I Like to Draw Pictures of Random Molecules

[DotChem]

I know on Wikipedia it says it's a reuptake inhibitor but I doubt this claim...

It seems counter-intuitive but actually IT IS a reuptake inhibitor unlike MDMA. It reverses inward-pre-pulse synaptic current in fashion similar to Cocaine and not AMP-like releasers such as methylone which basically dump dopamine in synaptic cleft without reversing the current. The SAR (at that alfa-position) is that the more substituents you put there beyond a methyl the more cocaine-like reuptake inhibitors you end up with. This is true for both AMP-like and methylone-like(bk-AMPs.

So you got from Methylone(---->ethylone--->butylone---.pyrovalerone from (releaser ----> reuptake inhibitor). or from AMP ----> Prolintane which is more cocaine-like DRI and less AMP-like). Here is a thorough review on this question by the upmost expert on the field Pr Rick Glennon : (a gold mine to design new and improved Cocaine-like):

“Deconstruction” of the Abused Synthetic Cathinone Methylenedioxypyrovalerone (MDPV) and an Examination of Effects at the Human Dopamine Transporter ACS Chem Neurosci. 2013 Dec 18; 4(12): 1524–1529.

The data on UWA-101 reported by the references on the wiki entry refer to Reuptake Inhibition. Granted, we dont know whether the UWA series are also releaser as the authors didin't mention it in their abstracts but one thing is certain: their pharmacology is dramatically different from MDMA and very much closer to cocaine. Which bring back my question: Do they have anything in common(structurally, electronically...etc) with the tropanes like the RTI-83? Or may be they bind to the transporter similarly (same site and triggering same conformational change of the transporter leading to current reversal.. who knows?

Those aren't RTI-83s values, those are:

RTI-304s values. RTI-83s are:

(Ki)
55 nM @ DAT
28.4 nM @ SERT
4,030 nM @ NET

As for your question, it seems, if you look at the difference between DA & NE, that the ethyl or cis-propenyl (and in the amphetamine skeleton, the alpha methyl lengthened to a cyclopropane) somehow leaves the hydroxy group that alters NEs binding free to pry itself into the transporter that are otherwise blocked when it comes to DA or 5-HT; of course, that's an obvious non-explanation explanation, but such is QSAR.

Thanks @nag for pointing that out. The Ki data refer to the 4propenylphenyl tropane instead of the 4ethylbenzene dervative. It is even more intriguing now considering the rgidity put by the propenyl. if you consider the DAT and NET, (any) substitutenst that kill NET activity wil also kill DAT binding but obviously this is not the case!

 

[roi]

I wish UWA-001 was available =/

The diarylethylamines on the market so far only substituted the other phenyl ring. I wonder if it's still a dissocoiative. Or a stim. Or whatever.

 

[Incunabula]

What a fascinating molecule.

 

[adder]

I wish UWA-001 was available =/

The diarylethylamines on the market so far only substituted the other phenyl ring. I wonder if it's still a dissocoiative. Or a stim. Or whatever.

Well, if one looks into this article, one might wonder if it would be possible to derive some new psychedelic phenethylamines with alpha-aryl substituents, perhaps it would even be therapeutic. If UWA-001 has 10x increased affinity to 5-HT2A vs. MDMA, then what would N-desmethyl-UWA-001 do vs. MDA and what would 2,5-dimethoxy & mescaline derivatives of that derivative do? There's no guarantee that they would be psychedelics, but they may be. Moreover, if an alpha-phenyl group increases affinity to 5-HT2A receptors 10x & alpha-isopropyl and alpha-cyclopropyl decrease it 5x and ~2x (also let's keep it mind how the effects change from DOM to alpha-ethyl-2C-D), that means the phenyl group must bind to something, perhaps one could play with it by putting EDG or EWG groups onto the ring to get some interesting stuff.

 

[roi]

 

[pharmakos]

so looking at potential modifications of UWA-001, here's one of the first obvious ones i suppose?

can't imagine that no one has ever made it before

and yeah then like adder said, start sticking various groups on that bare phenyl ring to see what happens.

 

[roi]

2,5-dimethoxy-4-bromo would be even more obvious, given its theoretically much higher potency than 3,4,5-trimethoxy and likely easier synth (also I love 2C-B).

If that works, 4,N-dimethyl + beta-ketone. Pyrophenidone (4-methyl, N-pyrrolidine, beta-ketone) was briefly sold and got mixed reviews...I don't know I loved it. 25mg vaped -> insane euproria for 25-35 minutes.

 

[clubcard]

When I look at 5HT2a ligands, I overlay them with LSD. Note how DMT & AMT are both buried in the structure.

 

[TheBlackPirate]

When I look at 5HT2a ligands, I overlay them with LSD. Note how DMT & AMT are both buried in the structure.

5HT1A is also influential and worth thinking about. Actually LSD binds most strongly with 5HT1A. LSD is a super agonist at the 5HT1A site.

 

[DotChem]

If that works, 4,N-dimethyl + beta-ketone. Pyrophenidone (4-methyl, N-pyrrolidine, beta-ketone) was briefly sold and got mixed reviews...I don't know I loved it. 25mg vaped -> insane euproria for 25-35 minutes.

Any reasons as to why pyrophenidone effects last only half hour so. If anything one would expect it to last longer than alfa-PVP(4-8hours). Since only difference is the phenyl replacing the propyl group of PVP. More metabolically stable

 

[roi]

a-PVP definitely doesn't last 4-8 hours vaped, hah. Not sure where you're getting that from.

 

[Midnight Sun]

Any reasons as to why pyrophenidone effects last only half hour so. If anything one would expect it to last longer than alfa-PVP(4-8hours). Since only difference is the phenyl replacing the propyl group of PVP. More metabolically stable

With all of the pyrrolidine stimulants the main enemy is rapid lactamization of the pyrrolidine ring...

***

linking 2 images because they're huge, but:

http://imgur.com/a/bpn7l

discounting potential metabolic nasties for the moment, would it be possible to use powerfully electronegative N-substituents in an attempt to get a ligand to conform in a certain manner? (see images, MET vs N-methyl-N-trifluoroethyltryptamine) - in this case I believe the nitrogen still has some kind of positive charge and I was hoping to maybe use CF3 to make the "antlers" bend a certain way...

 

[adder]

When I look at 5HT2a ligands, I overlay them with LSD. Note how DMT & AMT are both buried in the structure.

Yes, they are, but that doesn't mean all psychedelic phenethylamines or tryptamines have to be share key structural elements with LSD. N-benzyl-2C-X's can be overlaid with LSD too in theory if the o-anisyl can substitute for the amide, but it appears they bind differently. Obviously not all 5-HT2A agonists are psychedelics though, nor-UWA-001 may not be, but it'd still be a nice find if it was a mellow therapeutic empathogen.

2,5-dimethoxy-4-bromo would be even more obvious, given its theoretically much higher potency than 3,4,5-trimethoxy and likely easier synth (also I love 2C-B).

Provided that the 2,5-dimethoxy pattern would work with alpha-phenyl, it might be that alpha-phenyl is the missing part for the 3,4,5-trimethoxy pattern to show its full capacity if it boosts affinity vs. alpha-methyl for 3,4-methylenedioxy. :D I'd start with the primary amine analogue of UWA-001 and see how it works out, at least it seems logical to compare nor-UWA-001 with MDA having UWA-001 already compared to MDMA in the article.

discounting potential metabolic nasties for the moment, would it be possible to use powerfully electronegative N-substituents in an attempt to get a ligand to conform in a certain manner? (see images, MET vs N-methyl-N-trifluoroethyltryptamine) - in this case I believe the nitrogen still has some kind of positive charge and I was hoping to maybe use CF3 to make the "antlers" bend a certain way...

Having a strongly electron-withdrawing group that close to the amine you make the amine less basic (less able to donate its lone pair), thus likely to bind less strongly with its target residue.

 

[roi]

Furanylpsilocin

 

[aced126]

Any reasons as to why pyrophenidone effects last only half hour so. If anything one would expect it to last longer than alfa-PVP(4-8hours). Since only difference is the phenyl replacing the propyl group of PVP. More metabolically stable

Pyrophenidone is extremely lipophilic and deposits itself in fat tissues, is one explanation given previously. Lactamisation is probably another good one.

 

[Dresden]

I doubt pyrophenidone could be all that more lipophilic than alpha-pyrrolidinylvalerophenone based on the fact that there is only a single CH3's difference between the two molecules as anyone can see here below by comparing their molecular structures:

alpha-PVP

pyrophenidone

I would imagine pyrophenidone would, like alpha-PVP, still have no problem getting you high were you to ingest some within the confines of its therapeutic dosage range, but I don't know that for a fact.

 

[Midnight Sun]

I doubt pyrophenidone could be all that more lipophilic than alpha-pyrrolidinylvalerophenone based on the fact that there is only a single CH3's difference between the two molecules as anyone can see here below by comparing their molecular structures:

alpha-PVP

pyrophenidone

I would imagine pyrophenidone would, like alpha-PVP, still have no problem getting you high were you to ingest some within the confines of its therapeutic dosage range, but I don't know that for a fact.

That's pyrovalerone bruh

pyrophenidone is a-phenyl (so very lipophilic actually)

Kinda strange that it doesn't [apparently?] really affect half-life (if only by virtue of a long drawn out crash) -- see the long H/L beta-phenyl stims... of course those are different animals, yes, but the relation is there nontheless

Having a strongly electron-withdrawing group that close to the amine you make the amine less basic (less able to donate its lone pair), thus likely to bind less strongly with its target residue.

mmm... do we know how much legwork the ethanamine does vs indolamine in terms of how tryptamines bind?

really just morbid curiosity at this point

 

[belligerent drunk]

Having a strongly electron-withdrawing group that close to the amine you make the amine less basic (less able to donate its lone pair), thus likely to bind less strongly with its target residue.

But then again, the population of that less basic substance wouldn't be protonated as much. Would that help, what do you think?

 

[adder]

But then again, the population of that less basic substance wouldn't be protonated as much. Would that help, what do you think?

The interaction of the amine with aminoacid residues with negatively charged side-chain (aspartic or glutamic acid) is based on proton transfer (the amine must be protonated first to interact with the residue), so lower basicity can't be any good, also higher lipophilicity doesn't mean more compound getting to the brain, it will be deposited to fat tissues, no advantage here. One example of a compound with a less basic amine than the parent compound and less activity is beta,beta-difluoro-p-chloroamphetamine, it's pKa is 6.8 while p-CA have a pKa of 9.3, so you can see that the amine is strongly deactivated by those two fluorine atoms. As a result beta,beta-difluoro-p-CA needed five times the dose of p-CA to reach similar levels in the brain, but they are not maintained as it's metabolized much faster (source). In the case of the tryptamine analogue we're discussing there are three fluorine atoms located on the beta position to the amine nitrogen atom, so one can expect a solid decrease in basicity here as well.

 

[DotChem]

Pyrophenidone is extremely lipophilic and deposits itself in fat tissues, is one explanation given previously. Lactamisation is probably another good one.

That makes sense. It is a bit too lipophilic but then again so is THC. But yeah much of the dose will just sit in fat tissues and release slowly overtime. Which will give it longer t1/2 but less rush. imho First-pass metabolism via Lactamization may be bigger issue. It is hard to replace a pyrolidine though as playing around with it "kill" DAT activity (see original paper of SAR of pyrovalerones here).

1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) analogs. A promising class of monoamine uptake inhibitors

MDPP (methylenedioxy pyrophenidone LogP:3.35 vs LogP of PVP 3.88. More reasonable LogP!
But probably not a stim (if UWA-001 is any indication: it has ZERO DAT affinity) maybe a Disso similar to diphenidine..who knows?



may be the bk analog of UWA-001 (mephedrone homolog)