4-Hydroxytryptamine

4-Hydroxytryptamine

Clinical data
Other names	4-HT; 4-HTA; N,N-Didesmethylpsilocin; Dinorpsilocin
Drug class	Serotonin receptor agonist; Non-hallucinogenic serotonin 5-HT2A receptor agonist
Identifiers
IUPAC name 3-(2-aminoethyl)-1H-indol-4-ol
CAS Number	570-14-9
PubChem CID	11297
ChemSpider	10823
UNII	DP0D1701D1
KEGG	C21762
ChEBI	CHEBI:139217
ChEMBL	ChEMBL18855
CompTox Dashboard (EPA)	DTXSID30205607
Chemical and physical data
Formula	C10H12N2O
Molar mass	176.219 g·mol^−1
3D model (JSmol)	Interactive image
SMILES C1=CC2=C(C(=C1)O)C(=CN2)CCN
InChI InChI=1S/C10H12N2O/c11-5-4-7-6-12-8-2-1-3-9(13)10(7)8/h1-3,6,12-13H,4-5,11H2 Key:FKIRTWDHOWAQGX-UHFFFAOYSA-N

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]

The compound is a serotonin receptor agonist, including of the serotonin 5-HT_2A 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

4-HT is a potent agonist of the serotonin 5-HT_2A receptor similarly to psilocin (EC₅₀Tooltip half-maximal effective concentration = 38 nM and 21 nM, respectively).[4] It produces serotonergic peripheral effects in animals,[1][10] 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-HT_2A 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][11]

History

4-HT was first described in the scientific literature by 1959.[1][12][13] Its pharmacology was first thoroughly characterized in 2024.[4]

References

1. Keeper of the Trout and Friends (2007). "4-Hydroxytryptamine". Some Simple Tryptamines (2 ed.). Austin, Texas: Mydriatric Productions. p. 54. ASIN B0041OLXM0. ISBN 978-0977087655. OCLC 948674100.
2. Wieczorek PP, Witkowska D, Jasicka-Misiak I, Poliwoda A, Oterman M, Zielińska K (2015). "Bioactive Alkaloids of Hallucinogenic Mushrooms". Studies in Natural Products Chemistry. Vol. 46. Elsevier. pp. 133–168. doi:10.1016/b978-0-444-63462-7.00005-1. ISBN 978-0-444-63462-7. ISSN 1572-5995.
3. Wurst M, Kysilka R, Flieger M (2002). "Psychoactive tryptamines from basidiomycetes". Folia Microbiologica. 47 (1): 3–27. doi:10.1007/BF02818560. PMID 11980266.
4. Rakoczy RJ, Runge GN, Sen AK, Sandoval O, Wells HG, Nguyen Q, et al. (October 2024). "Pharmacological and behavioural effects of tryptamines present in psilocybin-containing mushrooms". British Journal of Pharmacology. 181 (19): 3627–3641. doi:10.1111/bph.16466. PMID 38825326. Norpsilocin, 4-hydroxytryptamine and 4-hydroxy-N,N,Ntrimethyltryptamine have similar stability, metabolism and blood brain barrier penetration to psilocin. [...] As norpsilocin and 4-HT (active forms of baeocystin and norbaeocystin, respectively) are evidenced to be capable of crossing the BBB and bind with 5-HT2A receptors, it was surprising that neither induced significant head twitch responses at any concentration tested. However, these results concur with previous studies demonstrating these compounds do not significantly induce head twitch responses in rodents (Glatfelter et al., 2022; Sherwood et al., 2020).
5. "4-Hydroxytryptamine". PubChem. Retrieved 5 December 2024.
6. Lowe H, Toyang N, Steele B, Valentine H, Grant J, Ali A, et al. (May 2021). "The Therapeutic Potential of Psilocybin". Molecules. 26 (10): 2948. doi:10.3390/molecules26102948. PMC 8156539. PMID 34063505.
7. Sherwood AM, Halberstadt AL, Klein AK, McCorvy JD, Kaylo KW, Kargbo RB, et al. (February 2020). "Synthesis and Biological Evaluation of Tryptamines Found in Hallucinogenic Mushrooms: Norbaeocystin, Baeocystin, Norpsilocin, and Aeruginascin". Journal of Natural Products. 83 (2): 461–467. doi:10.1021/acs.jnatprod.9b01061. PMID 32077284.
8. Repke DB, Leslie DT, Guzmán G (1977). "Baeocystin in psilocybe, conocybe and panaeolus". Lloydia. 40 (6): 566–578. PMID 600026.
9. Irvine W, Tyler M, Delgoda R (June 2023). "In silico characterization of the psilocybin biosynthesis pathway". Computational Biology and Chemistry. 104: 107854. doi:10.1016/j.compbiolchem.2023.107854. PMID 36990027.
10. Cerletti A, Taeschler M, Weidmann H (1968). "Pharmacologic studies on the structure-activity relationship of hydroxyindole alkylamines". Adv Pharmacol (1962). 6 (Pt B): 233–246. doi:10.1016/s1054-3589(08)60322-1. PMID 5658327.
11. "4-HYDROXYTRYPTAMINE". ChemSpider. 10 June 2024. Retrieved 5 December 2024.
12. Vane JR (March 1959). "The relative activities of some tryptamine analogues on the isolated rat stomach strip preparation". British Journal of Pharmacology and Chemotherapy. 14 (1): 87–98. doi:10.1111/j.1476-5381.1959.tb00933.x. PMC 1481817. PMID 13651584.
13. Erspamer V, Glasser A, Mantegazzini P (November 1960). "Pharmacological actions of 4-hydroxytryptamine and 4-hydroxytryptophan". Experientia. 16 (11): 505–506. doi:10.1007/BF02158367. PMID 13697285.