AMT binding & MDMA binding

[bloodshed344]

How do the ways AMT and MDMA bind to the serotonin receptor compare and contrast? Do they bind with the same conformation? Does the pyrrolidine part of the AMT molecule take the same place as the methylenedioxy part of MDMA in its conformation to the receptor, or is it the position of the amine that is the same? (or is it neither?)

Are there any other structurally unique TRI/5-ht agonists (that means, more structurally unique than the apbs)
Also, do AMT and MDMA favor 5ht-1a and 2a/2b more than the other receptors? Which serotonin receptors do cocaine and aminorex bind to?

Thanks!

Also, are there any known selective serotonin releasers that are also psychedelic? (If not, I'm looking to design a molecule to fit this description)

 

[MrSpeedyG]

Cocaine and aminorex are not receptor agonists directly, it is the increase in synaptic monoamine levels that cause the effects. Unlike MDMA/MDA where not only does release cause receptor activation but they also bind to the 5HT1AB/2AB

 

[sekio]

Aminorex is a direct agonist at at least 5ht2b.

 

[MrSpeedyG]

My apologies, 4methly-aminorex is a direct receptor agonist I know that. Its the cocaine I am quite sure is transporter only

 

[ebola?]

Also, are there any known selective serotonin releasers that are also psychedelic? (If not, I'm looking to design a molecule to fit this description)

One candidate might be 3-methoxy,4-methyl-amphetamine (mmm....I hope I don't have the substitutions switched around here). Subjective reports suggest strong 5ht release (one person said, "like BDB...that sweaty, under water feel") and 5ht2a agonism (clear geometric patterning). Then again, it could also release a good bit of NE, al a MBDB.

I dunno. To some extent, I think 'the future' is development of highly selective ligands and then selective combination of them, not hoping for discovery of one compound that does everything desired.

ebola

 

[Hammilton]

I can't believe no one thought of that before.

 

[bloodshed344]

I'm wondering why there are more chemicals like this with the phenethylamine backbone than with the tryptamine backbone. There's also apparently some similar chemicals that are a combination of phenyl and pyrolle (right, that's the name of the pentagonal part of tryptamine?) at different locations than regular tryptamines. However, alpha-methyl tryptamine is a much more fascinating chemical than even alpha-methyl phenethylamine, in my opinion at least. Does 5-MeO-AMT release an appreciable amount of serotonin at all? (From what I've seen, all serotonin releasers have a much larger dose than 5-MeO-AMT)

But anyway, AMT's similarity to serotonin (and even closer is 5-MeO-AMT, coincidentally) and the way it affects DA,NE,and SERT amazes me. There is no other chemical that has this depth of pharmacology while still displaying it's similarity to natural chemicals within the brain.

 

[ebola?]

I'm wondering why there are more chemicals like this with the phenethylamine backbone than with the tryptamine backbone

Are there?

There is no other chemical that has this depth of pharmacology while still displaying it's similarity to natural chemicals within the brain.

I dunno. Ring-substituted, alpha-methylated phenethylamines aren't THAT far off from dopamine.

ebola

 

[bloodshed344]

Are there?



I dunno. Ring-substituted, alpha-methylated phenethylamines aren't THAT far off from dopamine.

ebola

Well, off the top of my head:

Phenethylamines: APB series, MD* series
Tryptamines: AMT, MDAI (that doesn't even count either), and.. that's all I can think of? I'm thinking of SRAs when I say this, btw.

Also, I say that AMT is more fascinating than said alpha-methylated ring-substituted phenethylamines that are stimulants because of its psychedelic and empathogenic effects.

 

[ebola?]

I'm thinking of SRAs when I say this, btw.

Ah. I was thinking more generally of monoamine transporter interactions.

ebola

 

[MagickalKat777]

Does 5-MeO-AMT release an appreciable amount of serotonin at all? (From what I've seen, all serotonin releasers have a much larger dose than 5-MeO-AMT)

Its a TRI/TRA just like AMT

α-Metyltryptamine (AMT), a tryptamine derivative, was one of the strongest re-uptake inhibitors and releasers of the three monoamines. The tryptamine derivative, 5-methoxy-α-methyltryptamine (5-MeO-AMT), also strongly inhibited re-uptake and increased the release of the three monoamines.

http://www.sciencedirect.com/science/article/pii/S0014299906013811

Unfortunately the abstract doesn't say much else about it.

From experience with 5-MeO-AMT, its a much speedier version of AMT with more side effects. It can be just as pleasant of an experience as AMT (which I always found AMT to be like a candyflip with very mild visuals and slightly more body load) but only when you get past the first two or three hours which are pukey and dysphoric and it remains fairly tachycardic throughout the experience but when you hit the plateau things settle down and its pretty much a full-blown candyflip at that point that is longer lived and much more visual.

I'd imagine it has slightly less effects on serotonin release than AMT though. It doesn't have the warm fuzzy feeling that AMT does and I'd favorably compare that feeling between AMT and MDMA any day. I'd say 5-MeO-AMT is the MDA of AMT. Its sharp, its very psychedelic, its speedy, its confusing, it has more side effects, and it is longer-lived than AMT just how MDA is to MDMA.

It would be interesting to see that full paper though. It compares a number of psychedelics for their reuptake and release capabilities.

 

[ebola?]

Unfortunately the abstract doesn't say much else about it.

The full text of the article shows 5meoamt to be an order of magnitude or less effective as a releaser, and it's active at a lower dosage, suggesting that it functions primarily as a reuptake inhibitor.

ebola

 

[MagickalKat777]

The full text of the article shows 5meoamt to be an order of magnitude or less effective as a releaser, and it's active at a lower dosage, suggesting that it functions primarily as a reuptake inhibitor.

ebola

Thank you, that's what I suspected. I think its sad that I was able to extrapolate that from subjective effects. I've used far too much of those two chemicals in the past.

Is it still an effective releaser of norepinephrine and dopamine or does it primarily function as a TRI?

I've always found AMT and 5-MeO-AMT fascinating but I don't have access to the papers on them so I am very limited in learning about their functions.

 

[bloodshed344]

The full text of the article shows 5meoamt to be an order of magnitude or less effective as a releaser, and it's active at a lower dosage, suggesting that it functions primarily as a reuptake inhibitor.

ebola

What is the strongest SRA you can think of? Even the most potent ones have a high dose (70 mg or so) unless I'm ignoring some that are much stronger. Is this high dosage requirement a property inherent to release agents or just serotonin release agents?

I meant SRAs, not TRIs. Not sure why I typed that in the first post, but are AMT and MDMA both TRAs?

 

[MagickalKat777]

AMT and MDMA are both TRAs but AMT is also a TRI.

 

[MrSpeedyG]

If its a releasing agent it is automatically a reuptake inhibitor...

 

[ebola?]

^^^^
precisely.
...

Is it still an effective releaser of norepinephrine and dopamine or does it primarily function as a TRI?

My best guess would be function as a TRI at reasonable doses (with some selectivity for 5ht), but it's hard to say. Wanna look at the numbers?

reuptake inhibition IC50s (assays using in vitro rat synaptosomes, concentrations for half-maximal inhibition):

DA: 1.8±0.35 x10^−5 5ht: 2.9±0.71×10^−6 NE: 3.7±0.62×10^−5

release EC50s (assay using in vitro rat synaptosomes, concentration for half-maximal "acceleration"):

DA: 1.5±0.38×10^−6 5ht: 4.6±1.4×10^−7 NE: 8.9±x10^−6

The cut-off for outright lack of activity is orders of magnitude of 10^-4. Now, I'm recalling that the dosage range for 5-meo-amt is something like 3-15 mg, right? At doses higher than this, I see release coming into play more significantly.

What is the strongest SRA you can think of?

AMT actually, and most people need quite a bit less than 70 mg of it. Not remotely selective though.

Is this high dosage requirement a property inherent to release agents or just serotonin release agents?

I don't think that either is the case; rather, it's just an accident of the ligands we've invented so far.

ebola

 

[bloodshed344]

Okay, well interesting that AMT is the most potent yet discovered. That brings me back to my original question, do AMT and MDMA (and say, MDAI?) conform to the receptor in the same way... or am I fundamentally misunderstanding something?

It is exciting that AMT is the most potent though, because that means there could still be some hope left for new tryptamine-based serotonin releasers.

 

[MagickalKat777]

The cut-off for outright lack of activity is orders of magnitude of 10^-4. Now, I'm recalling that the dosage range for 5-meo-amt is something like 3-15 mg, right? At doses higher than this, I see release coming into play more significantly.

This is what I was looking for.

Considering my dosage was always over 15mg after the first two times, now I see why I and my friends got so much enjoyment from it - we all had quite high doses, generally around 18-28mg (26mg was my usual dose, 18 was the lowest dose for a friend of mine with an average of 22mg) - I specifically remember a trip where I gave 20mg to a friend, took 26mg myself, and her roommate walked in from work to her and I writhing around on the carpet moaning like we were on a strong roll. That phase was consistent and lasted for a good 3 or 4 hours each time and then dropped to a pleasant rushing euphoria that lasted for a good 16 hours or so.

I very much disliked low doses of 5-MeO-AMT and found them to be dysphoric. Guess that would explain why.

AMT being the strongest SRA doesn't surprise me. 30 to 40mg of freebase is sufficient for most people - including me. I took higher doses just because I wanted to push it and see how far I could take it but to be honest, nobody should require more than 50mg of freebase to get a very strong +++