4-Hydroxytryptamine

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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 affinity for the serotonin 5-HT2C receptor (Ki = 40 nM), the serotonin 5-HT1A receptor (Ki = 95 nM), and the serotonin 5-HT1B receptor (Ki = 1,050 nM). [10] [11] [12] The drug produces serotonergic peripheral effects in animals, [1] [13] 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] [14]

Derivatives

A large number of 4-hydroxytryptamine derivatives are known. [15] [16] [17] [18] [19] [20] 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. [15] [16] [17] [18] 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. [15] [16] [17] [18] [19] [20] Many or all of these compounds are serotonin receptor agonists and/or serotonergic psychedelics. [15] [16] [17] [18]

History

4-HT was first described in the scientific literature by 1959. [1] [21] [22] Its pharmacology was first thoroughly characterized in 2024. [4]

See also

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. 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,N-trimethyltryptamine 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. Bibcode:2020JNAtP..83..461S. 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. ↑ Glennon RA (January 1987). "Central serotonin receptors as targets for drug research". J Med Chem. 30 (1): 1–12. doi:10.1021/jm00384a001. PMID   3543362. Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites
  13. ↑ Cerletti A, Taeschler M, Weidmann H (1968). Pharmacologic studies on the structure-activity relationship of hydroxyindole alkylamines. Advances in Pharmacology. Vol. 6. pp. 233–246. doi:10.1016/s1054-3589(08)60322-1. ISBN   978-0-12-032906-9. PMID   5658327.
  14. ↑ "4-HYDROXYTRYPTAMINE". ChemSpider. 10 June 2024. Retrieved 5 December 2024.
  15. 1 2 3 4 Araújo AM, Carvalho F, Bastos Mde L, Guedes de Pinho P, Carvalho M (August 2015). "The hallucinogenic world of tryptamines: an updated review". Arch Toxicol. 89 (8): 1151–1173. Bibcode:2015ArTox..89.1151A. doi:10.1007/s00204-015-1513-x. PMID   25877327.
  16. 1 2 3 4 Catalani V, Corkery JM, Guirguis A, Napoletano F, Arillotta D, Zangani C, et al. (August 2021). "Psychonauts' psychedelics: A systematic, multilingual, web-crawling exercise". Eur Neuropsychopharmacol. 49: 69–92. doi:10.1016/j.euroneuro.2021.03.006. PMID   33857740.
  17. 1 2 3 4 Malaca S, Lo Faro AF, Tamborra A, Pichini S, Busardò FP, Huestis MA (December 2020). "Toxicology and Analysis of Psychoactive Tryptamines". Int J Mol Sci. 21 (23): 9279. doi: 10.3390/ijms21239279 . PMC   7730282 . PMID   33291798. S2CID   228080489.
  18. 1 2 3 4 Shulgin A, Shulgin A (September 1997). TiHKAL: The Continuation. Berkeley, California: Transform Press. ISBN   0-9630096-9-9. OCLC   38503252.
  19. 1 2 Glatfelter GC, Naeem M, Pham DN, Golen JA, Chadeayne AR, Manke DR, et al. (April 2023). "Receptor Binding Profiles for Tryptamine Psychedelics and Effects of 4-Propionoxy-N,N-dimethyltryptamine in Mice". ACS Pharmacol Transl Sci. 6 (4): 567–577. doi:10.1021/acsptsci.2c00222. PMC   10111620 . PMID   37082754.
  20. 1 2 Kozell LB, Eshleman AJ, Swanson TL, Bloom SH, Wolfrum KM, Schmachtenberg JL, et al. (April 2023). "Pharmacologic Activity of Substituted Tryptamines at 5-Hydroxytryptamine (5-HT)2A Receptor (5-HT2AR), 5-HT2CR, 5-HT1AR, and Serotonin Transporter". J Pharmacol Exp Ther. 385 (1): 62–75. doi:10.1124/jpet.122.001454. PMC   10029822 . PMID   36669875.
  21. ↑ 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.
  22. ↑ 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.
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