Fluorine in psychedelic phenethylamines

[23536]

Abstract

The so-called psychedelic phenethylamines represent a class of drugs with a large range of psychoactive properties in humans, ranging from naturally occurring mescaline to amphetamine analogues and homologues. The interest in many of these compounds, occasionally referred to as designer-drugs, is widely dispersed across popular culture and political and scientific communities. In recent decades, fluorine has become a powerful and important tool in medicinal chemistry. In addition, fluorine-containing compounds and medicines can be found in numerous commercially successful pharmaceuticals that have gained a market share of some 5-15%. One might anticipate this trend to increase in the future. As far as fluorinated phenethylamines are concerned, much less is known about their chemistry and pharmacology. This paper provides an overview regarding the biological properties of over 60 fluorinated phenethylamines and discusses both historical and recent chemistry-related developments. It was shown that the introduction of fluorine into the phenethylamine nucleus can impact greatly on psychoactivity of these compounds, ranging from marked loss to enhancement and prolongation of effects. For example, in contrast to the psychoactive escaline (70), it was observed that its fluoroescaline (76) counterpart was almost devoid of psychoactive effects. Difluoroescaline (77), on the other hand, retained, and trifluoroescaline (78) showed increased human potency of escaline (70). Difluoromescaline (72) and trifluoromescaline (73) increasingly surpassed human potency and duration of mescaline (22) effects.

Copyright © 2012 John Wiley & Sons, Ltd.

http://onlinelibrary.wiley.com/doi/10.1002/dta.413/abstract

 

[shishigami]

Wow, this is a winner.

 

[LogicSoDeveloped]

This is quite fascinating! Quick question for you chem wizzes out there, why are there so many mescaline analogues?

I know that there are analogues for many, many drugs but it seems like the mescaline ones come up in conversation and in articles the most online.

 

[skillet]

You think? There are only a handful that have been tested, compare with 2C-B analogs... Which is a shame, because mescaline analogs are by far my favourite PEA's.

 

[shishigami]

This is quite fascinating! Quick question for you chem wizzes out there, why are there so many mescaline analogues?

I know that there are analogues for many, many drugs but it seems like the mescaline ones come up in conversation and in articles the most online.

My only thought is that there are three identical positions to make analogues from. So if you wanted a single ethyl analogue of mescaline you could have it substituted at the 3,4, or 5 position. For diethyl 34,35, or 45, and for tri ethyl you only have one. That's my thought.

 

[skillet]

Yeah symmetry will reduce the number of possible analogs (there's only two diethoxy mescalines, 3,4 and 4,5 are equivalent). But the 4-substituent is the most interesting, and there have only been a few 4-position analogs of mescaline/TMA made compared with 2,5-dimethoxyphenethylamine/amphetamine. The remaining ones are relatively hard to make, and likely less potent and selective than the 2,5's, so it's probably hard to justify funding for it, though I bet there'd be some great drugs there.

 

[23536]

There's this however:

4-trifluoromethoxy-3,5-dimethoxyphenethylamine

No go I think, o-demethylation will cause problems when the fluoromethyl group gets bumped off and gets to cause havoc on its own.

Deamination is the foremost method of metabolism, but after that you get n-acetyl-3,4-dimeo-5-ho-mescaline, then n-acetyl mescaline... there are a bunch of other urinary metabolites too in very small number, and I'm willing to bet one of them has a 4-hydroxy group, but then, how much do you need of trifluoromethanol/trifluoroformic acid to cause problems in your body/brain? I don't know, but it wouldn't be foremost on my tasting list because of that, probably something for rats to try first.

http://www.bluelight.ru/vb/threads/...uture-Thread?p=4659199&viewfull=1#post4659199

I wonder if the authors thought of that.

 

[wirreddreams]

Has anyone got this article yet the journal its in is one of the few journals i don't have access to.

 

[amanitadine]

Yeeeessss thank you seep, good find. And I'm with you skillet, the 3,4,5's are me fav as well. Had my first experience with thiomescaline not too long ago, quite lovely at 40mg I must say! Mescaline is still hard to beat IMO.

 

[JacksinPA]

When I was researching the occurrence of mescaline in the cactus plants I had collected during my travels in AZ & CA, IIRC the content was 0.1%. The dosage was 500 mg, which equated to about 500 grams of cactus. To show you the influence of lipophilic fluorine atom substitution on the 4-methoxy functional group, this Wikipedia article https://en.wikipedia.org/wiki/Trifluoromescaline states the following: Trifluoromescaline (TF-M) is a derivative of the phenethylamine hallucinogen mescaline, which has a trifluoromethoxy group replacing the central methoxy group of mescaline. Synthesis of this compound was first reported by Daniel Trachsel in 2011, alongside many other related compounds.^[1][2] Trifluoromescaline was found to be one of the most potent compounds in the series, with a reported dosage of 15-40mg (and 60mg being described as a "strong overdose"), and a slow onset of action and long duration of effects, lasting 14-24 hours or more.<sup>[3]

So the fluorine substitution resulted in something like a ten-fold increase in potency, with a narrow margin between an effective dose & a 'strong overdose.' I had a strong OD on mescaline once & for 12+ hours couldn't even remember what day of the week it was.</sup>

 

[Limpet_Chicken]

THANKS for this link! I'll do my best to bypass the paywall and get the paper.

Because 3-bromo-4-(1,1-difluoromethoxy)-5-methoxyphenethylamine and the corresponding TMA (and possibly cathinone if there is enough aldehyde left), is in the pipeline. The unusual 3-halogen is making it really look interesting, since its something that has just not been explored, highly electronegative, EWGs at the 3' phenyl carbon is seemingly about as looked into by mainstream science as the bloody black art of necromancy, voodoo and tribal sorcery.