Electronegative Substitution on the Indole Ring: Application to Agonists/Stimulants

[nuke]

Ring substitutions were largely ignored in TiHKAL, so it's worth talking about.

-The fluorination five and six position on the indole ring in reference to a-MT has been investigated in the mouse and found to induce 5-HT receptor-mediated head-twitch response. Assumptively the alpha-methylation inhibits MAO-A mediated metabolism.
-4,5-Dihydroxytryptamine, 5,6-Dihydroxytryptamine and 5,7-Dihydroxytryptamine are strong neurotoxins with an affinity for SERT greater than that of NET/DAT
-7-Hydroxytryptamine is a putative neurotoxin with a remarkably greater affinity for NET/DAT than SERT. An interesting compound to assay would be 7-F-a-MT, to see if it had stimulant properties.
-Fluorination of the 4 and 7 position of the neurotoxin 5,6-Dihydroxytryptamine results in a dramatically higher affinity for SERT
-5-Fluorotryptamine is a partial agonist at 5HT3 receptors, demonstrating the necessity of 5-position EN for receptor affinity at 5HT3
-One hydroxylated tryptamine neurotoxin derivative actually has an inverse neurotoxic profile (it chronically increases the amounts of all three monoamines in the CNS after administration) -- reference/compound name somewhere buried under papers
-6-OH-Tryptamines are known to be stimulants in animals
-6-OH-DMT is reported to be inactive IV in TiHKAL, while 6-OH-DET is reported to be active but the activity/data suspect. They are minor metabolic products of their non-hydroxylated counterparts.
-5,6-DiMEO-MIPT/5,6-MDO-MIPT/5,6-MDO-DMT is reported inactive in TiHKAL. 5,6-MDO-DIPT is unknown. 4,5-MDO-DIPT is supposed active at 25mg as a psychedelic.

Perhaps you guys have some more information, too.

 

[immad]

Ring substitutions were largely ignored in TiHKAL, so it's worth talking about.

......
-One hydroxylated tryptamine neurotoxin derivative actually has an inverse neurotoxic profile (it chronically increases the amounts of all three monoamines in the CNS after administration) -- reference/compound name somewhere buried under papers
.....

How'ld this work? Wouldn't this cause a monster tolerance in no time? Wouldn't this be a perfect antidepressant, since (nearly) all modern antidepressants are monoamine reuptake inhibitors and this results in the same, only just with one pill?

 

[dread]

If 4,5-dihydroxy-T:s are strong neurotoxins, wouldn't that make 4,5-MDO-T:s kinda sketchy?

Anyway... what about the 4,5-dihydrofuro-T:s, where the O is in the 5-position? Weren't some of these made? I could swear I've seen them somewhere...

 

[nuke]

3,4-Dihydroxyamphetamine is a strong neurotoxin too and a metabolite of MDA, clearly this doesn`t detract from the recreational potential of the drug. Keep in mind too that these drugs are usually metabolized quickly by the body anyway and require intracranial/IP injection usually to demonstrate the strong toxicity seen in many studies. I wouldn't try it (and I'm guessing that's why Shulgin personally avoided it), but someone may be interested.

I'm not sure about the potency of the cyclic alkoxylated derivatives. Methylation in the 5-position produces a substance equipotent to tryptamine in the study of arterial/aortic heart strips, but 300 times less potent than the 5-Methoxy and hydroxy derivatives. Another study identifies 5-Methyltryptamine as a 5HT1A and possible 5HT2A receptor substrate, but also an antagonist there.

How'ld this work? Wouldn't this cause a monster tolerance in no time? Wouldn't this be a perfect antidepressant, since (nearly) all modern antidepressants are monoamine reuptake inhibitors and this results in the same, only just with one pill?

No idea of the mechanism, I'll try to dig up the study today. It increases monoamines in the spinal column as well, by about 35% on average if I'm recalling correctly. I'll have to see if there's a behavioural section too. Problematically, if it doesn't work, you're left with a permanently altered brain. I suppose that isn't a lot different from ECT.

 

[dread]

I'm not sure about the potency of the cyclic alkoxylated derivatives. Methylation in the 5-position produces a substance equipotent to tryptamine in the study of arterial/aortic heart strips, but 300 times less potent than the 5-Methoxy and hydroxy derivatives. Another study identifies 5-Methyltryptamine as a 5HT1A and possible 5HT2A receptor substrate, but also an antagonist there.

Yes but the oxygen would be in the 5-position. This would in a way be analogous to the FLY series of phens, where the 5-methoxy is extended to a ring system to keep the lone pairs on the right side...

There's AL-37350A, but it has a pyran instead of furan...

 

[nuke]

Well, then I'd be willing to bet it'd be a 5HT2A agonist, but then again with a cyclic system who knows for sure exactly. For instance, if you replace the pyrrolidine group in pyrovalerone with a piperidine group there is a large loss in potency.

Anyway,
I found the study I had been looking for. It is titled "Degenerative effects of various neurotoxic indoleamines on central monoamine neurons." and is authored by Nobin A and Björklund A.

- 5-HO-6-MeO-T, 5-MeO-6-HO-T, 5-HO-7-Cl-T, 4-HO-T, 6-HO-T, and 7-HO-T did not cause any sign of toxic damage to monoaminergic fiber systems
- Alpha-methylation of 5,6-DiHO-T dramatically decreases neurotoxic effect, while the alpha-methylated derivative of 5,7-DiHO-T is only slightly reduced in 5HT/NE neutoxicity (DA neurotoxicity is ameliorated by the structural change)
- It should be noted that neurotoxic amines are usually cytotoxic in general and will damage severely any type of neuronal tissue, not just monoaminergic neurons
- 4-HO-T, 6-HO-T and 7-HO-T paradoxically increase monoamines in the brain and spine of rats ten days after they are injected with the drugs

The following chart was included in the study:

 

[dread]

blah blah blah blah

If I ever find the guy who invented ad bots, I'll strangle him to death.