Discovery of Highly Selective 5-HT2A Agonists Using Structure-Guided Design

Abstract With a resurgence in interest in psychedelics as rapid-acting and durable neuroplastic therapies, there is a critical need to develop more selective 5-HT2A agonists to investigate the basic neurobiological mechanisms of psychedelics. Here, we show that selectivity for 5-HT2A over the closely related 5-HT2C receptor can be leveraged using structure-based design to target residue L1232.53 in transmembrane 2 (TM2) of the extended binding pocket by increasing steric aliphatic bulk on the α-methylene group of the N-benzyl chemical scaffold. Furthermore, we comprehensively confirm selectivity at 5-HT2C RNA editing isoforms, TM2 reciprocal 5-HT2A and 5-HT2C mutants, and mouse 5-HT2A and 5-HT2C orthologs, to form a complete profile for highly selective 5-HT2A agonists to date. Using a combination of structure–activity relationships, molecular docking, and mouse head-twitch response assays, we show that 5-HT2A-selective agonists can be rationally designed to improve 5-HT2A target engagement, further advancing the study into the neurobiological mechanisms of psychedelic effects.