4-Hydroxytryptamine
Serotonin receptor agonist From Wikipedia, the free encyclopedia
4-Hydroxytryptamine (4-HT, 4-HTA), also known as N,N-didesmethylpsilocin, is a naturally occurring tryptamine alkaloid.[1][2][3][4] It is closely related chemically to the neurotransmitter serotonin, the psychedelic psilocin, and is the active form of the tryptamine alkaloid norbaeocystin.[5][6][4]
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| Other names | 4-HT; 4-HTA; N,N-Didesmethylpsilocin; Dinorpsilocin |
| Drug class | Serotonin receptor agonist; Non-hallucinogenic serotonin 5-HT2A receptor agonist |
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| Formula | C10H12N2O |
| Molar mass | 176.219 g·mol−1 |
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The compound is a serotonin receptor agonist, including of the serotonin 5-HT2A receptor, but in contrast to certain closely related compounds like psilocin, appears to be non-hallucinogenic.[4][7]
4-HT may occur naturally in Psilocybe baeocystis and Psilocybe cyanescens.[1][8] It may serve as an alternative precursor in the biosynthesis of psilocybin (4-PO-DMT) in psilocybin mushrooms.[2][9][3]
Pharmacology
Summarize
Perspective
4-HT is a potent agonist of the serotonin 5-HT2A receptor similarly to psilocin (EC50 = 38 nM and 21 nM, respectively).[4][10][11] It also shows high affinity for the serotonin 5-HT1A receptor.[10][11] The drug produces serotonergic peripheral effects in animals,[1][12] shows similar metabolism and metabolic stability to psilocin,[4] and appears to cross the blood–brain barrier and hence is centrally penetrant.[4]
Surprisingly however, the compound, similarly to baeocystin, norbaeocystin, and norpsilocin, does not produce the head-twitch response, a behavioral proxy of psychedelic effects, in animals, and hence is putatively non-hallucinogenic.[4][7] In older literature, the psychoactive effects of 4-hydroxylated tryptamines have been said to increase in the series of 4-hydroxytryptamine, 4-hydroxy-N-methyltryptamine (norpsilocin], and 4-hydroxy-N,N-dimethyltryptamine (psilocin).[3]
The reason for the lack of hallucinogenic effects with 4-HT and related compounds is unknown, but may be due to biased agonism of the serotonin 5-HT2A receptor; or, more specifically, biased agonism for the β-arrestin2 signaling pathway.[4]
Norbaeocystin is thought to be a prodrug of 4-HT, analogously to how psilocybin is a prodrug of psilocin and how baeocystin is thought to be a prodrug of norpsilocin.[6][4]
Chemistry
4-HT, also known as 4-hydroxytryptamine, is a substituted tryptamine derivative.[5] It is a positional isomer of the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT), an analogue of the serotonergic psychedelic psilocin (4-HO-DMT), and the dephosphorylated form of the tryptamine alkaloid norbaeocystin (4-phosphoryloxytryptamine; 4-PO-T).[5]
The predicted log P of 4-HT is 0.65 to 1.1.[5][13]
Derivatives
A large number of 4-hydroxytryptamine derivatives are known.[14][15][16][17][18][19] These include psilocin (4-HO-DMT), norpsilocin (4-HO-NMT), 4-HO-DALT, 4-HO-DBT, 4-HO-DET, 4-HO-DiPT, 4-HO-DPT, 4-HO-MET, 4-HO-MiPT, 4-HO-MPT, 4-HO-NiPT, 4-HO-pyr-T, and 4-HO-TMT, among others.[14][15][16][17] In addition, 4-methoxy derivatives such as 4-MeO-DiPT, 4-MeO-DMT, and 4-MeO-MiPT; 4-acetoxy derivative such as 4-AcO-DMT (psilacetin), 4-AcO-DET, 4-AcO-DALT, 4-AcO-DiPT, 4-PrO-DiPT, and 4-PrO-DMT; and 4-phosphoryloxy derivatives such as psilocybin (4-PO-DMT), baeocystin (4-PO-NMT), norbaeocystin (4-PO-T), and aeruginascin (4-PO-TMT) are known.[14][15][16][17][18][19] Many or all of these compounds are serotonin receptor agonists and/or serotonergic psychedelics.[14][15][16][17]
History
4-HT was first described in the scientific literature by 1959.[1][20][21] Its pharmacology was first thoroughly characterized in 2024.[4]
References
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