Substituted Alphamethyl Tryptamine

[psynce of sound]

In reading threads on future psychedelics and RCs in general I began to wonder about substitutions to amt. First off what analogs already exist of amt and how do they alter the nature of the parent compound?
Second if 4 and 5 substitutions haven't been made/tried would they be possible and how would they differ from the parent?
For instance 4 subbed esters of amt, would they be worthwhile exploring? How would they differ from the parent?
What about alterations that would allow it to bind in a manner like lysgeramides, substituted PEAs/DOxs or even substitutions that allow binding in line with stimulants (e.g. morpholine stimulant analogs or amphetamine analogs)
It would most interesting to if amt could be taken further in a stimulant realm owing to being a homolog of amphetamine.
Thank you for your time and responses.

Psynce.

 

[Bagseed]

5-MeO-AMT was on the market (never had it) but many thought it to be inferior to AMT, because of nasty physical side effects (besides higher potency iirc). I haven't heard of other AMT subs, but I always thought that going 4-sub-AMT would have been interesting.

 

[Hodor]

5-MeO-AMT was on the market (never had it) but many thought it to be inferior to AMT, because of nasty physical side effects (besides higher potency iirc). I haven't heard of other AMT subs, but I always thought that going 4-sub-AMT would have been interesting.

5-MeO-AMT is, from what I understand, a very powerful psychedelic; since dosages are typically below 10 mg, the stimulant effect (as in "monoamine release") would be less pronounced than with regular AMT.

Shulgin also investigated 4-HO-AMT, but it seemed to be even less well-tolerated than 5-MeO-AMT.

AET (the Alpha-Ethyl-homologue) was originally marketed as an antidepressant, and had weaker psychedelic effects than AMT, and was primarily a serotonin releasing agent - unfortunately it was apparently also a fairly effective MAOI.

 

[Solipsis]

It's quite possibly a mistake to try and carry over regular tryptamine SAR over to AMT... AMT is not at all simply a 5HT2A agonist psychedelic but has a lot of empathogenic effects (via monoamines), even if something like putting a 5-MeO on it makes it more potent as a psychedelic, you can't disregard what it does to that monoaminergic action, like MAOI activity and some such.

So it's very tricky to explore the substitutions we are so fond of like 4-HO because it can do creepy things to the non-psychedelic activity.

I wouldn't mind trying to summarize what we do know about making modifications to AMT, to see if there are open avenues that may be less dodgy but also less conventional, when speaking of tryptamines.

- Clearly fortifying the alpha-alkyl prevents MAO even more from doing its job.
- I think 5-Fluoro-AMT may have been made, let me check it.. https://en.wikipedia.org/wiki/5-Fluoro-AMT may very well have the same issues as 5-MeO-AMT
- Now, 6-Fluoro-AMT (https://en.wikipedia.org/wiki/6-Fluoro-AMT) is even more unusual, you can see my point about SAR with the 6-subbing with F and honestly it vaguely reminds me of 4-FA, but of course you can't really compare.

- @ bk-AMT: interesting direction

I'm not sure of the results you are talking about but it seems likely that making AMT a beta-ketone would differentially effect its binding to monoamine transporters vs. its effects on 5-HT2A receptors. If bk-AMT has less of an effect on 5-HT2A then that might attenuate its effects on the GI tract and the sympathetic nervous system, resulting in less "body load". Perhaps people like the beta-ketone version of AMT better because it is more of an entactogen-like stimulant and less of a hallucinogen?

My question is: would a 6-methyl on AMT or bk-AMT hold any promise from enhancing serotonin release, with 4-MMC in mind? It will come down to a very delicate balance not only between affinities for the transporters and vesicular transporters of the main three monoamines, but also the balance between releasing, reuptake inhibition and MAOI.

This is territory that could be explored but is very hazardous as an imbalance in the wrong direction can mean that one drug's activity can make another activity unsafe or toxic. 5-MeO-AMT is an example of that.

 

[psynce of sound]

Thank you for the responses guys. Gives me a nice little bit of reading to do.
Solipsis your response is very informative indeed, lots of food for thought.
I hear what your saying about the hazards of exploring this area of tryptamine SAR. I feel with the right precautions and patience in researching and creating analogs another gem maybe uncovered. Then again maybe not if as you said no real balance can be found. A 4-mmc homolog would be a most intriguing if it proved to be active and not horribly dangerous.

I'm definitely going to have to go away and do some research into these ideas.
Many thanks for the input thus far.

Psynce.

 

[Solipsis]

A homologue refers to an analogous series in which a certain branch is extended, like 2C-D (4-methyl), 2C-E, (4-ethyl), 2C-P (4-propyl), so extending the carbon chain usually. Similar derivatives are called analogues.

I hope you have a lot of fun puzzling with these structures, maybe we'll see you in the "I like to draw random molecules" thread in the NSP forum. :D

 

[Kaleida]

This is the one that interested me most recently: 5-Chloro-AMT, which is both a 5-HT2A agonist and a selective serotonin-dopamine releasing agent. It's hard to say how safe it would be in humans, but interestingly, according to Wikipedia, in animals it's been investigated for treatment of cocaine dependence.

 

[psynce of sound]

@Solipsis That makes sense and thank you for clearing that up for me.
I have definitely been having fun thus far just looking through wiki pages on these ideas. Hopefully when I can get something to draw molecules either on the tablet or sort out my desktop I'll definitely enjoy contributing to that thread.

@Kaleida I've just read the wiki page on that analog, seems promising as long as it doesn't have powerful maoi properties or cause long-term damage to serotonin pathways a la 4-mta or 4-cma.
It could be a promising start for a gem though.

 

[Hodor]

It's quite possibly a mistake to try and carry over regular tryptamine SAR over to AMT... AMT is not at all simply a 5HT2A agonist psychedelic but has a lot of empathogenic effects (via monoamines), even if something like putting a 5-MeO on it makes it more potent as a psychedelic, you can't disregard what it does to that monoaminergic action, like MAOI activity and some such.

Correct me if I'm wrong, but don't a number of psychedelics have quasi-empathogenic effects despite not being effective monoamine releasing agents (ex. certain 2C-B, 4-HO MiPT, 5-MeO-DiPT)?
With strong activity shown at less than 5 mg, 5-MeO-AMT would have to be obscenely potent as a releasing agent of serotonin if monoamine release was a major part of its effects - yes, AMT is an effective releasing agent, but the dose range is typically five times that of the 5-MeO version. Likewise, the serotonin releasing substances in Pihkal typically require far higher doses than their agonist relatives.
Then again, you may be right that we can't rule out the possibility that 5-MeO-AMT could be such a potent MAOI that it would strongly potentiate whatever serotonin is released, thus producing "true" empathogenic effects after all.

But yeah, even Shulgin himself was pretty fascinated by the mysterious SAR of AMT, discussing the issue at length in his entry on a,N,O-TMS (= N-Methyl 5-MeO-AMT) in TIHKAL.

 

[Solipsis]

I see what you're saying but am not sure if I thoroughly get the point. 5-F-AMT is a potent and selective MAO-A inhibitor so there's not really a question of whether this becomes an issue when we were really focussing on other pharmacological actions that make these drugs psychedelic, empathogenic, or somehow an aid in dependency.

I don't know for certain what 5-MeO-AMT's deal is (that question is ill-defined anyway you could say hehe), but are you saying you're unconvinced that modifying AMT can easily result in a compound that causes dangerous monoamine imbalances?

5-MeO-AMT has quite a narrow therapeutic index and the main explanations for this would be found in MAOI activity or monoamine reuptake inhibition, the point is to try and narrow it down. That the analogous 5-F-AMT is such a potent MAOI could be construed as a sign, but if multiple mechanisms of action are negatively synergistic it certainly wouldn't help.

I wasn't really talking about monoamine release as the "true" correlate of empathogenic effects which is what you seem to be implying. I just think that even if one of the MOA's has a higher efficacy than another MOA, still that can lead to a narrowed therapeutic index, because it increases chances of neurotransmitter balances being thrown too hard.

 

[Hodor]

are you saying you're unconvinced that modifying AMT can easily result in a compound that causes dangerous monoamine imbalances?

Not at all
- I'm saying that modifying AMT could easily result in a compound that could kill you via serotonin syndrome (monoamine release + MAO inhibition) AND/OR excessive receptor agonism (+ MAO inhibition).

I'm not denying that experienced psychonauts could absolutely find some of these compounds worthwhile, but if RC vendors were to start churning out AMT analogs in the hope of stumbling upon a mephedrone-like SNDRA I wouldn't be particularly surprised if some of them turned out to be disasters à la 4,4-DMAR or 5-IT.