Discovery of a functionally selective serotonin receptor (5-HT <sub>1A</sub> R) agonist for the treatment of pain
The heterotrimeric G protein-coupled serotonin receptor 5-HT<sub>1A</sub> receptor (5-HT<sub>1A</sub>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<sub>1A</sub>R agonist that revealed highly potent and functionally selective G<sub>i/o</sub> signaling without G<sub>s</sub> 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<sub>1A</sub>R in complex with the G<sub>i</sub> protein compared to the canonical agonist befiradol bound to complexes of 5-HT<sub>1A</sub>R with G<sub>i</sub> or G<sub>s</sub> 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.
Authors
- Sian Rodriguez-Rosado (ORCID: https://orcid.org/0009-0001-0440-1974)
- Allan I. Basbaum (ORCID: https://orcid.org/0000-0002-1710-6333)
- Brian K. Shoichet (ORCID: https://orcid.org/0000-0002-6098-7367)
- J. Blahová
- Markus Stanek
- Dorothée Weikert (ORCID: https://orcid.org/0000-0003-2259-9002)
- Annika Ullrich
- Anni Allikalt (ORCID: https://orcid.org/0000-0002-3056-3088)
- Elissa A. Fink (ORCID: https://orcid.org/0000-0001-5531-1971)
- Schneider Johannes (ORCID: https://orcid.org/0009-0006-3719-2829)
- Asuka Inoue (ORCID: https://orcid.org/0000-0003-0805-4049)
- Eduard Neu (ORCID: https://orcid.org/0000-0003-2999-1488)
- Bettina Böttcher (ORCID: https://orcid.org/0000-0002-7962-4849)
- Tim Rasmussen (ORCID: https://orcid.org/0000-0003-1126-846X)
- Karnika Bhardwaj (ORCID: https://orcid.org/0009-0000-1769-0210)
- Peter Gmeiner (ORCID: https://orcid.org/0000-0002-4127-197X)
- João M. Bráz (ORCID: https://orcid.org/0000-0001-8955-0735)
- Harald Hübner (ORCID: https://orcid.org/0000-0002-7892-599X)
- Nico Staffen
- Tamsanqa Hove
- Tamara Albert
- Stefan Löber
Institutions
- University of California, San Francisco (US)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Tohoku University (JP)
- Kyoto University (JP)
- University of Würzburg (DE)
- Kyoto Pharmaceutical University (JP)
Publication Details
- Journal
- Science Advances
- Published
- 2025-06-18
- DOI
- https://doi.org/10.1126/sciadv.adv9267
- Citations
- 5
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 4.03