4-Hydroxytryptamine
{{Short description|Serotonin receptor agonist}}
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| image = File:4-Hydroxytryptamine.svg
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| class = Serotonin receptor agonist; Non-hallucinogenic serotonin 5-HT2A receptor agonist
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| CAS_number = 570-14-9
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| PubChem = 11297
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| DrugBank =
| ChemSpiderID = 10823
| UNII = DP0D1701D1
| KEGG = C21762
| ChEBI = 139217
| ChEMBL = 18855
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| synonyms = 4-HT; 4-HTA; N,N-Didesmethylpsilocin; Dinorpsilocin
| IUPAC_name = 3-(2-aminoethyl)-1H-indol-4-ol
| C=10 | H=12 | N=2 | O=1
| SMILES = C1=CC2=C(C(=C1)O)C(=CN2)CCN
| StdInChI = 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
| StdInChIKey = FKIRTWDHOWAQGX-UHFFFAOYSA-N
}}
4-Hydroxytryptamine (4-HT, 4-HTA), also known as N,N-didesmethylpsilocin, is a naturally occurring tryptamine alkaloid.{{cite book | author = Keeper of the Trout and Friends | chapter = 4-Hydroxytryptamine | title = Some Simple Tryptamines | edition = 2 | date = 2007 | publisher = Mydriatric Productions | location = Austin, Texas | isbn = 978-0977087655 | oclc = 948674100 | page = 54 | chapter-url = https://bitnest.netfirms.com/external/SST/54 | url = https://archive.org/details/SomeSimpleTryptamines2ndEd2007WithAddendum/}}{{cite book | vauthors = Wieczorek PP, Witkowska D, Jasicka-Misiak I, Poliwoda A, Oterman M, Zielińska K | title=Studies in Natural Products Chemistry | chapter=Bioactive Alkaloids of Hallucinogenic Mushrooms | publisher=Elsevier | year=2015 | volume=46 | issn=1572-5995 | doi=10.1016/b978-0-444-63462-7.00005-1 | pages=133–168| isbn=978-0-444-63462-7 }}{{cite journal | vauthors = Wurst M, Kysilka R, Flieger M | title = Psychoactive tryptamines from basidiomycetes | journal = Folia Microbiologica | volume = 47 | issue = 1 | pages = 3–27 | date = 2002 | pmid = 11980266 | doi = 10.1007/BF02818560 }}{{cite journal | vauthors = Rakoczy RJ, Runge GN, Sen AK, Sandoval O, Wells HG, Nguyen Q, Roberts BR, Sciortino JH, Gibbons WJ, Friedberg LM, Jones JA, McMurray MS | title = Pharmacological and behavioural effects of tryptamines present in psilocybin-containing mushrooms | journal = British Journal of Pharmacology | volume = 181 | issue = 19 | pages = 3627–3641 | date = October 2024 | pmid = 38825326 | doi = 10.1111/bph.16466 | doi-access = free | quote = 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).}} It is closely related chemically to the neurotransmitter serotonin, the psychedelic psilocin, and is the active form of the tryptamine alkaloid norbaeocystin.
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-HT may occur naturally in Psilocybe baeocystis and Psilocybe cyanescens.{{cite journal | vauthors = Repke DB, Leslie DT, Guzmán G | title = Baeocystin in psilocybe, conocybe and panaeolus | journal = Lloydia | volume = 40 | issue = 6 | pages = 566–578 | date = 1977 | pmid = 600026 | doi = | url = }} It may serve as an alternative precursor in the biosynthesis of psilocybin (4-PO-DMT) in psilocybin mushrooms.{{cite journal | vauthors = Irvine W, Tyler M, Delgoda R | title = In silico characterization of the psilocybin biosynthesis pathway | journal = Computational Biology and Chemistry | volume = 104 | issue = | pages = 107854 | date = June 2023 | pmid = 36990027 | doi = 10.1016/j.compbiolchem.2023.107854 }}
Pharmacology
4-HT is a potent agonist of the serotonin 5-HT2A receptor similarly to psilocin ({{Abbrlink|EC50|half-maximal effective concentration}} = 38{{nbsp}}nM and 21{{nbsp}}nM, respectively).{{cite journal | vauthors = Chen X, Li J, Yu L, Maule F, Chang L, Gallant JA, Press DJ, Raithatha SA, Hagel JM, Facchini PJ | title = A cane toad (Rhinella marina) N-methyltransferase converts primary indolethylamines to tertiary psychedelic amines | journal = J Biol Chem | volume = 299 | issue = 10 | pages = 105231 | date = October 2023 | pmid = 37690691 | pmc = 10570959 | doi = 10.1016/j.jbc.2023.105231 | doi-access = free | url = }}{{citation | vauthors = Chen X, Li J, Yu L, Dhananjaya D, Maule F, Cook S, Chang L, Gallant J, Press D, Bains JS, Raithatha S | title=Bioproduction platform using a novel cane toad (Rhinella marina) N-methyltransferase for psychedelic-inspired drug discovery | date=10 March 2023 | doi=10.21203/rs.3.rs-2667175/v1 | doi-access=free | url=https://www.researchsquare.com/article/rs-2667175/latest.pdf | access-date=18 March 2025 | page=}} It also shows high affinity for the serotonin 5-HT1A receptor. The drug produces serotonergic peripheral effects in animals,{{cite book | vauthors = Cerletti A, Taeschler M, Weidmann H | title = Pharmacologic studies on the structure-activity relationship of hydroxyindole alkylamines | series = Advances in Pharmacology | volume = 6 | issue = Pt B | pages = 233–246 | date = 1968 | pmid = 5658327 | doi = 10.1016/s1054-3589(08)60322-1 | isbn = 978-0-12-032906-9 | url = }} shows similar metabolism and metabolic stability to psilocin, and appears to cross the blood–brain barrier and hence is centrally penetrant.
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.{{cite journal | vauthors = Sherwood AM, Halberstadt AL, Klein AK, McCorvy JD, Kaylo KW, Kargbo RB, Meisenheimer P | title = Synthesis and Biological Evaluation of Tryptamines Found in Hallucinogenic Mushrooms: Norbaeocystin, Baeocystin, Norpsilocin, and Aeruginascin | journal = Journal of Natural Products | volume = 83 | issue = 2 | pages = 461–467 | date = February 2020 | pmid = 32077284 | doi = 10.1021/acs.jnatprod.9b01061 | bibcode = 2020JNAtP..83..461S }} 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).
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.
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.{{cite journal | vauthors = Lowe H, Toyang N, Steele B, Valentine H, Grant J, Ali A, Ngwa W, Gordon L | title = The Therapeutic Potential of Psilocybin | journal = Molecules | volume = 26 | issue = 10 | page = 2948 | date = May 2021 | pmid = 34063505 | pmc = 8156539 | doi = 10.3390/molecules26102948 | doi-access = free }}
Chemistry
4-HT, also known as 4-hydroxytryptamine, is a substituted tryptamine derivative. 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).
The predicted log P of 4-HT is 0.65 to 1.1.{{cite web | title=4-Hydroxytryptamine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/11297 | access-date=5 December 2024}}{{cite web | title=4-HYDROXYTRYPTAMINE | website=ChemSpider | date=10 June 2024 | url=https://www.chemspider.com/Chemical-Structure.10823.html | access-date=5 December 2024}}
=Derivatives=
A large number of 4-hydroxytryptamine derivatives are known.{{cite journal | vauthors = Araújo AM, Carvalho F, Bastos Mde L, Guedes de Pinho P, Carvalho M | title = The hallucinogenic world of tryptamines: an updated review | journal = Arch Toxicol | volume = 89 | issue = 8 | pages = 1151–1173 | date = August 2015 | pmid = 25877327 | doi = 10.1007/s00204-015-1513-x | bibcode = 2015ArTox..89.1151A | url = }}{{cite journal | vauthors = Catalani V, Corkery JM, Guirguis A, Napoletano F, Arillotta D, Zangani C, Vento A, Schifano F | title = Psychonauts' psychedelics: A systematic, multilingual, web-crawling exercise | journal = Eur Neuropsychopharmacol | volume = 49 | issue = | pages = 69–92 | date = August 2021 | pmid = 33857740 | doi = 10.1016/j.euroneuro.2021.03.006 | url = https://cronfa.swan.ac.uk/Record/cronfa55715}}{{cite journal | vauthors = Malaca S, Lo Faro AF, Tamborra A, Pichini S, Busardò FP, Huestis MA | title = Toxicology and Analysis of Psychoactive Tryptamines | journal = Int J Mol Sci | volume = 21 | issue = 23 | date = December 2020 | page = 9279 | pmid = 33291798 | pmc = 7730282 | doi = 10.3390/ijms21239279 | doi-access = free | s2cid = 228080489 }}{{CiteTiHKAL}}{{cite journal | vauthors = Kozell LB, Eshleman AJ, Swanson TL, Bloom SH, Wolfrum KM, Schmachtenberg JL, Olson RJ, Janowsky A, Abbas AI | title = Pharmacologic Activity of Substituted Tryptamines at 5-Hydroxytryptamine (5-HT)2A Receptor (5-HT2AR), 5-HT2CR, 5-HT1AR, and Serotonin Transporter | journal = J Pharmacol Exp Ther | volume = 385 | issue = 1 | pages = 62–75 | date = April 2023 | pmid = 36669875 | pmc = 10029822 | doi = 10.1124/jpet.122.001454 }} 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. 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.{{cite journal | vauthors = Glatfelter GC, Naeem M, Pham DN, Golen JA, Chadeayne AR, Manke DR, Baumann MH | title = Receptor Binding Profiles for Tryptamine Psychedelics and Effects of 4-Propionoxy-N,N-dimethyltryptamine in Mice | journal = ACS Pharmacol Transl Sci | volume = 6 | issue = 4 | pages = 567–577 | date = April 2023 | pmid = 37082754 | pmc = 10111620 | doi = 10.1021/acsptsci.2c00222 | url = }} Many or all of these compounds are serotonin receptor agonists and/or serotonergic psychedelics.
History
4-HT was first described in the scientific literature by 1959.{{cite journal | vauthors = Vane JR | title = The relative activities of some tryptamine analogues on the isolated rat stomach strip preparation | journal = British Journal of Pharmacology and Chemotherapy | volume = 14 | issue = 1 | pages = 87–98 | date = March 1959 | pmid = 13651584 | pmc = 1481817 | doi = 10.1111/j.1476-5381.1959.tb00933.x }}{{cite journal | vauthors = Erspamer V, Glasser A, Mantegazzini P | title = Pharmacological actions of 4-hydroxytryptamine and 4-hydroxytryptophan | journal = Experientia | volume = 16 | issue = 11 | pages = 505–506 | date = November 1960 | pmid = 13697285 | doi = 10.1007/BF02158367 }} Its pharmacology was first thoroughly characterized in 2024.
References
{{Reflist}}
{{Serotonin receptor modulators}}
{{Tryptamines}}
{{Chemical classes of psychoactive drugs}}
{{DEFAULTSORT:Hydroxytryptamine, 4-}}
Category:Human drug metabolites
Category:Non-hallucinogenic 5-HT2A receptor agonists