Speculation or insight on novel amphetamine substitutions?

[clubcard]

I remember seeing some formulae of non-amine dopamine reuptake inhibitors, one of them was like a methylphenidate molecule but with an ether oxygen in the place of the ordinary amine nitrogen. This is probably a more interesting line of development.

Potency way, way lower. They were made to compare O: & N: and I'm kind of surprised that the phenyl(piperidin-2-yl)methanones haven't shown up. By tweaking the cyclic amine you can move that N: quite a lot. My only tip on this one is don't trust Reaxys. Their reference is WRONG.

 

[polymath]

https://www.ncbi.nlm.nih.gov/pubmed/14612136

It's surprising that the atom replacing the nitrogen doesn't even need to have an unshared pair of electrons, as a methylene substitution also retains some activity.

It would be an interesting but tedious exercise to draw structures for this kind of derivatives from many different stimulants (e.g. desoxypipradrol and others with a nitrogen heterocycle) and try to find whether those compounds already exist in nature (maybe in some plant of fungus).

Edit: In the case of desoxypipradrol, it looks like some 2-(diphenylmethyl)tetrahydropyrans have already been found to be monoamine (including dopamine) reuptake inhibitors, but the ones with data available also seem to have a nitrogen atom somewhere else in the molecule. https://patents.google.com/patent/US7915433

NSFW:

 

[Hodor]

O-2172 is an analogue of methylphenidate that is approximately 1/3rd the potency of regular MPH, despite lacking the piperidine nitrogen.

At first glance, this may seem impressive, but not so much so once you consider that it is more specifically an analogue of 3,4-Dichloromethylphenidate (3,4-CTMP), which is approximately 10 times as potent as plain ritalin. So as clubcard already said, we're talking about a pretty drastic decrease in activity.

Then again, even if it is only 1/30th of the potency of 3,4-CTMP, the fact that O-2172 is even active *at all* despite the absence of a lone pair on the ring is pretty fascinating.

 

[polymath]

Then again, even if it is only 1/30th of the potency of 3,4-CTMP, the fact that O-2172 is even active *at all* despite the absence of a lone pair on the ring is pretty fascinating.

So, with both chlorines and the nitrogen removed, the compound would cause some effects for a non-tolerant person when taken in an estimated 300-500 mg dose.

There didn't seem to be any info about sulfur or selenium replacements of the nitrogen in MPH.

 

[Limpet_Chicken]

It'd be a good idea, if those were to be assayed, to test the sulfurous analog first, since there could be the potential for toxicity in seleniuretted compounds.

If that ether is cleaved off metabolically, then one would end up with methanol in vivo, no? although probably in doses the human body could get rid of, but methanethiol would be most unpleasant to have as a metabolite.

And methyl selenomercaptan? no THANKS

 

[Hodor]

It'd be a good idea, if those were to be assayed, to test the sulfurous analog first, since there could be the potential for toxicity in seleniuretted compounds.

If that ether is cleaved off metabolically, then one would end up with methanol in vivo, no? although probably in doses the human body could get rid of, but methanethiol would be most unpleasant to have as a metabolite.

Are we talking about replacing the piperidine with a tetrahydrothiopyran ("thiane") ring? I don't see how that would give you methanethiol... I would expect thioethers to mostly get oxidized to sulfoxides and sulfonyls rather than getting cleaved outright.

Now, replacing the ester with a thioester would indeed yield methanethiol... however, thioesters are *very* easy to cleave (and good thing, too, otherwise CoA would have a hard time feeding all those acetyls into the Krebs cycle), so "thio-methylphenidate" might not even survive the acidic environment in your stomach.

And yes, your body can generally handle minor amounts of methanol - keep in mind that pectins (the polysaccharides found in fruit and vegetables) are heavily esterified with methoxy groups, and as such yield methanol in your body.

And methyl selenomercaptan? no THANKS

Why stop there? Two words:
methyl tellurol 8(

 

[Limpet_Chicken]

Yeah, I meant the thioester, and just thinking of something that liberated methaneselenol in-vivo is bad enough.

Having one's body turned into a weapons-grade stink bomb factory isn't a pleasant experience. Never had the..well I wouldn't use the term 'pleasure', with selenium or Te, but sulfurous nasties of that general flavour (quite literally, when it also comes out in one's saliva and nasal mucus, along with pretty much any, and for that matter EVERY possible kind of bodily leavings or loose parts), and after a week of that, you'll never want to smell volatile mercaptanesque substances again for the remainder of your natural lifespan, if for some strange reason, anybody would have wanted to to begin with

And agreed about ethers, I'd expect them to undergo oxidative metabolism rather than cleavage.

As for Ac-CoA, well don't forget to take into account, in that specific context, just how specifically tuned they are to act as in essence, surgically precise and pinpoint-accurate, high-efficiency instruments, with hydrogen bonding, electrostatic considerations, steric constraints, solvent shell effects, potentially halogen bonding, to make them very good at performing their specific tasks, generally better than we can accomplish with traditional wet-chem, no?

Just look at phytochemistry/mycochemistry, and how with a few enzymes and basic substrates to start with, plants, fungi can produce the likes of morphine, galantamine (which coincidentally have quite a lot in common, indeed one can do, if one were to be so inclined and have the competency, so much as to begin a total sythesis, and have it diverge so as to use a common precursor to either to produce both), alkaloids like strychnine, or in the fungal case, the ergoloids from dimethylallyl pyrophosphate. They do in very mild conditions, what would take a human chemist a staggering amount of effort in comparison, and a long bloody time to do it in too.

So perhaps an enzymatically mediated process isn't the best case for illustrating stability, relatively speaking.

And who the fuck would think to include tellurium in a drug? potential for toxicity aside, Te is notorious for the unspeakable stench given off by people who have intaken only small quantities of the element, as 'tellurium breath', which from everything I've read, sounds like it affects bodily off-castings in general rather than specifically the breath, kind of similar sounding to my unfortunate sulfurous experience of a few years back, only much, much worse.

 

[Hodor]

You are of course right about enzymes; my point was this, though: Hydrolyzing a thioester is a pretty exergonic reaction. Even without enzymatic catalysis, such a compound should be highly susceptible to hydrolysis in water, especially under the acidic conditions in the stomach.

 

[polymath]

A Google search found a Vespiary thread referring to some old Bluelight discussion about thio analogs of phenmetrazine (only the oxygen atom replaced by a heavier element from the same group). Didn't find anything about 3,4-dichloro phenmetrazines... Those would be quite interesting, as older people who remember using phenmetrazine often tell that it's even more euphoric than (meth)amphetamine.

 

[(zonk)]

I was wondering if there are any thoughts on using pyrrole as a substitute for pyrrolidine for pvp substitutes

Pyridine seems to be a suitable substitute for desoxypipradrol analog

 

[Pomzazed]

pyrrole N is not basic in nature; seems to make the "new-pvp" inactive as that position required a basic nitrogen to bind.

 

[S.J.B.]

I was wondering if there are any thoughts on using pyrrole as a substitute for pyrrolidine for pvp substitutes

Pyridine seems to be a suitable substitute for desoxypipradrol analog

2-(Diphenylmethyl)pyridine is apparently a potent dopamine reuptake inhibitor, as are the 2- and 3- substituted analogues. But the different in basicity between pyrrolidine and pyrrole is much more drastic than that between piperidine and pyridine (see Pomzazed's post). In the case of pyridine, the nitrogen lone pair is not involved in aromaticity, and can therefore act as a base, albeit a weaker one than in aliphatic amines. In pyrrole, however, the lone pair is involved in the aromaticity of the ring and will not be protonated except with a very strong acid.

 

[clubcard]

2-(Diphenylmethyl)pyridine is apparently a potent dopamine reuptake inhibitor, as are the 2- and 3- substituted analogues. But the different in basicity between pyrrolidine and pyrrole is much more drastic than that between piperidine and pyridine (see Pomzazed's post). In the case of pyridine, the nitrogen lone pair is not involved in aromaticity, and can therefore act as a base, albeit a weaker one than in aliphatic amines. In pyrrole, however, the lone pair is involved in the aromaticity of the ring and will not be protonated except with a very strong acid.

The diphenylethylsmine scaffold has been exhaustively researched. The morpholine homologue was a lot smoother but still lasted far, far too long. ADME is at least as important when considering if something is of utility. I guess the thioamide might be shorter acting and substitution of one or both aromatics might be of interest. I honestly can't remember if the isomers of the p-(pseudo)halo amphetamines (or p-(m)ethyl amphetamines) have been studied BUT if things are favourable, a chiral compound in which one of the aryl moieties has a p-Me might solve several problems. More SR & SRI activity, a sacrificial moiety (to what is a potent compound given LogP) and the option of including a beta O: in the system. Morpholine rings have always worked out in stims (for me). 3-[(4-methylphenyl)(phenyl)methyl]morpholine would be worth a thought is what I wish to convey.

The 4-phenyl-1,2,3,4-tetrahydroisoquinolin-8-amine class (nomifensine, dichlorfensine) refer to those earlier compounds many times in the papers & patents. Now we see the 1,2,3,5,6,10b-Hexahydro-6-[phenyl]-pyrrolo[2,1-a]isoquinoline class with people noting McN 5652. Of course, J. Med. Chem. 27. 943 'Pyrroloisoquinoline Antidepressants. Potent, Enantioselective Inhibition of Tetrabenazine-Induced Ptosis and Neuronal Uptake of Norepinephrine, Dopamine, and Serotonin' is a really impressive piece of work i.e. it provides a lot of useful information. The related patents are easy to find.

Modelling them in 3D gives useful insights when overlaid by mazindol. Expansion of the 4,5-dihydro-imidazole ring to a 1,4,5,6 tetrahydropyrimidine ring is supposed to increase affinity for dopamine transport... but that's just to play with the software. The pyrrolo[2,1-a]isoquinoline class has a lot more paperwork on it than people think but it's also reasonable to say that few people are going to invest the time & money coming up with samples of something with no very clear medical utility. We live in an age where meth-cooks are so chaotic that they don't stop and think 'there must be a batter way than this' and sadly that's true to medicinal chemistry at all levels. If the ARs (novel i.e. have to practice) 1-step synthesis is too much, building these classes is going to be much too much.

The PEA class are great educational tools. from amphetamine to mescaline to

 

[(zonk)]

What about azolium or pyrroline

 

[Hodor]

What about azolium or pyrroline

The azolium cation (i.e. protonated pyrrole) is extremely acidic, roughly on par with a strong acid like HNO3.

This is because protonation causes pyrrole to lose its aromaticity, greatly detracting from the molecule's stability. Azolium salts can thus be expected to fully dissociate in water, releasing both the protons and the counterion almost immediately, with the organic ring returning to its uncharged aromatic pyrrole form.

 

[S.J.B.]

The azolium cation (i.e. protonated pyrrole) is extremely acidic, roughly on par with a strong acid like HNO3.

This is because protonation causes pyrrole to lose its aromaticity, greatly detracting from the molecule's stability. Azolium salts can thus be expected to fully dissociate in water, releasing both the protons and the counterion almost immediately, with the organic ring returning to its uncharged aromatic pyrrole form.

Azoles (and azoliums) are actually five-membered heteroaromatics containing two or more heteroatoms, such as imidazole (3-aza-pyrrole) or oxazole (3-aza-furan). In these cases, at least one of the nitrogen lone pairs won't be involved in aromaticity, so they are far more basic than pyrrole.

 

[(zonk)]

I'm trying to search for data regarding known amine ring substitutions and the corresponding dopaminergic activity for cathinone based compounds, of course we all know pyrrolidine is optimal but how would others compare such as azetidine, aziridine, piperidine or semiringed alkyls like cyclopropylamine, cyclobutylamine? If you say pyrroline and other dehydrated substituents are too difficult to work with. Is there a published comparison of binding profiles of the different n-subs?

 

[clubcard]

I remember a very dubious claim made by a US meth chemist in the 1980s. He said he could replace with benzene ring with a pyridine & that N-methyl-1-(pyridin-4-yl)propan-2-amine & meth were identical....

 

[(zonk)]

What about cyclopentadiene instead of benzene

 

[Limpet_Chicken]

You definitely DON'T want anything to do with the aziridine one you mentioned, aziridines are generally extremely toxic in-vivo.