4-HO-TMT explained

Width:	175px
Class:	Serotonin receptor agonist
Pubchem:	17868117
Chemspiderid:	13318696
Chebi:	193061
Synonyms:	4-OH-TMT; 4-hydroxy-N,N,N-trimethyltryptammonium; 4-Hydroxy-N,N,N-trimethyltryptamine; 4-HO-N,N,N-TMT; Dephosphorylated aeruginascin; Dephosphorylaeruginascin
Iupac Name:	2-(4-hydroxy-1H-indol-3-yl)ethyl-trimethylazanium
C:	13
H:	19
N:	2
O:	1
Charge:	+
Smiles:	C[N+](C)(C)CCC1=CNC2=C1C(=CC=C2)O
Stdinchi:	1S/C13H18N2O/c1-15(2,3)8-7-10-9-14-11-5-4-6-12(16)13(10)11/h4-6,9,14H,7-8H2,1-3H3/p+1
Stdinchikey:	RMPOMMZKJNCOTM-UHFFFAOYSA-O

4-HO-TMT, or 4-OH-TMT, also known as 4-hydroxy-N,N,N-trimethyltryptammonium or as dephosphorylated aeruginascin, is a substituted tryptamine derivative and the active form of aeruginascin (4-PO-TMT), analogously to how psilocin (4-HO-DMT) is the active form of psilocybin (4-PO-DMT).^[1] ^[2] ^[3] ^[4] 4-HO-TMT is closely related to bufotenidine, the N-trimethyl analogue of serotonin.

Like psilocin, 4-HO-DMT shows affinity for the serotonin 5-HT_1A, 5-HT_2A, and 5-HT_2B receptors. However, its affinities for these receptors are lower than those of psilocin (by 8-, 6-, and 26-fold, respectively). Additionally, in another study, the value of 4-HO-TMT in activating the serotonin 5-HT_2A receptor was 324-fold lower than that of psilocin (6800 and 21nM, respectively). Similarly to psilocin, 4-HO-TMT does not bind to the serotonin 5-HT₃ receptor. This was in contrast to predictions, as the related compound bufotenidine is a strong and selective serotonin 5-HT₃ receptor agonist.

4-HO-TMT is a quaternary trimethyl ammonium compound, and as a result, is less likely to be able to cross the blood–brain barrier (BBB) and enter the central nervous system than other tryptamines. Accordingly, 4-HO-TMT showed no ability to cross an artificial BBB-like membrane in a study.^[5] In rodents, 4-HO-TMT showed no head-twitch response (a behavioral proxy of psychedelic effects), hypolocomotion, or hypothermia, in contrast to psilocin and norpsilocin, but similarly to aeruginascin.

A synthetic prodrug of 4-HO-TMT, 4-AcO-TMT, has been developed. It is analogous to psilacetin (4-AcO-DMT), a prodrug of psilocin.

External links

4-OH-TMT⁺ - isomer design

Notes and References

Chadeayne AR, Pham DN, Reid BG, Golen JA, Manke DR . Active Metabolite of Aeruginascin (4-Hydroxy-N,N,N-trimethyltryptamine): Synthesis, Structure, and Serotonergic Binding Affinity . ACS Omega . 5 . 27 . 16940–16943 . July 2020 . 32685863 . 7365549 . 10.1021/acsomega.0c02208 . 2470-1343 .
Glatfelter GC, Pottie E, Partilla JS, Sherwood AM, Kaylo K, Pham DN, Naeem M, Sammeta VR, DeBoer S, Golen JA, Hulley EB, Stove CP, Chadeayne AR, Manke DR, Baumann MH . Structure-Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice . ACS Pharmacol Transl Sci . 5 . 11 . 1181–1196 . November 2022 . 36407948 . 9667540 . 10.1021/acsptsci.2c00177 .
Chue P, Andreiev A, Bucuci E, Els C, Chue J . A Review of Aeruginascin and Potential Entourage Effect in Hallucinogenic Mushrooms . European Psychiatry . Royal College of Psychiatrists . 65 . S1 . 2022 . 0924-9338 . 10.1192/j.eurpsy.2022.2297 . free . S885. 9568164 .
Glatfelter GC, Pham DN, Walther D, Golen JA, Chadeayne AR, Baumann MH, Manke DR . Synthesis, Structural Characterization, and Pharmacological Activity of Novel Quaternary Salts of 4-Substituted Tryptamines . ACS Omega . 7 . 28 . 24888–24894 . July 2022 . 35874244 . 10.1021/acsomega.2c03476 . 9301952 .
Rakoczy RJ, Runge GN, Sen AK, Sandoval O, Wells HG, Nguyen Q, Roberts BR, Sciortino JH, Gibbons WJ, Friedberg LM, Jones JA, McMurray MS . Pharmacological and behavioural effects of tryptamines present in psilocybin-containing mushrooms . Br J Pharmacol . 181 . 19 . 3627–3641 . October 2024 . 38825326 . 10.1111/bph.16466 . free .