Photoswitchable Serotonins for Optical Control of the 5-HT2A Receptor.

Johannes Morstein, Giovanna Romano, Belinda E Hetzler, Ambrose Plante, Caleb Haake, Joshua Levitz, Dirk Trauner

Angewandte Chemie (International ed. in English) 2022 Apr 25

filter terms:

Serotonin receptors play central roles in neuromodulation and are critical drug targets for psychiatric disorders. Optical control of serotonin receptor subtypes has the potential to greatly enhance our understanding of the spatiotemporal dynamics of receptor function. While other neuromodulatory receptors have been successfully rendered photoswitchable, reversible photocontrol of serotonin receptors has not been achieved, representing a major gap in GPCR photopharmacology. Herein, we develop the first tools that allow for such control. Azo5HT-2 shows light-dependent 5-HT2A R agonism, with greater activity in the cis-form. Based on docking and test compound analysis, we also develop photoswitchable orthogonal, remotely-tethered ligands (PORTLs). These BG-Azo5HTs provide rapid, reversible, and repeatable optical control following conjugation to SNAP-tagged 5-HT2A R. Overall, this study provides a foundation for the broad extension of photopharmacology to the serotonin receptor family. © 2022 Wiley-VCH GmbH.

Citation

Johannes Morstein, Giovanna Romano, Belinda E Hetzler, Ambrose Plante, Caleb Haake, Joshua Levitz, Dirk Trauner. Photoswitchable Serotonins for Optical Control of the 5-HT2A Receptor. Angewandte Chemie (International ed. in English). 2022 Apr 25;61(18):e202117094