Discovery of a functionally selective serotonin receptor (5-HT 1A R) agonist for the treatment of pain
- Annika Ullrich
- Johannes Schneider
- Joao M. Braz
- Eduard Neu
- Nico Staffen
- Markus Stanek
- Jana Bláhová
- Tamsanqa Hove
- Tamara Albert
- Anni Allikalt
- Stefan Löber
- Karnika Bhardwaj
- Sian Rodriguez-Rosado
- Elissa Fink
- Tim Rasmussen
- Harald Hübner
- Asuka Inoue
- Brian K. Shoichet
- Allan I. Basbaum
- Bettina Böttcher
- Dorothee Weikert
- Peter Gmeiner
2025-06-18
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.