Psychedelic-like Activity of Norpsilocin Analogues

Abstract

Primary metabolites of mushroom tryptamines, psilocybin and baeocystin (i.e., psilocin and norpsilocin), exhibit potent agonist activity at the serotonin 2A receptor (5-HT 2A ) in vitro but differ in their 5-HT 2A -mediated effects in vivo. In particular, psilocin produces centrally mediated psychedelic effects in vivo, whereas norpsilocin, differing only by the loss of an N-methyl group, is devoid of psychedelic-like effects. These observations suggest that the secondary methylamine group in norpsilocin impacts its central nervous system (CNS) bioavailability but not its receptor pharmacodynamics. To test this hypothesis, eight norpsilocin derivatives were synthesized with varied secondary alkyl-, allyl-, and benzylamine groups, primarily aiming to increase their lipophilicity and brain permeability. Structure−activity relationships for the norpsilocin analogues were evaluated using the mouse head-twitch response (HTR) as a proxy for CNS-mediated psychedelic-like effects. HTR studies revealed that extending the N-methyl group of norpsilocin by a single methyl group, to give the corresponding secondary N-ethyl analogue (4-HO-NET), was sufficient to produce psilocin-like activity (median effective dose or ED 50 = 1.4 mg/kg). Notably, N-allyl, N-propyl, N-isopropyl, and N-benzyl derivatives also induced psilocin-like HTR activity (ED 50 = 1.1−3.2 mg/kg), with variable maximum effects (26−77 total HTR events). By contrast, adding bulkier tert-butyl or cyclohexyl groups in the same position did not elicit psilocin-like HTRs. Pharmacological assessments of the tryptamine series in vitro demonstrated interactions with multiple serotonin receptor subtypes, including 5-HT 2A , and other CNS signaling proteins (e.g., sigma receptors). Overall, our data highlight key structural requirements for CNS-mediated psychedelic-like effects of norpsilocin analogues.

In vitro and in vivo metabolism of psilocybin’s active metabolite psilocin

“…It is nearly a full agonist at the mouse and human 5-HT 2A receptor in G q -dependent calcium flux assays (EC 50 < 10 nM) but interestingly did not show any psychoactive properties in head-twitch response experiments with mice ( Sherwood et al, 2020 ). This may be due to the inability to cross the blood-brain barrier or rapid degradation of the secondary amine group ( Sherwood et al, 2020 ; Sherwood et al, 2024 ). Nevertheless, further analysis with NMR or high-resolution mass spectrometry is needed to confirm the structure of this minor psilocin metabolite.…”

Review of Psilocybin Use for Depression among Cancer Patients after Approval in Oregon

“…The 4-hydroxyl group of psilocin likely contributes to its oral bioavailability and enhanced metabolic stability, aiding in improved central nervous system penetration [62]. The levels of 5-hydroxyindoleacetic acid (5-HIAA) in relation to serotonin were found to be elevated in specific brain regions such as the hypothalamus and pons [63].…”