thianaphthene analogs of tryptamines

[pr0d1gy]

As Nichols has proven, the substation of the indole heterocycle in tryptamines allows for some retention of activity. The question would seem to be what would result if the heterocycle were to be thianaphthene. I have acquired the thianaphthene analogs of AMT and DIPT in good purity. It's interesting that the analogs of tryptamines with aromatic ether or phenolic moieties were very unstable.

On to the point. Can ADD's extensive brain power help me out here? Would these compounds be expected to be active or toxic? I haven't been able to find many common drugs based on this particular heterocycle and it is certainly more reactive than indole or benzofuran, so I can't imagine what it might be like in vivo. If anyone can take the time to offer their opinion, I'd greatly appreciate it.

 

[sekio]

I thought it was known and had even been tested in humans, although that maybe the benzofuran analog. (It is indeed - dimemebfe. What a mouthful. It's actually the benzofuran anlog of 5-MeO-DMT.)

Pubchem has an entry for at least two isomers of DMT-thianapthene. That's the first one and here's the second. The first having the sulfur in what would be the 4' position means I would expect it to be a little closer to psilocin.

But there's only one way to try

 

[pr0d1gy]

Those are indeed quite interesting and way more creative than what I came up with. Especially as you said the first isomer. Maybe my nomenclature was incorrect, but I don't think those contain the thianaphthene structure. Here is the compound in question:

Thanks so much for your input!

 

[DL-ark]

Here is something kinda silly:

 

[blueberries]

I'm watching this like a hawk as it sounds very interesting!

My meagre 2 pence: the aMT compound would probably be quite a heavy inhibitor of MAO, so watch yourself there. Looking at the T-x's (I know, not a great vantage point) but thio's there produce MAOI properties too.

The DiPT analogue I'd go with first as it seems like it'd be the least toxic but as for any actual pharmacological knowledge on these compounds I have none. They're a complete blank but I cannot wait to see what happens. I assume you're going to bioassay yourself rather than rats, yeah? For the aMT, I'd want to use rats, personally, but it's up to you.

Good luck!

EDIT: I seemed to have jumped the gun a bit and have only just seen the actual structure of your compounds. I'm thinking along the lines of Dimemebfe as sekio mentioned but possibly more potent. The DiPT I'd expect to produce some quite high HT1a agonism, with a possible lack of psychedelic effects but the aMT...well could be a winner tbh, besides the bodyload that is, which I reckon will be quite high, so get yourself some Zofran and Muscle relaxants.

The two isomers sekio mentioned IMO would be a little more exciting perhaps but then again Dimemefbe showed quite high HT2 affinity so it's all up in the air.

 

[sekio]

this compound is known, the thianapthene analog of dmt.

chemspider
pubchem paper on metabolism in rat

 

[tryp2fun]

I thought it was known and had even been tested in humans, although that maybe the benzofuran analog. (It is indeed - dimemebfe. What a mouthful. It's actually the benzofuran anlog of 5-MeO-DMT.)

Pubchem has an entry for at least two isomers of DMT-thianapthene. That's the first one and here's the second. The first having the sulfur in what would be the 4' position means I would expect it to be a little closer to psilocin.

But there's only one way to try

J Med Chem. 1999 Mar 25;42(6):1106-11.
Thieno[3,2-b]- and thieno[2,3-b]pyrrole bioisosteric analogues of the hallucinogen and serotonin agonist N,N-dimethyltryptamine.
Blair JB1, Marona-Lewicka D, Kanthasamy A, Lucaites VL, Nelson DL, Nichols DE.
Author information
Abstract

The synthesis and biological activity of 6-[2-(N, N-dimethylamino)ethyl]-4H-thieno[3,2-b]pyrrole (3a) and 4-[2-(N, N-dimethylamino)ethyl]-6H-thieno[2,3-b]pyrrole (3b), thienopyrroles as potential bioisosteres of N,N-dimethyltryptamine (1a), are reported. Hallucinogen-like activity was evaluated in the two-lever drug discrimination paradigm using LSD- and DOI-trained rats. Neither 3a nor 3b substituted for LSD or DOI up to doses of 50 micromol/kg. By comparison, 1a fully substituted in LSD-trained rats. However, 3a and 3b fully substituted for the 5-HT1A agonist LY293284 ((-)-(4R)-6-acetyl-4-(di-n-propylamino)-1,3,4, 5-tetrahydrobenz[c,d]indole). Both 3a and 3b induced a brief "serotonin syndrome" and salivation, an indication of 5-HT1A receptor activation. At the cloned human 5-HT2A receptor 3b had about twice the affinity of 3a. At the cloned human 5-HT2B and 5-HT2C receptors, however, 3a had about twice the affinity of 3b. Therefore, thiophene lacks equivalence as a replacement for the phenyl ring in the indole nucleus of tryptamines that bind to 5-HT2 receptor subtypes and possess LSD-like behavioral effects. Whereas both of the thienopyrroles had lower affinity than the corresponding 1a at 5-HT2 receptors, 3a and 3b had significantly greater affinity than 1a at the 5-HT1A receptor. Thus, thienopyrrole does appear to serve as a potent bioisostere for the indole nucleus in compounds that bind to the serotonin 5-HT1A receptor. These differences in biological activity suggest that serotonin receptor isoforms are very sensitive to subtle changes in the electronic character of the aromatic systems of indole compounds.

These compounds, which are thienopyrroles, not thianaphthenes, were made by Nichols, as you can see above, and do not appear to be psychedelic.

 

[adder]

According to this old paper, the substitution of the indolic nitrogen by a sulphur atom doesn't impact affinity, which is interesting because a sulphur atom is bigger than nitrogen or oxygen atom. The same paper states that the indene analogue is half as potent as DMT, which is weird. If benzothiophene substituted for the indole in tryptamine, then why not alpha-N,N-dimethylaminoethyl-7-methoxynaphthalene? I seriously doubt that it would be a psychedelic.

Anyway, this is all theory though derived from numbers and not actual measurements. If dimemebfe is several times less potent than DMT, then I see no reason for the benzothiophene analogue to be as potent as DMT. The indolic nitrogen doesn't seem to be involved in binding, it just provides steric and electronic effects for the indole, the nitrogen has one lone pair of electrons and a hydrogen bound to it while the oxygen in dimemebfe has two lone pairs, so a logical step would be to test the indene analogue to see whether going in the opposite way produces a positive effect. A 2,3-dihydro-1H-benzimidazole analogue could be interesting too if not the most interesting.