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Alternative Psychedelic Backbones

T

thecookiemonster

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Dec 13, 2009
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What do you think is to come in the future of new psychedelics? I know that the vast majority (using the term "psychedelic kind of loosely") have phenethylamine or tryptamine "backbones." Also, the majority of pscyhedelics have a loose homology to a neurotransmitter's structure.

Are there any other structural "backbones" that seem promising or that you think might be an avenue worth exploring? Given the widely different effects of different substituted phenethylamines / tryptamines based on the same backbone, I'm assuming that the backbone is used just because it's relatively inert biologically and holds the "business end" of the molecule in the right geometry to be a good receptor agonist/antagonist / competitive inhibitor, as well as having good lipophilicity / metabolic characteristics / etc.

Sorry that this is a really vague (and not particularly scientific-sounding) question.
 
Also, the majority of pscyhedelics have a loose homology to a neurotransmitter's structure.
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Both of which are based on the structure of available amino acids. I think that except for the odd case where spacing between atoms is similar, they're all going to be based on either tryptophan (serotonin) or phenylalanine/tyrosine (dopamine/noradrenaline). Something like the lysergic acid backbone might pop up, but eventually it'll be either a tryptamine or phenethylamine that's got a lot more added to it
 
OK, cool. I'm a chemistry major (undergraduate), so I don't have an in-depth knowledge of neurotransmitter receptors. I guess I was thinking that perhaps instead of having a molecule that actually binds the receptor, you might be able to design one that binds elsewhere and enhances the affinity for the receptor's natural partners (and presumably this molecule would have a much different backbone than that of the receptor's normal partners). So instead of changing the signal it gets (like taking a psychedelic) or changing the availability of its regular signal (like an SSRI or something), maybe we can change the way the receptor itself responds to a normal level of its typical ligand (for example, I read a paper about Zn2+ being used as an allosteric modulator of the 5-HT1a receptor...perhaps molecules could be designed to exploit these characteristics -- could either be taken alone or perhaps used to potentiate the affects of some other agents).

Again...all very theoretical and qualitative, but just the kind of stuff I daydream about in organic chemistry. Looks like I should hit the books and brush up on pharmacology / neuroscience this summer so I can better assess the feasibility of this stuff.
 
Recently there were some funky new quinazoline-based 5HT2a partial agonists.

Not particularly high affinity, iirc but that means little, and potency isn't equal to quality.
Just look at 5-MeO-AMT compared to say, something quantitively weak but qualitatively infuckingcredible like DMT.
 
Yes actually, Yohimbe like alkaloids do have potential.

Ibogaine is related to Yohimbe and Ibogaine is an Indole alkaloid.

It's very interesting too because it acts on the kappa opiate receptor which is thought to take away withdrawl rather quickly and way less painful than withdrawling by yourself.


So I think that drugs that act on the kappa opioid receptors have great potential.

And Indole alkaloids.
 
Nexius said:
So I think that drugs that act on the kappa opioid receptors have great potential.
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After salvia, they just sound like shit. Salvia could turn out to be the 5-MeO-DMT of kappa opioid agonists, but ibogaine also gets described as unpleasant.

The piperazine family looked like it could've produced at least one half-decent molecule, but nope, they all suck. Well, there's that piperazine that mimics oxytocin and crosses the BBB that might be interesting to combine with other substances, but that's not psychedelic and therefore doesn't have to do with the topic at hand.
 
ibogaine also gets described as unpleasant.
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You call this unpleasant? Powerful, sure... but remember ibogaine also hits NMDA and 5-ht2a

The piperazine family looked like it could've produced at least one half-decent molecule, but nope, they all suck
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Even quipazine? I wouldn't take it orally, but its binding profile looks kinda promising.
 
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The Smoking Man said:
After salvia, they just sound like shit. Salvia could turn out to be the 5-MeO-DMT of kappa opioid agonists, but ibogaine also gets described as unpleasant.

The piperazine family looked like it could've produced at least one half-decent molecule, but nope, they all suck. Well, there's that piperazine that mimics oxytocin and crosses the BBB that might be interesting to combine with other substances, but that's not psychedelic and therefore doesn't have to do with the topic at hand.
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I really do not get the piperazines.


On paper they look awesome, but yet they suck terribly.



edit--------------I guess their 5HT3 affinities?
 
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atara said:
You call this unpleasant? Powerful, sure... but remember ibogaine also hits NMDA and 5-ht2a


Even quipazine? I wouldn't take it orally, but its binding profile looks kinda promising.
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I didn't say everyone who's tried ibogaine called it unpleasant, but there's a pretty good number of people who've had unpleasant experiences, moreso than with classical psychedelics.

Quipazine also seems to agonize 5-HT3, which would likely cause anxiety. Doesn't sound very nice to me.
 
I've been wondering if quinoline analogues of tryptamines would be a good idea... At the very least they should fit through several legal loopholes... They should be able to bind just as well as tryptamines, as far as I can tell. (which is not very far though...)
 
There are some new structures, EZS-8 and RH-34 based on a 2,4-quinazolinedione core, developed by tweaking ketanserin until an agonist resulted at 5HT2a.

Moderate efficacy at 5HT2a.
 
shulgin was always hinting at "the 3rd" psycadelic amine to be found based on histamine. (well sure he did mention it as least once, maybe I exagerate).

alas, never saw the logic with that one, can't see that happening. Not to diss the legend himself of couse :)
 
fastandbulbous said:
Both of which are based on the structure of available amino acids. I think that except for the odd case where spacing between atoms is similar, they're all going to be based on either tryptophan (serotonin) or phenylalanine/tyrosine (dopamine/noradrenaline). Something like the lysergic acid backbone might pop up, but eventually it'll be either a tryptamine or phenethylamine that's got a lot more added to it
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Yeah this would definately be where big pharma would(if ever wanted to)/(could accidently) get involved. The MASS screening of highly complex new chemical entities MUST spring up the occasional 5HT2a agonism (which is duely ignored or seen as a side effect). In fact highly likely it already has (imagine some of the research ala risperidone and atypical antipsychotics must have revealed some odd stuff). Of course - as epected this information is often lost to the general domain.

Instead your pubmed type publications of 5ht2a (nichols etc) agonism tend to lend themselves to the university lead departments who are certainly less cash strapped to afford such MASS screening and x 100 phd students. (+ professors willing to publish such studies - what with the CRAZY mephedrone replacement search very much on the go right now - imagine this will only reduce such publications)

Can you imagine big pharma going after psychadelics - whooa that would be one interesting decade! 8o
 
Phener said:
shulgin was always hinting at "the 3rd" psycadelic amine to be found based on histamine. (well sure he did mention it as least once, maybe I exagerate).

alas, never saw the logic with that one, can't see that happening. Not to diss the legend himself of couse :)
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Histamine's effects are so undesirable that even Wikipedia's page on the histamine receptor doesn't list any agonists -- only antagonists! I'd call that "pretty bad". The H3 receptor is the only interesting one as far as I can tell, because Wiki and Google don't know what the hell H3 even does. This is interesting:

http://www.ncbi.nlm.nih.gov/pubmed/15530639
 
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