Receptor binding profiles and behavioral effects of psilocybin analogs
The FASEB Journal – May 01, 2022
Source: OpenAlex
Summary
A compelling finding reveals psilacetin, a synthetic psilocybin analog, acts as a potent hallucinogen with potential intrinsic psychedelic activity, not merely as a prodrug. *In vivo* studies in male mice, using doses from 0.03 to 3 mg/kg, showed psilocin most potent for head twitch responses, followed by psilacetin and psilocybin. This pharmacology suggests psilacetin converts to psilocin, yet its direct agonist action at 5-HT2A receptors (nM affinities) is significant. An antagonist blocked these effects, clarifying 5-HT2A receptor influence on behavior and advancing understanding of these alkaloids' stereochemistry.
Abstract
4‐phosphorloxy‐ N,N ‐dimethyltryptamine (psilocybin) is a naturally occurring psychedelic compound that is being investigated in clinical studies in conjunction with psychotherapy for treatment of several psychiatric disorders. It is well established that 4‐hydroxy‐ N,N ‐dimethyltryptamine (psilocin) is the bioactive metabolite of psilocybin which mediates its in vivo psychedelic activity in humans and rodents (e.g., head twitch response) via agonist actions at 5‐HT 2A receptors. Several psilocybin analogs have emerged on recreational drug markets as new psychoactive substances (NPS), some of which are being investigated for their potential clinical utility in psychedelic assisted psychotherapy. For example, 4‐acetoxy‐ N,N ‐dimethyltrytpamine (psilacetin) is a psychedelic NPS that is hypothesized to be a prodrug which is metabolized to psilocin, similar to psilocybin. Little is known about the pharmacology of psilacetin and related psilocybin analogs, especially with regard to how differences in receptor activity profiles might modulate in vivo behavioral, physiological, and potential clinical effects. The present study investigated the in vitro receptor affinities for a series of psilocybin analogs with differing N ‐alkyl substitutions (dimethyl, dipropyl, methylallyl, or methylisopropyl) or 4‐position ring‐substitutions (hydroxy, acetoxy or methoxy). Additionally, in vivo dose‐response (0.03 – 3 mg/kg s.c.) and antagonist reversal experiments were conducted to examine head twitch responses (HTRs) in male C57BL/6J mice after administration of psilocybin, psilacetin, and psilocin. The in vitro receptor screening results revealed that all psilocybin analogs have low to mid nM affinities for 5‐HT 1A , 5‐HT 2A , 5‐HT 2B , and 5‐HT 2C subtypes, as well as other 5‐HT receptors. Non‐serotonergic targets included adrenergic, dopaminergic, histaminergic, and sigma receptor subtypes, and monoamine transporters (dopamine & serotonin). However, affinities for the non‐serotonergic sites were less consistent across the various compounds and much weaker when compared to activity at 5‐HT receptors. The in vivo mouse studies revealed that the rank order of potency to induce HTRs was psilocin > psilacetin > psilocybin, suggesting that psilacetin may indeed be converted to psilocin in vivo . Perhaps more importantly, psilacetin may have psychedelic activity on its own based on pharmacological screening data showing nM binding affinity to 5‐HT 2A receptors. The HTRs induced by psilocybin, psilocin, and psilacetin (all 0.6 mg/kg s.c.) were blocked by pretreatment with the 5‐HT 2A antagonist M100907 (0.01 mg/kg s.c.), indicating the involvement of 5‐HT 2A receptors. Taken together, our data provide key information about structure‐activity relationships for receptor binding profiles of psilocybin analogs and suggest that psilacetin may be an alternative prodrug for psilocin, with possible psychedelic activity of its own. Future studies comparing the pharmacokinetics and metabolism of psilocybin and psilacetin seem warranted to confirm the conversion of these parent compounds to psilocin in vivo .