Pharmacology Beta-Keto-Phenethylamines

[tuppingtoncity]

Interesting, would be cool to see some sort of proposed metabolic pathway, even if it is guesswork.

The question is why does mescaline require large doses

As to this, I think the simplest answer would have to be Mescaline's relatively low, but non-negligible 2a affinity. Although potentially active metabolites are certainly worth exploring, I don't think they are necessary (if they exist) to explain the high doses required for mescaline activity.

 

[Allylbenzene]

Interesting, would be cool to see some sort of proposed metabolic pathway, even if it is guesswork.

Hopefully soon.

Although potentially active metabolites are certainly worth exploring, I don't think they are necessary (if they exist) to explain the high doses required for mescaline activity.

It would be fairly straightforward to trial a very low dose of mescaline with the appropriate enzyme inhibition (ALDH only). If a miniscule dose of mescaline shows impossible potency then it's another clue. The same potentiation strategy applies to plain phenethylamine and tryptamine.

This is swerving off topic...

I'd refer you to that linked post for context on people's trials with potentiating mescaline by acknowledging the aldehyde/aminated metabolite route and choosing the appropriate potentiation methods.

 

[Skorpio]

Presumably he's comparing plain mescaline with mescaline-NBOMe. If we consider that mescaline is a mildly active prodrug (for which the pharmacokinetics haven't been properly elucidated) then his comparison is misleading as are all receptor affinity analyses of mescaline (even the PLOS recepterome study).

If mescaline was a prodrug, why would the NBOMe form be stronger than people report with enzyme inhibition.


Not everything has to be some kind of forbidden knowledge. Sometimes a drug can just be weak. The balance of probability that the 3,4,5 substitution pattern is weaker (consider the TMAs versus the DOXs) rather than that there is some multi step bioactivation process.

Pharmacological ALDH inhibitors are quite reactive and usually quite nonselective. Many are MAOIs.

Occam’s razor

 

[Allylbenzene]

If mescaline was a prodrug, why would the NBOMe form be stronger than people report with enzyme inhibition.

It's important to specify active prodrug otherwise the reader might get the wrong idea.

The SAR of 2Cx-NBOMe might not be what it seems which implies a re-evaluation of mescaline-NBOMe and subsequently your comparison with mescaline.

...in this study, we find the 2,4-dimethoxy pattern to result in a higher potency and similar efficacy as the 2,5-dimethoxy pattern in NBOMes with no further phenethylamine moiety substituents.
— 10.1021/acsptsci.0c00189

If you overlay the 2,4 & 2,5 NBOMe pattern with LSD you'll see what I mean. 2,4 overlays in a very different manner.

Not everything has to be some kind of forbidden knowledge.

Indeed, sometimes it's just spectacularly overlooked. Academia doesn't appear to acknowledge the extent of what it overlooks.

 

[4DQSAR]

Affinty ≠ effaciacy

EC50 is often the more useful metric.