4-Hydroxytryptamine

Last updated

4-Hydroxytryptamine
4-Hydroxytryptamine.svg
Clinical data
Other names4-HT; 4-HTA; N,N-Didesmethylpsilocin; Dinorpsilocin
Drug class Serotonin receptor agonist; Non-hallucinogenic serotonin 5-HT2A receptor agonist
Identifiers
  • 3-(2-aminoethyl)-1H-indol-4-ol
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C10H12N2O
Molar mass 176.219 g·mol−1
3D model (JSmol)
  • C1=CC2=C(C(=C1)O)C(=CN2)CCN
  • 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]

Contents

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

4-HT is a potent agonist of the serotonin 5-HT2A receptor similarly to psilocin (EC50 Tooltip half-maximal effective concentration = 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]

History

4-HT was first described in the scientific literature by 1959. [1] [14] [15] Its pharmacology was first thoroughly characterized in 2024. [4]

References

  1. 1 2 3 4 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. 1 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. 1 2 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. 1 2 3 4 5 6 7 8 9 10 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. 1 2 3 4 "4-Hydroxytryptamine". PubChem. Retrieved 5 December 2024.
  6. 1 2 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. 1 2 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. 1 2 Chen X, Li J, Yu L, Maule F, Chang L, Gallant JA, et al. (October 2023). "A cane toad (Rhinella marina) N-methyltransferase converts primary indolethylamines to tertiary psychedelic amines". J Biol Chem. 299 (10): 105231. doi:10.1016/j.jbc.2023.105231. PMC   10570959 . PMID   37690691.
  11. 1 2 Chen X, Li J, Yu L, Dhananjaya D, Maule F, Cook S, et al. (10 March 2023), Bioproduction platform using a novel cane toad (Rhinella marina) N-methyltransferase for psychedelic-inspired drug discovery (PDF), doi: 10.21203/rs.3.rs-2667175/v1 , retrieved 18 March 2025
  12. ↑ 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.
  13. ↑ "4-HYDROXYTRYPTAMINE". ChemSpider. 10 June 2024. Retrieved 5 December 2024.
  14. ↑ 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.
  15. ↑ 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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.