Conformationally Constrained Analogues of Stimulants?

[Ham-milton]

Hey, I know that Nichols has looked at some of these sorts of things, especially with MDMA, and didn't find them to be as active, but has there been any research into how the pure stimulant analogues are?

I'm thinking of something like this analogue of phenmetrazine

As I recall, these sorts of analogues had less peripheral effects, but maintained activity although there was a loss of potency. Does that sound accurate?

On a side note, does anyone know if bemegride or it's relatives had potential as recreational drugs? I don't think it has any analogues that are stimulants, though. It's described in one of the Future Synthetic Drugs of Abuse as having "obvious" abuse potential. I can't find though how it works. It a gaba-antagonist or is a dopaminergic like other stimulants?

 

[vecktor]

Hey, I know that Nichols has looked at some of these sorts of things, especially with MDMA, and didn't find them to be as active, but has there been any research into how the pure stimulant analogues are?

I'm thinking of something like this analogue of phenmetrazine

As I recall, these sorts of analogues had less peripheral effects, but maintained activity although there was a loss of potency. Does that sound accurate?

I believe for release activity the amino group has to be out of the plane of the phenyl ring. For plain agonism or reuptake inhibition it can lie in plane or almost in plane.
For reuptake inhibition at DAT the requirements are pretty simple an amino and a phenyl or other aromatic ring a certain distance apart, hence the huge numbers and diversity of DAT inhibitors.

 

[dorothyperkins]

It's interesting that Nichols found similar correlations of ring size in both bicyclic hallucinogen and MDMA analogs:

http://www.erowid.org/references/refs_view.php?A=ShowDoc1&ID=816

The tetralin series were all inactive while the indans were active though of somewhat reduced potency compared to the open chain compounds. I wonder if the trend continues with the cyclobutane's, which seems to be the best conformation found so far for 5HT2A agonism. Would the benzocyclobutane MDMA analog be much more potent, and also show less neurotoxicity?

Also, if that conformation works for monoamine releasers as well as 5HT2A agonists maybe it will work with plain amphetamine?

 

[haribo1]

Interesting that the T1/2 was shortened. With meth, its the fact that it lasts too long (amongst other problems) which is why I don't like it. Now, if you had meth that lasted 2 hours, that would be perfect (to me)

 

[Smyth]

I have this file to bring to the discussion.

My favorite idea is what is known as 2-exophenyl-7-azabicyclo[2.2.1]heptane. The compound was made in the scientific literature, but more as a "dry run" en route to epibatidine. I dont think pharmacological activity was discussed, the compound was just used as an analytical benchmark.

Variations of the above theme are possible, and Dr Malpass devoted the last decade of his career towards changing the heterocyclic part of epibatidine to try and "fine-tune" nicotinic activity in an attempt to "design-out" respiratory paralysis but retain the analgesic activity.

However, such educational research is not well suited external to academic institutions where the profitability of these concepts is unlikely to gain much sympathy in a globalized economy where "winner takes all" mentality runs rife.

 

[haribo1]

^+10 on that, mate. Branding is SO important. I remember in the first days of rsves when E was 10-20 quid a go. 1 pill was enough for the whole night and if it was a Dove, it ***WAS*** good. Now people trust unmarked powders!
Now I would only touch MDMA if I KNEW it was pure & that others had taken it firt and could confirm it...
In the case of these compounds, it would fall outside UK MoDA laws, I assume, but better safe than sorry..

 

[dorothyperkins]

Variations of the above theme are possible, and Dr Malpass devoted the last decade of his career towards changing the heterocyclic part of epibatidine to try and "fine-tune" nicotinic activity in an attempt to "design-out" respiratory paralysis but retain the analgesic activity.

He didn't try the plain phenyl analog then, or just screened it for analgesia and respiratory depression?

Are you sure its not just overuse haribo? The first pill i took lasted a good 8 hours, now a good dose (~120mg) of pure MDA lasts maybe 5 hrs.

With meth it depends what you use it for, the higher you get the longer it lasts. A dose that gets you obviously high can last 24 hours, or more i expect. It's quite subtle at lower doses so it's easy to keep taking more until you're really wired, then you're up for a long time.

 

[vecktor]

I have this file to bring to the discussion.

My favorite idea is what is known as 2-exophenyl-7-azabicyclo[2.2.1]heptane. The compound was made in the scientific literature, but more as a "dry run" en route to epibatidine. I dont think pharmacological activity was discussed, the compound was just used as an analytical benchmark.

A sort of tropane fencamfamine hybrid. I assume you know that in the tropane series with a methoxycarbonyl, ring contraction results in a spectacular loss of activity at DAT.
Care to explain the logic behind your interest in the phenyl azanorbornane???
1-phenyl-2-aminocyclohexane appears to have made it some distance into trials but FCF was better from a clinical POV.
V

 

[Smyth]

It's not really a hybrid of anything, just conformationally constrained amphetamine.

This compound is a releaser, and besides, in contrast to fencamfamine it's a nonsense choice due to the fact that it's improbable that it has the necessary 'umph factor' to cut any ice outside of the research labs.

True that on contracting the ring of phenyltropane, e.g. WIN-35,065-2, an appalling diminution in activity was noticed (Trudell, et al.).

 

[Riemann Zeta]

This exo-2-phenyl-7-azabicyclo[2.2.1]heptane compound is a DAT substrate (that is, an amphetaminergic monoamine releaser)? Interesting. I would think that it would be too sterically bulky to be a right proper substrate. I guess it is not particularly likely to be a potent uptake inhibitor, as it would have to be N-methyl to be a tropane-esque inhibitor (but it would still be weaker than a tropane, for reasons mentioned above).

 

[fastandbulbous]

1-phenyl-2-aminocyclohexane appears to have made it some distance into trials but FCF was better from a clinical POV.

2-phenylcyclopentylamine (1-phenyl-2-aminocyclopentane) made it further - even got as far as an approved name (Cypenamine). Both the cyclohexyl & the cyclopentlyl structure can be overlayed fencamfamine to take the same conformation. I reckon tag on an N-ethyl group & you'll have a winner!

 

[MattPsy]

What's the reasoning behind the N-Et ? Why not N-Me, for instance?

 

[Ham-milton]

because that's what's on fencamfamine? Can't think of any other reason.

 

[fastandbulbous]

And the N-ethyl group has the lowest toxicity/ highest theraputic ratio (N-methyl deriv of fcf is twicve the toxicity). The N-ethyl group is very popular in anorectic/stimulant compounds eg diethylpropion, fencamfamine, fenfluramine etc, so seemed like the natural choice if treating fencamfamine as the model for the drug

 

[Smyth]

Hmm, I think the bicyclic compound I suggested, with which im more-or-less trained to do the synthesis needs something on the phenyl to stop it from looking so bare. Something like a p-chloro, minus the pyridyl nitrogen of epibatidine might harbor some sort of medicinal potential. I was trained to make the N-BOC-7-azabicyclo[2.2.1]heptan-2-one but even if my chemical company proves a success, it will probably be many years before I would want to risk losing alot of money on these unaffordable ideas.

Now, the paper I included in the above link also discusses the N-isopropyl amine as a possible substitution. Then, the bare amine is also an idea at least worth considering. Law enforcement give off the impression that they just want to immediately jump on and ban any compound/s that have demonstrated favorable bioactivity. The fact that Shulgin said why compounds like atropine, scopolamine and arsenic arent illegal yet compounds like 2cb are, proves this point. It just seems odd that highly qualified chemists like myself find themselves out of a job and the government starts babbling about there being a skills deficit etc.

Also, it was on the frontpage news in the UK today about how in 4 years time crystal meth is projected to be as much of a problem as the more commonly known crack cocaine. Theres two distinct reasons for this: 1) the synthesis of xtal meth doesnt even require a chemist (at least not for the pseudofed pills method), and 2) drugs laws are so nasty that the drugs themselves come out looking nasty to reflect this, serving to restore karma.

The prime minister is well known for his preaching on the slogan "education, education, education!" but everybody knows that society is anti-science and more generally anti-education. Why he keeps saying that word? it's like he's only just learnt it in his foreign travel dictionary and is trying to commit it to memory. The amount of migrants he's let into the country, that's probably not far from the truth Or maybe like a baby would do reflecting his failed policy on teenage pregnancy. Perhaps he suffered a stroke and only recently relearn the alphabet?

I mean on quiz shows when people are asked for example what element has the formula K or Sn they just look on in blind amazement, completely dumbfounded. Drug laws are a cheap gimmick.

 

[vecktor]

can we confine ADD discussion to advanced drug discussions and not use it as a soap box for rants against the status quo? there are other places on BL for that.

FWIW the azanorbornane is childs play (diels adler)

I would like to see activity data for substituted 1-phenyl 2 amino cyclohexanes, I have not come across any information.

 

[Smyth]

FWIW the azanorbornane is childs play (diels adler)

That's an uneducated slurr. I have actually made these compounds. Have you checked on the price of epibatidine recently? The cost and rarity of this chem is indicative that it is actually far from it ("childs play" that is). Stick with "E" if you want something that's trivial.

This file is a bit outdated now, but it's still a comprehensive review. You have to realize that just because you can scribble down a mechanism on a scrap piece of paper, that's a long way away from saying that you have a synth that is workable in the laboratory (assuming you even have access to one).

And the only reason I included the rant in ADD is because this is where most of the genuine scientists hang. Alot of the other boards wont be occupied by chemists.

 

[vecktor]

^ I bow to your superior knowledge and equally huge ego
one should leave chemistry to the master chemists....

 

[Riemann Zeta]

Well, preaching that contemporary drug policy is fucked up to this crowd is akin to talking about Jesus at a Southern Baptist convention.
But anyway folks, I want to return to something F&B said: that is, that N-ethyl is the prefered substitution for CNS stimulants. This sounds fairly reasonable, considering the reports of the rare N-ethyl-amphetamine. I wonder if N-ethylamphetamine is as neurotoxic as meth, or if it is equivalent to our old friend Dexedrine?

 

[vecktor]

Well, preaching that contemporary drug policy is fucked up to this crowd is akin to talking about Jesus at a Southern Baptist convention.
But anyway folks, I want to return to something F&B said: that is, that N-ethyl is the prefered substitution for CNS stimulants. This sounds fairly reasonable, considering the reports of the rare N-ethyl-amphetamine. I wonder if N-ethylamphetamine is as neurotoxic as meth, or if it is equivalent to our old friend Dexedrine?

it does require higher doses than amphetamine which may be a problem in itself, I think there were some reports about it here.