posted on 2024-01-08, 13:07authored byAlexander M. Sherwood, Elise K. Burkhartzmeyer, Samuel E. Williamson, Michael H. Baumann, Grant C. Glatfelter
Primary metabolites
of mushroom tryptamines, psilocybin
and baeocystin
(i.e., psilocin and norpsilocin), exhibit potent agonist activity
at the serotonin 2A receptor (5-HT2A) in vitro but differ in their 5-HT2A-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 ED50 = 1.4 mg/kg). Notably, N-allyl, N-propyl, N-isopropyl, and N-benzyl derivatives also induced psilocin-like HTR activity (ED50 = 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-HT2A, 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.