Discovery of a functionally selective serotonin receptor (5-HT1AR) agonist for the treatment of pain

  • Sci Adv. 2025 Jun 20;11(25):eadv9267. doi: 10.1126/sciadv.adv9267.
Annika Ullrich  1 ,  Johannes Schneider  1 ,  João M Braz  2 ,  Eduard Neu  1 ,  Nico Staffen  1 ,  Markus Stanek  1 ,  Jana Bláhová  1 ,  Tamsanqa Hove  3 ,  Tamara Albert  1 ,  Anni Allikalt  1 ,  Stefan Löber  1 ,  Karnika Bhardwaj  2 ,  Sian Rodriguez-Rosado  2 ,  Elissa Fink  4  5 ,  Tim Rasmussen  3 ,  Harald Hübner  1 ,  Asuka Inoue  6  7 ,  Brian K Shoichet  4 ,  Allan I Basbaum  2 ,  Bettina Böttcher  3 ,  Dorothee Weikert  1  8 ,  Peter Gmeiner  1  8
Affiliations
  • 1. Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  • 2. Department of Anatomy, University of California, San Francisco, CA, USA.
  • 3. Rudolf-Virchow-Center, Julius-Maximilians-Universität, Würzburg, Germany.
  • 4. Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
  • 5. Graduate Program in Biophysics, University of California, San Francisco, CA, USA.
  • 6. Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
  • 7. Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
  • 8. FAU NeW, Erlangen, Germany.
PMID: 40531992 DOI: 10.1126/sciadv.adv9267
Abstract

The heterotrimeric G protein-coupled serotonin receptor 5-HT1A receptor (5-HT1AR) 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-HT1AR agonist that revealed highly potent and functionally selective Gi/o signaling without Gs activation and marginal β-arrestin recruitment. ST171 is effective in acute and chronic pain models. Cryo-electron microscopy structures of ST171 bound to 5-HT1AR in complex with the Gi protein compared to the canonical agonist befiradol bound to complexes of 5-HT1AR with Gi or Gs 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.

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