Backfolding of 4-Something Tryptamines

[EN21]

Backfolding is a common phenomenon that can be observed in stretched molecules when one end is able to interact with the other in any way. There might be H donor groups that interact with H acceptor groups, or there might be some p - p interaction.

Drawing psilocin with the sidechain folded back to the 4-OH where the H is shared by the nitrogen and the phenol I got a quasi 8-membered structure. When I compare this to the structure of LSD, the nitrogen might be in an similar position. I drew the protonated form, because this is the form that interacts with the Asp at the 5-HT receptor. -Hmmm, not bad, I thought and tried the same with the phosphate ester.

I drew it that way so the sour P-OH shared its H with the nitrogen. The resulting structure with a 10-membered scaffold shows (at least on the paper) exactly the same conformation like LSD. I was astouned!!! Is it only accidentally or is it of any relevance?
It is a shame that nobody really knows what molecule is really responsible for the action. If you eat 4-AcO-DMT or psilocybin, I bet that there are actually two active compounds that do the job in your brain, the esters and the free phenol. And it seems to be impossible to say what effect results from what compound
Intravenous application might be the only way to feel the effect that is mainly caused by the esters.
An other way to elucidate this, would be the comparison of binding data of the esters and the free phenol. Actually no one did it, -at least not to my knowledge.

Have a look at the drawn structurs and tell me what you mean. I was so fascinated by that idea and the similarity with LSD. Probably there’s something really wrong in my considerations. Every comment is welcome.

 

[vecktor]

I am really skeptical that the ester is the active form, given that o-acetylated phenols are hydrolysed by plasma esterases very quickly, with a half life of minutes. The acetyl derivatives are going however to depot in lipids more readily which would explain the delayed onset of 4-aco dmt.
the phosphate ester is not going to get through to the brain unchanged either.

psilocin is the active drug here.

 

[Smyth]

I run the structure of psilocin through energy mimization mode on chemdraw 3D and it still neglects the H-bond interaction for whatever reason.

Your quite right in drawing attention to this feature although I still feel that it is nothing to get overly hyped up about, given that DMT on its own is already a powerful hallucinogen.

I wonder why though DMT is a substrate for MAOI enzymes whereas 4-OH is orally active?

 

[nuke]

The acetyl derivatives are going however to depot in lipids more readily which would explain the delayed onset of 4-aco dmt.

Does that mean you should adjust for people much based on body weight? I have taken 4-AcO tryptamines with people who are larger with me and it sure always seemed like I got hit harder than them, when we ate the same amount. But I never thought too much of it.

 

[fastandbulbous]

I wonder why though DMT is a substrate for MAOI enzymes whereas 4-OH is orally active?

4-OH tryptamines will interact with the active site of MAO (which is there to deal withy 5HT among others), but because of the OH not being in the 'correct' place, it does not change conformation to the active enzyme and deal with the amine group. As DMT doesn't have any OH group, it doesn't have a chance to throw a spanner in the works of MAO and gets dealt with in the same way as 5HT. While increasing the size of the alkyl groups goes some way to reduce MAO's activity, 4-hydroxylation is obviously the best structure for 'buggering up' the activity of MAO

 

[Dondante]

At least for the phenethylamines, recent research has shown that there is definitely no backfolding, which means no structural relationship with the ergolines. Keeping the amine group pointing away from the benzene ring seems to greatly increase potency compared to when it is able to freely rotate. A few of these conformationally restricted phens have some resemblance of the tryptamines though. The Ki at 5HT2A for structure 2 is 130 nM in case you can't access the article. The cyclobutane compound has a higher affinity for the 5HT2A than LSD, but the article points out that it favors activation of the PLC pathway by 65 fold over the AA pathway. They also note that the AA production is a better indicator of hallucinogenic activity than IP3. The Ki for mescaline is 360 nM.

http://www.ncbi.nlm.nih.gov/entrez/..._uids=16821786&query_hl=1&itool=pubmed_docsum

http://www.ncbi.nlm.nih.gov/entrez/..._uids=16970404&query_hl=1&itool=pubmed_docsum

 

[nuke]

^^ If what they're saying in the second article is true, that might mean the most potent 2c-b analogue would active in the microgram range...that's impressive..

 

[Dondante]

^^I think they just mean that AA production is a better indicator of hallucinogenic action, not that it's actually responsible. Maybe? I see what you're saying though.

 

[nuke]

Sorry that I edited out that last response, the reason was that I looked it up and saw that aspirin didn't inhibit production but rather the conversion of AA into other useful things.

And, yeah, I think he's saying AA is just implicated somehow, I read it wrong. It's been a long weekend.

 

[EN21]

thanks for the input!

What I really wonder is that I can not find binding data of the phenol and the ester –Just for comparison.
I can’t belief that nobody ever did this. Is there anybody who has some data?

It was just an idea, with the backfolding. The phens, Dondate mentioned in the articles surely do not undergo, -but it looked so good when I drew the backfolded tryps.
I’d suppose that such a phenomenon could be investigated by some special NMR techniques, like Overhouser effects or something cross coupling and so on, but I am not a specialist in this field.
Additionally I would love to see a compound like that backfolded phosphate ester with covalent bonds and an real 10-membered ring. I mean something without that phosphate thing, -I mean something metabolic stabile compound with similar conformation. It might have some flexibility and the nitrogen might come close to the position where it is in the ergolines. Just imagine LSD with the central bond cleaved.

 

[vecktor]

^^ If what they're saying in the second article is true, that might mean the most potent 2c-b analogue would active in the microgram range...that's impressive..

in vitro 5ht2a receptor affinity and agonism doesn't always correlate with potent hallucinogenic action. for example DOB and DOI and the releated benzodifurans have much higher affinity for the receptor than LSD and yet LSD is more potent
I would like to see stability data for the benzocyclobutanes...

all this seems to fit with F and B's speculation that the beta methylenes will indeed be potent ligands at 5ht2a.
the other research group in this area is looking at asymetric dragonflies ie one 5 membered ring and one 6 membered ring to see if this allows selectivity between 2a and 2c sub types

 

[fastandbulbous]

all this seems to fit with F and B's speculation that the beta methylenes will indeed be potent ligands at 5ht2a.

It'd be nice if somebody (anybody - but most prob Dave Nichols) would synth them and do a receptor affinity assay or even (shock, horror) synth some and munch down some (note - if someone does, start in the single micrograms range and work up; a mg might be a nightmareish experience if they are active as psychedelics)- very unscientific I know, but I'm an impatient person!