Norpsilocin

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.^[1][2] It is hypothesized to be a dephosphorylated metabolite of baeocystin.^[2]

Norpsilocin

Clinical data
Other names	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
Identifiers
IUPAC name 3-[2-(methylamino)ethyl]-1H-indol-4-ol
CAS Number	28363-70-4
PubChem CID	14107683
ChemSpider	27283888
UNII	TL6QDJ5TMQ
ChEMBL	ChEMBL4648350
CompTox Dashboard (EPA)	DTXSID901336988
Chemical and physical data
Formula	C11H14N2O
Molar mass	190.246 g·mol−1
3D model (JSmol)	Interactive image
SMILES CNCCC1=CNC2=C1C(=CC=C2)O
InChI InChI=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 Key:MTJOWJUQGYWRHT-UHFFFAOYSA-N

Norpsilocin was found to be a near full agonist of the 5-HT_2A receptor and was found to be more potent than psilocin.^[3][4] It also has affinity for other serotonin receptors.^[5] Moreover, it has been found to cross the blood–brain barrier in animals and to have good metabolic stability similarly to psilocin.^[5]

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).^[6][7] 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.^[5] Likewise, norbaeocystin and aeruginascin failed to induce the head-twitch response.^[5] Only psilocybin was effective in this regard.^[5] In any case, norbaeocystin showed antidepressant-like activity (forced swim test) similarly to psilocybin and fluoxetine in spite of its putative non-hallucinogenic nature.^[5] Norpsilocin itself was not tested in this assay.^[5]

Norpsilocin is being evaluated under the developmental code name PLZ-1017 for the possible treatment of pervasive developmental disorders in children.^[8]

See also

• 4-HO-NALT
• 4-Hydroxytryptamine

References

1. Lenz C, Wick J, Hoffmeister D (October 2017). "Identification of ω-N-Methyl-4-hydroxytryptamine (Norpsilocin) as a Psilocybe Natural Product". Journal of Natural Products. 80 (10): 2835–2838. doi:10.1021/acs.jnatprod.7b00407. PMID 28929753.
2. "Two New Crystalline Forms of Norpsilocin".
3. "Study Finds Norpsilocin is More Potent Than Psilocin at 5-HT2A".
4. Sherwood AM, Halberstadt AL, Klein AK, McCorvy JD, Kaylo KW, Kargbo RB, Meisenheimer P (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.
5. Rakoczy RJ, Runge GN, Sen AK, Sandoval O, Wells HG, Nguyen Q, Roberts BR, Sciortino JH, Gibbons WJ, Friedberg LM, Jones JA, McMurray MS (October 2024). "Pharmacological and behavioural effects of tryptamines present in psilocybin-containing mushrooms". Br J Pharmacol. 181 (19): 3627–3641. doi:10.1111/bph.16466. PMID 38825326.
6. Keeper of the Trout and Friends (2007). "4-Hydroxy-MMT". Some Simple Tryptamines (2 ed.). Austin, Texas: Mydriatric Productions. p. 56. ASIN B0041OLXM0. ISBN 978-0977087655. OCLC 948674100. 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)
7. 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. 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]. [...]
8. "Norpsilocin - Pilz Bioscience". AdisInsight. 19 January 2021. Retrieved 27 October 2024.