Structure-based discovery of nonhallucinogenic psychedelic analogs

Introduction

Cao and colleagues frame the problem around the human serotonin 2A receptor (5-HT2A R), a receptor targeted by many neuropsychiatric drugs and by classical psychedelics such as LSD and psilocybin. Earlier research shows these psychedelics can produce rapid and persistent antidepressant effects, but their hallucinogenic properties limit wider clinical use. At the same time, lipid modulation of 5-HT2A R and the structural determinants of ligand bias at this receptor remained incompletely understood, constraining rational design of therapeutics that separate beneficial effects from hallucinations. This study set out to provide high-resolution structural information on 5-HT2A R bound to multiple ligands (serotonin, psilocin, LSD, lisuride and several drug-like scaffolds) and to use those structures to design and test nonhallucinogenic, arrestin-biased 5-HT2A R agonists with antidepressant-like activity in mice. The investigators aimed to characterise lipid interactions, reveal alternative ligand binding modes, and exploit those insights to create small-molecule analogs that preferentially engage β-arrestin pathways without eliciting hallucinatory behaviours in preclinical models.