4-phosphoryloxy-N,N,N-trimethyltryptamine

[Jaw Clenching]

Jensen, Niels: Tryptamines as Ligands and Modulators of the Serotonin 5‑HT2A Receptor and the Isolation of Aeruginascin from the Hallucinogenic Mushroom Inocybe aeruginascens

Abstract

Aeruginascin is a natural product from the hallucinogenic mushroom Inocybe aeruginascens. This compound was isolated and identified as 4-phosphoryloxy-N,N,N-trimethyltryptamine. Aeruginascin is the quaternary trimethylammonium analog of the hallucinogenic compound psilocybin. Synthetic aeruginascin was identical in all aspects to the isolated sample. Additionally, the mushroom alkaloids norbaeocystin and baeocystin were synthesized and a new synthetic approach to 4‑hydroxy-tryptamines was investigated.

In a related project the influence of N-terminal substituents of tryptamines on serotonin receptor binding was studied. A series of tryptamines carrying a broad range of structurally diverse amino-substituents was synthesized. Most compounds had binding affinities in the nanomolar range for the 5‑HT1A, the 5‑HT2A, and the 5‑HT2C receptor. In functional 5‑HT2A IP accumulation assays most ligands acted as antagonists or partial agonists. Several compounds had biphasic dose-response curves. Sometimes the response at higher concentrations exceeded even that of the natural agonist serotonin. As shown by additional experiments, this effect was probably caused by non-competitive positive allosteric modulation of the 5‑HT2A receptor at higher concentrations. These results indicate a new independent regulatory binding site of the 5‑HT2A receptor. In contrast to a previous publication, in our hands the lead compound N‑(4‑bromobenzyl)-5‑methoxy_tryptamine was a low-affinity antagonist at the 5‑HT2A receptor.

 

[fastandbulbous]

Quaternary amines wont pass the blood brain barrier, as the quaternary function can' t also exist in a non-ionic form (as primary, secondary and tertiary can), so it'll never get anywhere near any central 5HT receptors

 

[Jaw Clenching]

Here's the full write-up...

...and an excerpt from it:

Toxicology of aeruginascin

The human pharmacology and toxicology of aeruginascin (4) has not been tested yet. However,
several unintentional intoxications with Inocybe aeruginascens have been reported and
this mushroom is consumed for its hallucinogenic effects. Due to the quaternary ammonium
group it is unlikely that aeruginascin (4) is able to pass the blood-brain barrier, a requirement
for hallucinogenic effects in human. However, aeruginascin (4) might have profound peripheral
effects. Aeruginascin (4) is assumed to undergo a rapid metabolism into its dephosphorylation
product 31 by analogy to the known Psilocybe alkaloids. This metabolite has a striking
similarity with the peripherally acting 5-HT3 receptor agonist N,N,N-trimethylserotonin
(5-HTQ, 37) (Figure 25).

 

[Jaw Clenching]

Another excerpt:

Figure 8: 5-HT2A receptor ligands (III): Tryptamines.

The sterically constrained dihydropyrano tryptamine 16, the pyrrolidin-2-yl-methyl tryptamine analog 17, and the cyclopropanated tryptamine analog 18.

 

[fastandbulbous]

They're all 5-substituted tryptamines (well in the 1st example, the oxygen atom is on position 5), and they're not metabolites of fungi, as psilocin etc are all substituted with oxygen at the 5 position.

PS the last one (18) might have a good chance of being centrally active a la 5-methoxy AMT; the comparison being that between DOM and 1-(2,5-dimethoxy-4-methylphenyl)-2-cyclopropylamine (cant remember its PIHKAL no.)

 

[Smyth]

from what I recall #17 was highly potent relative to the isopropyl-amine side chain. This has got something to do with entropy and locking out degrees of freedom.

 

[fastandbulbous]

^^ #17 as a psychedelic (5HT2a agonist)?. Have you got a ref for that, as if that's the case, it opens up a potentially large series of 5HT2a agonists (a bit like methylphenidate etc is to amphetamine). Shulgin only ever experimented with making the N,N dialkyl substitution into a cyclic structure (and they're poisionous, reading his notes in TIHKAL).

The pyrrolidine ring would be in the same position as the D ring of LSD, so if a 5-membered ring worked in that position, it indicates a bit about the bonding nature of that nitrogen, and how important the D ring being as planar as possible is; basically, a lot about the nature odf the D ring and it's substituents.

 

[Smyth]

I actually read this here on BL about a year ago. If MGS is still about he should be able to provide the ref's since he was the one that made the 'discovery initially.

I know this area quite well since my research project was actually on making the highly rigid 7-azabicycloheptane scaffold. Thus I would also be highly interested in doors that might open up that employs conformational rigidity to test the binding affinity of compounds to receptors relative to the acyclic or monocyclic case.

On another note (sorry to hijack this thread), entropic studies on seco-fentanyl showed that the piperidine ring was critical; the openchain analog was only feebly active from what I recall [Although lots of scope here for testing the 3-methyl analog and anything that might raise potency up to a legible level of activity].

 

[Morninggloryseed]

"Further Studies on Oxygenated Tryptamines with LSD-like Activity
Incorporating a Chiral Pyrrolidine Moiety into the Side Chain" by
Madina Gerasimov,† Danuta Marona-Lewicka, Deborah M. Kurrasch-Orbaugh, Amjad M. Qandil, and
David E. Nichols*
s
This mentioned the analogue of 17 that has methyl on the pyrrolodine. Very potent molecules according to the article.

 

[fastandbulbous]

Thanks a lot. That means that there is a whole range that incorporates the chiral centre as part of heterocyclic ring also incorporating the nitrogen, where the heterocycle is effectively replacing the D ring. I'd wondered about these, but never seen anything about them.

I've got a very interseting paper to hunt down now, with yet more possibilities


Onwards and upwards

 

[scarmani]

SAR of psilocybin analogs

SAR of psilocybin analogs: Discovery of a selective 5-HT2C agonist.
Howard Sard, Govindaraj Kumaran, Cynthia Morency, Bryan L. Roth, Beth Ann Toth, Ping He and Louis Shuster
Bioorganic & Medicinal Chemistry Letters. 15, 4555–4559 (2005)
http://tinyurl.com/czprk

Some interesting ones covered... none of them looks too spectacular from a psychedelic standpoint...

4-halo-N,N-dimethyltryptamines still look somewhat promising, although keep in mind "agonist activity at 5-HT2B is strongly associated with heart valve toxicity"