Psychedelic Tryptamines and Serotonin 5HT2A Receptor

[paracelsius]

I have been looking at human 5HT2A crystal structures complex with psychedelics, from that Chinese x-ray Science paper of 2A with hallucinogenic (psilocin, LSD) and non-hallucinogenic (lisuride) tryptamines.

Structure-based discovery of nonhallucinogenic psychedelic analogs​

Cao et al... Science 2022, 375(), 403-411. DOI: 10.1126/science.abl861
Abstract
Drugs that target the human serotonin 2A receptor (5-HT2AR) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use. Here, we present structures of 5-HT2AR complexed with the psychedelic drugs psilocin (the active metabolite of psilocybin) and d-lysergic acid diethylamide (LSD), as well as the endogenous neurotransmitter serotonin and the nonhallucinogenic psychedelic analog lisuride. Serotonin and psilocin display a second binding mode in addition to the canonical mode, which enabled the design of the psychedelic IHCH-7113 (a substructure of antipsychotic lumateperone) and several 5-HT2AR β-arrestin–biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects. The 5-HT2AR complex structures presented herein and the resulting insights provide a solid foundation for the structure-based design of safe and effective nonhallucinogenic psychedelic analogs with therapeutic effects.

Well that study (I mean the X-ray structure) doesnt really tell you how a given agonist binding may lead to (selective) activation of one or the other pathways(or both) and lead to hallucinogenic effects (rather HTR) or not. I dont buy into the rational they proposed tho, I mean the structural basis for functional selectivity leading to hallucinogenic effect (or not) of a 5HT2A agonist.

Here is psilocin bound to human 5HT2A receptor (same ref; pdb code 7wc5 ). Processed to zoom on the active site details. 5-MeO-DMT is superimposed to psilocin (not optimized!) for comparison. Also substituted tryptamines structure (with atom numbering) from wikipage. well not quite fully numbered but notice the 4,5,6 and 7 position on the benzene ring.

If you actually look at the structure, it is easy to see rational for the SAR of psychedelics, at least tryptamine-types. A variety of substituents on the amine N can be tolerated. There is lots of empty space on that pocket of the receptor binding site (bottom-right corner in pic). Mostly large hydrophobic. You can fit variety of N-substitutents, even large ones like a benzyl to optimize fitting/binding: No wonder Nbome, N-benzyltryptamine, even N-Bromobenzyl are super-potent (fit better). As well as a variety of N,N-dialkyltryptamines made by Shulgin (DET, MET, DPT, MiPT, DiPT....etc).

View from indole phenyl side:

R5 Substituents at the 5-position (like Methoxy in 5-MeO-DMT or 5MeO-DiPT aka foxy...etc) fit nicely which explain why 5-sub tryptamines are more potent in general. So is the 4-sub and 7-sub positions but not the 6-position, there is just no space to accommodate any thing larger than a H at 6-position without paying energy penalty, maybe a Fluoro. That explains why 6-MeO-DMT is like 800x less potent than 5-MeO-DMT and is non-hallucinogenic.

Now that doesnt really tell you much about what may happen next, once the drug binds the receptor, ie which downstream signalling is selectively activated -> hallucinogenic or not, even type of “hallucinations”(visual, auditory, DMT entities, DPT religious theme..etc etc. Only that the designed drug may bind and activate the 2A receptor, predicting what happen next is the million$ question.

The interesting thing tho, the psychedelic effects can be dramatically different depending on the substituent. Like take Dipropyltryptamine DPT (one I always wanted to try), well that compound is purely auditory while some other tryptamines are pretty visual. I mean it is pretty hard to predict that from the drug chemical structure, kind like draw a Structure-Hallucinations-Relationship (SHR) of psychedelics! would be nice to see that tho: Structure-Hallucinations-Relationships of Psychechedelic Tryptamines!..anyway

If I was to design new psychedelics, I would focus on the N-subs and/or 7-substitued tryptamines. Shulgin made a bunch of N-sub-Tryptamines, but mostly N,N-disubstituted. Not so much mono-subs and 7-subs tryptamines (iirc only N-ethyltryptamine NET was mentioned in TIHKAL). But I believe there is lots to explore especially 7-subs tryptamines. Lots of tryptamines with interesting profile are yet be discovered. They certainly patentable too....hope you enjoy reading Good'day All BLighters.. You'all Stay Safe Out There.

EDIT: please note the imgs are © DM me if you intent to use, thx.

 

[Fertile]

small substitutions at the 7 position seem to increase extracellular serotonin levels and in the 1960s Upjohn (if memory serves) patented AET then 7-methyl AET. The problem with those is their considerable MAOI activity BUT their 5HT2a affinity is lowered. By contrast, 7-methyl AMT has more interesting properties. One isomer is an entactogen, the other is a hallucinogen. There is a window where the racemate acts primarily as an entactogen but it's not a huge window.

I'm presuming nobody is studying 7-methyl AMT because it's rather difficult to synthesize. You have to built that ring-substituted indole system.

 

[paracelsius]

Isnt it alfa-alkylation that makes those tryptamine MAOIs? I mean AMT-type. I was actually thinking about something like 7-hydroxy-DMT aka Isopsilocin. I doubt that compound has been ever made. iirc, alfa-alkylation doesnt affect much in term of 2A activity, or rather as you mentioned, decrease it by half ie only one enantiomer active. But anyway I was suggesting 7-subs-N-(di)subs tryptamines, ie in the same manner as psilocin (4-HO sub) tryptamines. something like isopsilocin (7-hydroxy-N,N-DMT), isoetacin (7-hydroxy-N,N-DET), isometacin (7-hydroxy-MET)...etc. afaik those tryptamines (7-sub with plain indolylethylamines) have not been investigated which is why I am saying they potentially patentable (anybody wants to explore that DM me).

I wouldnt worry too much about MAO (different subst on the amine can take care of that without affecting 2A affinity). What I worry about the most tho is 5HT2B activation and cardiac valves defect. See most tryptamines would activate 2A and 2B equally. few agonist are selective for 2A v 2B. Cardiac valve defect is pretty irreversible and a very serious condition. The valve that prevent blood from flowing back when pumped out by the heart gets "chew up" caused by chronic 5HT2B activation...very very serious s...t ! (cf PhenPhen fiasco). Granted, only happen after chronic activation of 2B. But the worrisome thing is ppl are now so-called "microdosing" mushroom for example.. well psilocin is actually MORE potent agonist at 2B than 2A. So is LSD. So I wont be surprised if 5-10 years from now when the craze about psychedelics dies down a bit, we'd see epidemic of heart valve issues. Hope not.

as for synth, 7-subs are not harder to make than 4-subs aka psilocin type. actually easier since you get only only isomer (the right one) starting from 7-benzyloxyindole>Anthony-Speeter>hydrogenolysis to get 7-HO-tryptamines!.. or from 7-methylindole or 7-methoxyindole..etc in fewer steps (no need for hydrogenolysis)...Certainly not cheaper than plain tryptamines starting from plain indole...anyway, I posted that b/c there is actually a lot (A LOT) research, or rather LOT of claims going around ppl claiming to have come up with non-hallucinogenic 2A agonists that retain antidepressant. That is why that paper claiming they know what makes agonists hallucinogenic or not from the X-ray complex is bs imho! But it is major advance for sure, one can easily design 2A agonists with the structure now available... Designin non-hallucinogenic 2A agonist psychedelics is another matter. ... Good'day all Blighters... Stay Safe Out There.

 

[Fertile]

From what I read, a methyl beyond the amine doesn't produce much MAOI activity. It's when they reached the ethyl that Upjohn even measured MAOI activity and noted it within the patent.

But people forget that AMT is chiral. The (S) isomer has significant 5HT2a affinity but the (R) isomer does not. I know this from experience because we had the two isomers resolved. I believe that the lab-team formed the tartrate salt. In fact, most of the techniques that can be applied to the resolution of amphetamine can be applied to AMT. Differences in solvent characteristics would be the main consideration.

I can tell you that the subjective activity of the 2 isomers is totally different. The (S) isomer produces classic hallucinogenic effects at 25mg while the (R) isomer significantly improved mood but significant entactogenic effects were not apparent until I reached 75mg and at that point nausea and other unpleasant (but not serious) side-effects.

Then we had a sample of 7-methyl-1H-indole-3-carbaldehyde produced with which we made 7,N,N-trimethyltryptamine and 7,α-dimethyltryptamine The former was very much like DMT but possibly with a shorter duration but less 'pressure' i.e. one could really enjoy the visuals while feeling very relaxed.

The racemic 7,α-dimethyltryptamine was more interesting. Initially we simply tried the racemate and their was significant entactogenic effects as low as 15mg with no trippy effects whatsoever. As the dose was increased, the classic AMT effects became present although the several people who sampled it all described it as being 'warmer',

Next day we sampled (R) 7,α-dimethyltryptamine and that was QUITE different. Very MDMA-like. I can totally understand how people were selling α-ethyltryptamine as MDMA (until producers took note and prices went through the roof.

So I would tacitly put (R) 7,α-dimethyltryptamine forwards as a decent MDMA alternative. Of course, the cost of obtaining the 7-methyl-1H-indole-3-carbaldehyde would be a major issue. I wish more people had sampled (R) AMT because a sample of 1 is not statistically significant. It may well have been a bad pie at lunch that produced the side-effects and with AMT being reasonably available, resolution would be possible.

Oh, and of course, unlike most other compounds, both the (R) and (S) are active. OK you might end up with a surfeit of (S) AMT especially since just 25mg makes a pretty potent dose... but there are enough dubious people out there who would cut it 1:1 with an inactive to then make it work like 'normal AMT'.

I'm totally against cutting actives because who knows if there will be hot-spots and what some people consider a 'reasonable' cutting agent is not what I would consider acceptable.

 

[Fertile]

Np - bit there are compounds that look like 2 thing but that do another.

 

[paracelsius]

From what I read, a methyl beyond the amine doesn't produce much MAOI activity. It's when they reached the ethyl that Upjohn even measured MAOI activity and noted it within the patent.

Do you have any ref for the MAOI activity of AMTs ? I have some doubt about that UpJohn patent re: MAOI of 7-Me-AMT. I mean they infer that from increase serotonin in rats brain assuming it is due to MAO inhbition and prevention of serotonin catabolism. well plain racemic AMT is actually a dopamine-norepinephrine serotonin releaser (in addition to 2A agonist). Quite potent and balanced. compound 13 here ->10.1007/s00213-014-3557-7: DAT-SERT-NET (nM): 78, 21,112 and 5HT2A: 23.1 nM. The serotonin increase they observed may well due to its release rather than inhibition of its degradation by MAO inhibition.. but who knows, there may be somewhere direct MAO assay of AMTs

Next day we sampled (R) 7,α-dimethyltryptamine and that was QUITE different. Very MDMA-like. I can totally understand how people were selling α-ethyltryptamine as MDMA (until producers took note and prices went through the roof.

wouldnt be surprised it is MDMA like. actually plain AMT (S-isomer?) has pretty much same profile as MDMA as triple releaser, just more potent like 2-3X (cf ref above). but are you sure it is the (R)-isomer you sampled not the (S)??? I would expect the S rather than the R be MDMA like if one goes by the SAR of other amph-like releasers!.. I am not sure about selectivity at 2A tho....

btw AMT is cheaper to make that dirt. well even the 7-methyl-4-formylindole you mentioned is not really hard. 7-methylindole+dmf+pocl3 will give you the 3-formylindole required. 7-methylindole is dirt cheap. I run that rx several time with bunch of indoles. yields are pretty much quantitative...Of course, that s not kitchen chemistry (pocl3 is toxic & could kill you!!!!)

Also, I wouldn't agree that DiPT is purely auditory. It seems to have a biphasic effect that semi-overlap: there is an emotionally clarifying effect that seems pharmacologically distinct from the DiPTogenia (my newly coined neologism for DiPT-induced auditory effects). This is big news, since if we can develop a compound that has a DiPT-like emotional clarifying with no visuals and no DiPTogenia then you will be one of the richest people on the planet within a few years.

My bet.. you right it is DiPT I was refereing to for auditory effects. DPT seems to have religious overtone more so than any other tryptamines. which is why I find it fascinating how small changes in the molecules (eg propyl->isopropyl) can have dramatically different psychedelic effects... I suspect it wont be easy to separate the emotional clarity from the DiPTogenia and visuals effect b/c so many variables: for one the emotional clarity could be due to .... well the Diptogenia and visuals!
When it comes to psychedelics, I happen to believe the positive mental effects (like antidepressant effect) cant be dissociated from the auditory/visuals..etc: The Hallucinations Are The Cure (there were a thread on that earlier)... Good'day all BLighter .. Stay Safe Out There.

 

[Fertile]

Do you have any ref for the MAOI activity of AMTs ? I have some doubt about that UpJohn patent re: MAOI of 7-Me-AMT. I mean they infer that from increase serotonin in rats brain assuming it is due to MAO inhbition and prevention of serotonin catabolism. well plain racemic AMT is actually a dopamine-norepinephrine serotonin releaser (in addition to 2A agonist). Quite potent and balanced. compound 13 here ->10.1007/s00213-014-3557-7: DAT-SERT-NET (nM): 78, 21,112 and 5HT2A: 23.1 nM. The serotonin increase they observed may well due to its release rather than inhibition of its degradation by MAO inhibition.. but who knows, there may be somewhere direct MAO assay of AMTs


wouldnt be surprised it is MDMA like. actually plain AMT (S-isomer?) has pretty much same profile as MDMA as triple releaser, just more potent like 2-3X (cf ref above). but are you sure it is the (R)-isomer you sampled not the (S)??? I would expect the S rather than the R be MDMA like if one goes by the SAR of other amph-like releasers!.. I am not sure about selectivity at 2A tho....

btw AMT is cheaper to make that dirt. well even the 7-methyl-4-formylindole you mentioned is not really hard. 7-methylindole+dmf+pocl3 will give you the 3-formylindole required. 7-methylindole is dirt cheap. I run that rx several time with bunch of indoles. yields are pretty much quantitative...Of course, that s not kitchen chemistry (pocl3 is toxic & could kill you!!!!)


My bet.. you right it is DiPT I was refereing to for auditory effects. DPT seems to have religious overtone more so than any other tryptamines. which is why I find it fascinating how small changes in the molecules (eg propyl->isopropyl) can have dramatically different psychedelic effects... I suspect it wont be easy to separate the emotional clarity from the DiPTogenia and visuals effect b/c so many variables: for one the emotional clarity could be due to .... well the Diptogenia and visuals!
When it comes to psychedelics, I happen to believe the positive mental effects (like antidepressant effect) cant be dissociated from the auditory/visuals..etc: The Hallucinations Are The Cure (there were a thread on that earlier)... Good'day all BLighter .. Stay Safe Out There.

I might have it the wrong way around. Just overlay with LSD. No surprise that the isomer that the one that overlays has 5HT2a affinity.

It would appear that given the difference in metabolism, the entactogen isomer of AMT isn't any more of an MAOI than, say, MDMA. I mean, I'm pretty sure that few people have suffered harm from either compound related to MAOI activity.

AMT (racemic) was used in Russia as an antidepressant. Even then, they did not separate isomers.

Oh, and consider mg/kg in animal models. Chances are that in humans, a useful dose will be much lower. Didn't Shulgin recommend 'not more than 1.5mg/kg nor more often than once every 6 weeks'? VERY conservative.

But indeed the doses of 7-methyl AMT needed for entactogenic effects is quite low. Certainly several times less than racemic MDMA.

I do appreciate your work. So FEW people put in the effort to find that data. I think you are in a field of 1.

 

[realgar]

Do you have any ref for the MAOI activity of AMTs ?

Wagmann, L; Brandt, SD; Kavanagh, PV; Maurer, HH; Meyer, MR. In vitro monoamine oxidase inhibition potential of alpha-methyltryptamine analog new psychoactive substances for assessing possible toxic risks. Toxicol. Lett., 17 Apr 2017, 272, 84–93. 1.9 MB. https://doi.org/10.1016/j.toxlet.2017.03.007

(provided by isomerdesign.com: https://isomerdesign.com/PiHKAL/explore.php?domain=tk&id=5596#references )

7-Me-AMT with IC₅₀ 0.049 µM was the strongest MAO-A inhibitor among several substituted AMTs tested (comparable with harmaline IC₅₀ 0.011 µM).

 

[polymath]

It's unfortunate that molecular docking can't currently predict which secondary messenger a ligand of a G-protein coupled receptor has most effect on, or even if it's agonist or antagonist. Usually you can tell that by comparing to similar previously tested compounds, though.