Discovery of a functionally selective serotonin 5-HT _1A receptor agonist for the treatment of pain

The G protein-coupled serotonin receptor 5-HT _1A R mediates antinociception and may serve as a valuable target for the treatment of pain. Starting from a chemical library, ST171, a bitopic chemotype activating 5-HT _1A R was evolved. In vitro pharmacological investigations of ST171 revealed potent and selective G _i activation (EC ₅₀ = 0.3 nM), with marginal G _s and β-arrestin recruitment. Preclinical studies in mice showed that ST171 was effective in acute and chronic (inflammatory and neuropathic) pain models, without causing sedation. Comparison of cryo-EM structures of a 5-HT _1A R-G _i complex bound to the functionally biased agonist ST171, with a structure bound to the functionally balanced agonist befiradol, showed that both ligands bind to the same orthosteric site, but address different exo-sites. The individual poses are associated with ligand-specific helical dispositions and rearrangements of microdomains. Complementation of these studies with molecular dynamics simulations allowed us to derive structural features associated with ST171’s functional selectivity, a phenomenon that may be crucial to the discovery of more effective and safe GPCR drugs.