Psychedelic-like Activity of Norpsilocin Analogues
ACS Chemical Neuroscience January 8, 2024 Alexander M. Sherwood, Elise K. Burkhartzmeyer, Samuel E. Williamson et al. 18 citations
Psilocin, a metabolite of psilocybin, produces psychedelic effects in vivo, while norpsilocin, which differs by a single N-methyl group, does not. To explore this, eight norpsilocin derivatives with varied secondary amine groups were synthesized to increase lipophilicity and brain permeability. In mouse head-twitch response (HTR) studies, extending norpsilocin's N-methyl group to an N-ethyl group (4-HO-NET) produced psilocin-like activity (ED50 = 1.4 mg/kg). N-allyl, N-propyl, N-isopropyl, and N-benzyl derivatives also induced HTRs (ED50 = 1.1–3.2 mg/kg), with variable maximum effects (26–77 total HTR events). Bulky tert-butyl or cyclohexyl groups did not elicit psilocin-like HTRs. In vitro, these tryptamines interacted with multiple serotonin receptor subtypes and other CNS proteins.