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

Research output: Contribution to journalArticlepeer-review


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-HT2AR 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-HT2AR. Overall, this study provides a foundation for the broad extension of photopharmacology to the serotonin receptor family.

Original languageEnglish (US)
Article numbere202117094
JournalAngewandte Chemie - International Edition
Issue number18
StatePublished - Apr 25 2022


  • GPCR
  • Photopharmacology
  • Photoswitch
  • SNAP Tag
  • Serotonin

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry


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