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

Ullrich A, Schneider J, Braz JM, Neu E, Staffen N, Stanek M, Bláhová J, Hove T, Albert T, Allikalt A, Löber S, Bhardwaj K, Rodriguez-Rosado S, Fink E, Rasmussen T, Hübner H, Inoue A, Shoichet BK, Basbaum AI, Böttcher B, Weikert D, Gmeiner P (2025)

Publication Language: English

Publication Type: Journal article

Publication year: 2025

Journal

Science Advances American Association for the Advancement of Science

Book Volume: 11

Article Number: eadv9267

Journal Issue: 25

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.

Authors with CRIS profile

Annika Ullrich Lehrstuhl für Pharmazeutische Chemie Johannes Schneider Lehrstuhl für Pharmazeutische Chemie Eduard Neu Lehrstuhl für Pharmazeutische Chemie Nico Staffen Lehrstuhl für Pharmazeutische Chemie Markus Stanek Lehrstuhl für Pharmazeutische Chemie Jana Bláhová Lehrstuhl für Pharmazeutische Chemie Tamara Albert Lehrstuhl für Pharmazeutische Chemie Anni Allikalt Lehrstuhl für Pharmazeutische Chemie Stefan Löber Lehrstuhl für Pharmazeutische Chemie Harald Hübner Lehrstuhl für Pharmazeutische Chemie Dorothée Weikert Lehrstuhl für Pharmazeutische Chemie Peter Gmeiner Lehrstuhl für Pharmazeutische Chemie

Additional Organisation(s)

FAU Forschungszentrum Neue Wirkstoffe (FAU NeW)

Involved external institutions

Julius-Maximilians-Universität Würzburg DE Germany (DE) Tohoku University JP Japan (JP) University of California San Francisco (UCSF) US United States (USA) (US)

How to cite

APA:

Ullrich, A., Schneider, J., Braz, J.M., Neu, E., Staffen, N., Stanek, M.,... Gmeiner, P. (2025). Discovery of a functionally selective serotonin receptor (5-HT1AR) agonist for the treatment of pain. Science Advances, 11(25). https://doi.org/10.1126/sciadv.adv9267

MLA:

Ullrich, Annika, et al. "Discovery of a functionally selective serotonin receptor (5-HT1AR) agonist for the treatment of pain." Science Advances 11.25 (2025).

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