Discovery of Highly Selective 5-HT_2A Agonists Using Structure-Guided Design

With a resurgence in interest in psychedelics as rapid-acting and durable neuroplastic therapies, there is a critical need to develop more selective 5-HT_2A agonists to investigate the basic neurobiological mechanisms of psychedelics. Here, we show that selectivity for 5-HT_2A over the closely related 5-HT_2C receptor can be leveraged using structure-based design to target residue L123^2.53 in transmembrane 2 (TM2) of the extended binding pocket by increasing steric aliphatic bulk on the α-methylene group of the <i>N</i>-benzyl chemical scaffold. Furthermore, we comprehensively confirm selectivity at 5-HT_2C RNA editing isoforms, TM2 reciprocal 5-HT_2A and 5-HT_2C mutants, and mouse 5-HT_2A and 5-HT_2C orthologs, to form a complete profile for highly selective 5-HT_2A agonists to date. Using a combination of structure-activity relationships, molecular docking, and mouse head-twitch response assays, we show that 5-HT_2A-selective agonists can be rationally designed to improve 5-HT_2A target engagement, further advancing the study into the neurobiological mechanisms of psychedelic effects.