Norpsilocin

{{Short description|Chemical compound}}

{{Infobox drug

| drug_name = Norpsilocin

| image = Norpsilocin.svg

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| CAS_number = 28363-70-4

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| PubChem = 14107683

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| ChemSpiderID = 27283888

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = TL6QDJ5TMQ

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| ChEMBL = 4648350

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| synonyms = 4-HO-NMT; 4-OH-NMT; 4-HO-MMT; 4-OH-MMT; 4-Hydroxy-NMT; 4-Hydroxy-MMT; 4-Hydroxy-N-methyltryptamine; 4-Hydroxy-mono-methyltryptamine; N-Desmethylpsilocin; Desmethylpsilocin; AS-63499; PLZ-1017; PLZ1017

| IUPAC_name = 3-[2-(methylamino)ethyl]-1H-indol-4-ol

| C=11 | H=14 | N=2 | O=1

| SMILES = CNCCC1=CNC2=C1C(=CC=C2)O

| StdInChI = 1S/C11H14N2O/c1-12-6-5-8-7-13-9-3-2-4-10(14)11(8)9/h2-4,7,12-14H,5-6H2,1H3

| StdInChIKey = MTJOWJUQGYWRHT-UHFFFAOYSA-N

}}

Norpsilocin, also known as 4-hydroxy-N-methyltryptamine (4-HO-NMT), is a tryptamine alkaloid recently discovered in 2017 in the psychedelic mushroom Psilocybe cubensis.{{cite journal |vauthors=Lenz C, Wick J, Hoffmeister D |title=Identification of ω-N-Methyl-4-hydroxytryptamine (Norpsilocin) as a Psilocybe Natural Product |journal=Journal of Natural Products |volume=80 |issue=10 |pages=2835–2838 |date=October 2017 |pmid=28929753 |doi=10.1021/acs.jnatprod.7b00407 |url= |issn=}}{{cite web|title=Two New Crystalline Forms of Norpsilocin|url=https://psychedelicreview.com/two-new-crystalline-forms-of-norpsilocin/}} It is hypothesized to be a dephosphorylated metabolite of baeocystin.

Norpsilocin was found to be a near full agonist of the 5-HT_2A receptor and was found to be more potent than psilocin.{{cite web|title=Study Finds Norpsilocin is More Potent Than Psilocin at 5-HT2A|url=https://psychedelicreview.com/event/study-finds-norpsilocin-is-more-potent-than-psilocin-at-5-ht2a/}}{{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 |url= |issn=}} It also has affinity for other serotonin receptors. Moreover, it has been found to cross the blood–brain barrier in animals and to have good metabolic stability similarly to psilocin.{{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 = Br J Pharmacol | volume = 181 | issue = 19 | pages = 3627–3641 | date = October 2024 | pmid = 38825326 | doi = 10.1111/bph.16466 | url = | doi-access = free }}

Norpsilocin has shown psilocin-related peripheral effects in animals, including decreased spinal reflexes such as knee jerk response (opposite effect to psilocin), antiserotonergic activity (14% of that of psilocin), and pressor activity (70% of that of psilocin).{{cite book | author = Keeper of the Trout and Friends | chapter = 4-Hydroxy-MMT | title = Some Simple Tryptamines | edition = 2 | date = 2007 | publisher = Mydriatric Productions | location = Austin, Texas | isbn = 978-0977087655 | oclc = 948674100 | asin = B0041OLXM0 | page = 56 | chapter-url = https://bitnest.netfirms.com/external/SST/56 | url = https://archive.org/details/SomeSimpleTryptamines2ndEd2007WithAddendum/ | quote = 4-Hydroxy-MMT [...] Activity: Ott 1996 notes Cerletti 1968 reported psychotropic effects in animals. In comparison to psilocin, Cerletti et al. 1968 determined that 4-Hydroxy-N-methyltryptamine decreased spinal reflexes such as knee jerk response (instead of increasing it as psilocin does), had 14% as much antagonism of serotonin as psilocin, and showed 70% as much pressor activity. [...] In comparison to psilocin, Cerletti et al. 1968 determined it had increased spinal reflexes, such as knee jerk response, had around 11% as much antagonism of serotonin activity, and showed as much pressor activity as psilocin.) [...] Cerletti, A. et al. (1968) Advances in Pharmacology 6B: 233-246. “Pharmacologic Studies on the Structure-Activity Relationship of Hydroxyindole Alkylamines.” (A. Cerletti, M. Taeschler & H. Weidmann) [...] Ott, Jonathan (1996) Pharmacotheon. Entheogenic Drugs, their Plant Sources and History. Second Edition Densified. Natural Products Co., Kennewick, WA 639 pp. ISBN 0-9614234-8-x (Hardcover)/ 0-9614234-9-8 (paperback) }}{{cite journal | vauthors = Cerletti A, Taeschler M, Weidmann H | title = Pharmacologic studies on the structure-activity relationship of hydroxyindole alkylamines | journal = Adv Pharmacol (1962) | volume = 6 | issue = Pt B | pages = 233–246 | date = 1968 | pmid = 5658327 | doi = 10.1016/s1054-3589(08)60322-1 | url = | quote = TABLE III: INFLUENCE OF SUBSTITUTION IN POSITION 3 OF INDOLE AND 4-HYDROXYINDOLE: [...] Substituent: R3: CH2—CH2—N(—H,—CH3). R4: OH. [(Norpsilocin/4-HO-NMT).] Knee Jerk: ↓ 20–50 [μg/kg i.v.]. Serotonin antagonism: 14[% of psilocin]. Pressure activity: [+]35 [mm Hg]. [...] }} Surprisingly however, in spite of its serotonin 5-HT_2A receptor agonism and psilocin-like effects, norpsilocin failed to induce the head-twitch response, a behavioral proxy of psychedelic effects, in animals. Likewise, norbaeocystin and aeruginascin failed to induce the head-twitch response. Only psilocybin was effective in this regard. In any case, norbaeocystin showed antidepressant-like activity (forced swim test) similarly to psilocybin and fluoxetine in spite of its putative non-hallucinogenic nature. Norpsilocin itself was not tested in this assay.

Norpsilocin is being evaluated under the developmental code name PLZ-1017 for the possible treatment of pervasive developmental disorders in children.{{cite web | title=Norpsilocin - Pilz Bioscience | website=AdisInsight | date=19 January 2021 | url=https://adisinsight.springer.com/drugs/800061882 | access-date=27 October 2024}}