For Smyth: Indolic Depressant

[Ham-milton]

I had been talking with smyth about the probable depressant effect of a-keto-DMT, and he mocked me lol

Anyway, I had forgotten about this little feller that Mad_Scientist found for me- that continues to confirm my theory that any-sort-o-Pentagon-C-C(=O)-N set up yields a GABA-A a1-subunit containing selective depressant ligand.

This lends a little more credence to my guess that a-keto-DMT would be an active depressant:

N-(p-methylbenzyl)-5-nitroindol-3-ylglyoxylamide

Ki 31.3 nM at the α1 subtype of the GABAa receptor, no activity at α2 or α5

J. Med. Chem., 2007; 50(7): 1627-1634. http://pubs.acs.org/cgi-bin/abstract.cg ... 07707.html

Big thanks to Mad_Scientist for originally pointing this out to me!

oh yeah, in your face

 

[MattPsy]

So, 5-nitroindole + oxayl chloride, then + p-tolylmethanamine, and you have the above, as far as I can see. Neat.
Yeah i'm liking your GABAergic depressant SAR work Hammilton, keep at it man !
Interestingly that doesn't look like it would be possible for that to fold up into a ring through hydrogen bonding so perhaps my previous idea of ring formation isn't correct, hmm.

 

[Ham-milton]

You're right, i didn't think about that.

I wonder if it'd be more potent if it were lacking that extra ketone. I can't see how it'd enable better binding affinity.

 

[Black]

nice find!
who's the first to synthesise an anxiolytic psychedelic?
BenzoSpice® Every Trip is a Good Trip
:D

the benzyl group on the nitrogen does increase affinity for 5-HT receptors (ortho methyl would be better than para though) and the nitro group at 5 shouldn't be detrimental to the potency either. with one keto group removed we might have a psychedelic with sedative properties. interesting…

 

[fastandbulbous]

^ MMDA pretty much fits that description though & it's already known about

 

[Ham-milton]

I've never had MMDA, but from what I've read in Shulgin and elsewhere, it doesn't sound like an anxiolytic in the classic sense. It really doesn't sound a classical psychedelic in any sense.

Have you sampled it? The visuals described sound like a less fleeting version of an opiate nod.

Are these like full-blown real-life quality images, or cartoony CGI-sort of visuals?

With something like DMT, you can probably see why a GABAergic sedative would be useful.

Shulgin didn't try any keto-tryptamines, on the carbon chain or otherwise, did he? I can't think of any right now. That makes it difficult to make an informed guess about what an alpha-keto-N,N-DMT would have for psychedelic properties, but if Zolpidem still produces some visuals (I found a case study of 10 patients who had visuals, 9 of them were on serotonergic antidepressants, indicating that they are caused by some serotonergic mechanism), it makes sense that a tryptamine analogue would do the same, and in all likelihood, even more.

I don't know why I always think I'd like to try a-keto-DMT, but with the metabolism issues and very strong trip, I think that 4-Acetoxy-alpha-keto-N,N-diisopropyltryptamine would probably be a better choice. Although if one was to want a smoked drug, then a-keto-DMT would have to be the best choice.

 

[Biphasic]

I recall a patent a while back that stated that alpha-alkylated tryptamines lowered blood pressure if the substitution was big enough -- forget where I saw it now...

 

[Ham-milton]

That would seem odd, since AMT raises blood pressure (mine anyway).

alpha-keto-T's were studied a bit in the 50s as potential anti inflammatories, but they were scrapped, apparently.

The patent that covered these was referenced almost 50 years later for the 'invention' of Zolpidem. I don't know if this was for synthesis purposes (seems a little unlikely, I guess) or if it was because they were found to be depressants.

 

[Riemann Zeta]

Okay, so I admit, I initially poo-poo'd the idea of these tryptamine-esque depressants. Mea culpa, Ham-milton. Now I can actually see an SAR description that could be built up if studied systematically.

 

[Ham-milton]

I knew if I kept up with my ideas I'd eventually change some minds. I just can't believe that no one has studied this before. I really can't. Hasn't someone looked at a pan-depressant theory of structure activity relationships? Or even just for alpha-1 selective depressants?

These alpha-1 selectives are certainly the area my ideas are best developed in.

It's certainly a lot simpler than the SARs of mu agonists. For these alpha-1's, there's a structural feature present in all of them.

I really wish that I could find data on Thalidomide's subunit preferences. That'd really clinch my feelings, although with the two ketones on phthalimide, there are other ways that it could potentially bind, not to mention the extra ketone on the piperidyl ring.

I don't think there are any ligands that are selective for a2, 3, 4 or 5. They seem to be a little more promiscuous. And eating them turns girls promiscuous... A trend?

 

[mad_scientist]

The alpha2/3 subtypes have very similar structural requirements for binding it seems as I haven't come across any compounds that distinguish between them, but there are heaps of compounds that bind to alpha2/3 but not to alpha1 or alpha5, all of those non-sedating anxiolytic compounds have that profile.

The only ligand selective for alpha5 so far is that QH-ii-066, but I'm sure people will come up with others in time.

The alpha4 subtype does not seem to be involved in the action of benzodiazepine or nonbenzodiazepine drugs, they don't bind to it and I'm not sure what it does or if there are selective ligands for it.