Discovery of a functionally selective serotonin receptor (5-HT<sub>1A</sub>R) agonist for the treatment of pain.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 40531992.
- Also identified by DOI 10.1126/sciadv.adv9267 and PMC identifier 12175894.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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.
Medical subject headings
- Receptor, Serotonin, 5-HT1A
- Serotonin 5-HT1 Receptor Agonists
- Pain