Discovery of Highly Selective 5-HT2A Agonists Using Structure-Guided Design
Tyler G. Fenske, J. M. T. Mckee, Natalie G. Cavalco, Serena S. Schalk, Emma M. Bonniwell, Josie C. Lammers, Naomi Shacham, Bruna Cuccurazzu, Adam L. Halberstadt, John D. Mccorvy
Journal of Medicinal Chemistry September 25, 2025 DOI: 10.1021/acs.jmedchem.5c01855 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Topics | Neuroplasticity |
| Keywords | Steric effects Agonist Functional selectivity Receptor Transmembrane protein Binding selectivity Binding site Combinatorial chemistry Computational biology Structure–activity relationship Drug discovery Molecular recognition Pharmacology Chemical synthesis Transmembrane domain Benzene derivatives |
| Key findings | Selectivity for 5-HT2A over 5-HT2C can be achieved by targeting residue L1232.53 in TM2 with increased steric aliphatic bulk on the α-methylene group of the N-benzyl scaffold. |
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-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 N -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.