2. Academic Validation
  3. Discovery of a functionally selective serotonin receptor (5-HT1AR) agonist for the treatment of pain

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

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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