Discovery of a functionally selective serotonin receptor (5-HT(1A)R) agonist for the treatment of pain.

The heterotrimeric G protein-coupled serotonin receptor 5-HT(1A) receptor (5-HT(1A)R) mediates antinociception and may serve as a valuable target for the treatment of pain. Starting from a chemical library, we evolved ST171, a bitopic 5-HT(1A)R agonist that revealed highly potent and functionally selective G(i/o) signaling without G(s) activation and marginal β-arrestin recruitment. ST171 is effective in acute and chronic pain models. Cryo-electron microscopy structures of ST171 bound to 5-HT(1A)R in complex with the G(i) protein compared to the canonical agonist befiradol bound to complexes of 5-HT(1A)R with G(i) or G(s) revealed that the ligands occupy different exo-sites. The individual binding poses are associated with ligand-specific receptor conformations that were further studied by molecular dynamics simulations, allowing us to better understand ligand bias, a phenomenon that may be crucial to the discovery of more effective and safe G protein-coupled receptor drugs.