Peer-reviewed article

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

Fenske TG iD, McKee JL iD, Cavalco NG iD, Schalk SS, Bonniwell EM iD, Lammers JC iD, Shacham N, Cuccurazzu B, Halberstadt AL iD, McCorvy JD iD

Journal of medicinal chemistrySep 25, 2025United States0 citationsDOI: 10.1021/acs.jmedchem.5c01855

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.

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Psychedelics

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