If the 4th position of a PEA is to the 5th position of a Tryptamine...

[fractal fountain]

How come we haven't seen research into Tryptamines with Alkyl or Halogen groups at the 5th position? The most 'defining' substituents on the Tryptamine molecule tend to be on the Nitrogen, whereas with PEAs, the unique substituent tends to be on the fourth position as we all know...

Would having a halogen or alkyl group at the 5th position cause complications with binding or nausea?

 

[Lucid Dream]

"whereas with PEAs, the unique substituent tends to be on the fourth position" Substitution at the 4th position on the indole ring makes for the best tryptamines, not phens. Also, most phens are substituted at several positions, the 2c-x compounds have halogens substituted at the 4th position on there ring. But they also have two Dimethoxy groups at the 2, and 5 positions.

I was just strolling through Shulgins Phikal, and noticed that the 5th position is used in most of his compounds. They just contain a Dimethoxy group instead of a halogen. I'm not sure if its just not possible, or if they just have no activity, but your right, I see no halogens on the 5th position of the ring. Maybe someone with more knowledge into this topic will help us out. I'm very curious myself now as well.

 

[Hammilton]

because binding studies say that the supposition that 4=5 is false.

 

[Astavats]

In short, what Hammilton said.

A bit of 'why', the tryptamine 5' position and the cyclical nitrogen are more similar to phenethylamine methoxyl groups in respects to 5-HT2A docking. However it's not a smooth comparison because both tryptamine and phenethylamine agonists dock uniquely. It's explained with far more depth in Towards a biophysical understanding of hallucinogen action.

The 5-MeO of tryptamines and the 5-MeO of phenethylamines both hydrogen bond to residues. An alkyl or non-fluorine halogen is incapable of H-bonding and would (probably) cause unfavorable hindrance. As for the 1-nitrogen of tryptamine and 2-MeO phenethylamine(?) these are uncertain if they actually contribute...might be mistaken with the latter but I don't think so. This is how I've understood it.

Edit: I had this switched, tryptamines are fine but phenethylamine 2-MeO is uncertain for the extent of contribution. See image in my next post.

 

[fractal fountain]

My main point behind starting this thread was Shulgin saying that the magical position of PEAs is the fourth position and likewise for theTryptamines, it's the fifth position...

I wonder if such bulky substituents would be allowed at the fourth position of Tryptamines instead? Hmm...

 

[ebola?]

We have to remember that Shulgin's philosophy was "Make 'em and taste 'em." The 'magic' of a bonding position might not map onto some specific type of receptor-activity.

ebola

 

[fryingsquirrel]

We have to remember that Shulgin's philosophy was "Make 'em and taste 'em."

The new philosiophy seems to be "Make 'em and let half the kids in England taste them." While this is beyond reckless, I wouldn't be at all surprised to see all sorts of trytamines with weird shit on the 4 posistion in the near future. Whether this leads to a great new drug or alot of deaths only time will tell.

 

[nuke]

It's not.

 

[Astavats]

I wonder if such bulky substituents would be allowed at the fourth position of Tryptamines instead?

It probably wouldn't help; the indole and phenylalanine benzene rings are pi-pi interacting in the diagram, adding a non-hydrogen acceptor or donor would probably just "get in the way of things" and add no benefit. 6 or 7th are more likely preferential areas for alkyl or halo groups but similar relatives exist naturally without activity (that I'm aware of). I'd try moving the 5-MeO to the 6th or 7th position and see how these played out. 5,7-DiMeO seems better but 5,7-Dihydroxytryptamine is supposed to be neurotoxic, so it may or may not play over from hydroxyl to methoxyl.

It should also be noted, though this image implies a flat binding area it's more complicated and three-dimensional in reality. Don't solely follow this as "it will" or "it won't work" basis, but it's not a bad place to begin.

Source: Towards a biophysical understanding of hallucinogen action. M.R. Braden, D.E. Nichols, et al.

 

[atara]

I was always under the impression that the 5-position needed to be a hydrogen bond acceptor. So 5-fluoro, 5-alkoxy and 5-acyl would work, whereas 5-alkyl and 5-halo would not.

Thing is that those tryptamines with weird 5-substituents tend to target other serotonin receptors, not 5ht2a. 5-carboxamidotryptamine goes primarily for 5-ht1a, 5-benzyloxytryptamine goes for 5-ht1d, etc.

You might be able to make interesting drugs with that pattern, but probably not psychedelics. 5-methoxy was pretty lame.

 

[nuke]

Ethers are terrible hydrogen bond acceptors... I think it's more electronegativety/dipole-dipole interaction dependent but at the same time lacking strong hydrogen bonding (otherwise it is too polar and readily excreted). Another gigantic problem with that theory is why methylation of phenethylamine psychedelics would abolish activity if Asp155 really is the responding residue to the ammonium ion. 5-MeO-DMT from that figure above is also missing the methylation.

It's really suprising no one has offered 5-EtO-DMT for sale yet on the internet underground, but perhaps I should hold my tongue on that one.