. The thing is, I thought the general code of conduct is that people try and discriminate against serotonin and not in favor of it. I may be wrong though. A similar result was also uncovered when dealing with methylnaphylate (c.f. methylphenidate) isomers. <- That is, the buck of the naphthyl compounds toward 5-HT did not fit-in with the general trend and was out of character.
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I agree, short, reversible SERT inhibitors must not be too good in treating ADHD or they wouldn't have gone for methylphenidate. I'm not sure exactly why. The 3,4-dihydroxy analogue seems to be a potentially good candidate for ADHD treatment, especially if the half life is slightly longer. The 3,4-dichloro might be interesting too. It has a preference for DAT and NET, but also affects SERT, only a little more weakly.

Anyone know why they tried to avoid the serotonin system with the discovery of methylphenidate and its analogues?
 
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I meant 2cg, I just havent consulted alot of pihkal recently. What im saying is that most of the ring substituted methylphenidate analogs are intrinsically psychostimulant in nature with little 5-HT affinity. The same holds for derivatives of pyrovalerone. 3,4-dichloro is the most potent DAT inhibitor in the series but its still follows the trend IC50 DAT << 5HT. It's the b-napthyl moiety that 'bucks the trend'. Im calling it methylnapthidate for slang but its by no means official. If you want ref's then send me a pm with youe email addy and i'll forward a couple of relevent articles to evidence it.
 
Helios. said:
Smyth is right about SERT being non-reinforcing, but moth ball based medicine is not where it's headed.
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I'm sorry man, but you really need to stop making worthless posts, some of which are blatantly wrong yet somehow you seem to state them with such confidence.

Anyway, I will preface this by saying that I am not the all-knowing specialist that Helios is, however, why would MDMA be so popular if SERT inhibition added nothing positive to the experience? MDMA is a potent inhibitor of SERT and DAT. Also, cocaine goes for all three transporters. Actually, I found an article supporting the idea that SERT may play a small role in reinforcement.

http://www.ncbi.nlm.nih.gov/entrez/..._uids=14612142&query_hl=1&itool=pubmed_DocSum

We have to remember that we're talking about rodents here, so just because SERT inhibition isn't reinforcing by itself doesn't mean that having SERT inhibition is a bad thing when it comes to drug design (depending on your goal). Also, theres a good chance that there's some interplay between SERT and DAT so that inhibition of SERT could add to the effects a DAT inhibitor.

Smyth, you are right that methylphenidate has no activity at SERT, and maybe that makes it a more effective ADHD drug. Amphetamine also has weak, although not necessarily negligible, inhibition of SERT. Anybody have any ideas why there is this preference?

Lastly, naphthalene is found in many medically relevant drugs (naproxen sodium for example). :p
 
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Are you a robot? It's not so damn simple.

If you had read my post, you would have noticed that cocaine is reinforcing even in DAT-KO mice, but not in DAT/SERT-KO mice. Think about it. Or is that asking too much?
 
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:

The reinforcing potency of cocaine is maintained in the absence of the DAT but decreased in the absence of the NET; its motivational rewarding effect is observed in the absence of the SERT, but not when both DAT and SERT are lacking. Moreover, a dichotomy between cocaine motor activating and reinforcing effects is reported. Such dichotomy is suggestive of independent mechanisms underlying the psychomotor stimulant and reinforcing effects of cocaine. Overall, these studies provide evidence that cocaine dynamically acts at multiple sites through pathways that might be exchangeable under certain circumstances.
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Smyth said:
The thing is, I thought the general code of conduct is that people try and discriminate against serotonin and not in favor of it.
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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.

Smyth said:
Dondante said:
1-Naphthalen-2-aminopropane? Any thoughts?
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Im sure people have tried it only it wasnt very popular and has subsequently never established any sort of reputation. Still, i'd like to hear any accounts on this compound also - even negative ones, just to try and find out what the crack is wit this shit.
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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.
 
This is an interesting application of the naphthyl group. The compound shown is related to venlafaxine. It has actually been made and is not theoretical.

ultrafaxinebs8.gif
 
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I hope it's more fun than venlafaxine. That stuff kind of murdered my brain.
 
nuke said:
I hope it's more fun than venlafaxine. That stuff kind of murdered my brain.
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same- ever since taking that stuff i have chronic yawning - funny the first few 100 times, but 100000 yawns later i am totally over them.
 
I would be interested to see the effects of alpha-methyl-napthylethylamine (amnetamine?). It is supposed to have dopaminergic and (unfortunately or fortunately, depending on your personal bias) serotonergic properties. I remember reading a paper where it was used as a prototype compound for putative cocaine-dependence therapy. It might be a kinder, gentler analogue of amphetamine. Another interesting compound would be the N-ethyl analogue of pyrovalerone--as the stimulant character of a phenethylamine compound seems to vanish if the N-alkyl moiety is more sterically bulky than an n-propyl chain (or in the case of ring-closed moieties, a pyrrolidine). And one that I have always wondered about is simply N-pyrrolidyl-amphetamine.
 
Riemann Zeta said:
Another interesting compound would be the N-ethyl analogue of pyrovalerone--as the stimulant character of a phenethylamine compound seems to vanish if the N-alkyl moiety is more sterically bulky than an n-propyl chain (or in the case of ring-closed moieties, a pyrrolidine). And one that I have always wondered about is simply N-pyrrolidyl-amphetamine.
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Am I reading this wrong? I thought there was a big thread here on MDPV as a stimulant.
 
Both pyrovalerone and MDPV have ring-closed N-pyrrolidyl moieties. This appears to be the largest ring-closed alkyl group that still confers CNS stimulant action (although, these compounds are DA reuptake inhibitors, rather than DAT substrates). The largest (sterically) open-chain N-linked alkyl group that preserves CNS stimulant activity appears to be n-propyl, as even N-isopropyl amphetamines are inactive.

Interestingly, the beta-keto amphetamines (cathinones, pyrovalerones) seem to exhibit more DA reuptake inhibition activity and less DAT substrate activity than the standard beta-methylene amphetamines. Take ethylcathinone versus N-ethylamphetamine or methylone versus MDMA--each cathinone congener appears to function more as a monoamine reuptake inhibitor, rather than a DAT/NET/SERT substrate.
 
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fastandbulbous said:
Fencamfamine also lends itself to a lot of fiddling and tweaking of the basic skeleton

59655fencamfamine_analogues.JPG



Pipradrol derivatives are the one where most hope lies.

59655pipradrol_analogues-med.JPG


Shulgin wrote about 2-(diphenylmethyl)piperidine as being a possible future drug of abuse, as it is estimated to have the same CNS stimulant properties as methamphetamine, but to be active at 2.5mg as opposed to 5mg for methamphetamine, and also to have less peripheral activity as well.

One last bit for the cocaine lovers among you.

59655cocaine_analogues.JPG
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Does anyone have first, second, third hand experience with these drugs? Pipradrol derivates included. Which ones do you think offers good alternatives to amphetamine when it comes to mental stimulation and euphoria?

Anyone actually tried the famous and easily synthed fluoro coke analog?

Replacing the ethyl group on fencamfamine with a methyl would probably make a very similar drug. Does anyone know if it has been done?

I'd also love to hear from someone that has tried amfonelic acid, can't seem to find anything else than in vitro data about it.

If a clandestine chemist would go about synthesising a drug that can match up to good ol' speed or cocaine in qualitative mental effects and would be legal in his/hers non-US jurisdiction, what different compunds do you think would come up as alternatives?
 
"Potency = 60x Cocaine" => 3,4-dichlorophenyl moiety or
3,4-methylenedioxyphenyl moiety. Provided only, of course, that you are willing, able, inclined, and allowed to do so.
 
2-benzyl-pyrrolidine.
2-piperonyl-pyrrolidine.

#9: 1-(3,4-dichlorophenyl)-1-(2-pyrrolidyl)methane.
 
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