Photoswitchable Serotonins for Optical Control of the 5‐HT _2A Receptor**

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 spatiotemporal dynamics function. While other neuromodulatory have been successfully rendered photoswitchable, reversible photocontrol not achieved, representing a major gap GPCR photopharmacology. Herein, we develop first tools that allow such control. Azo5HT-2 shows light-dependent 5-HT2AR agonism, with greater activity cis-form. Based on docking test compound analysis, also photoswitchable orthogonal, remotely-tethered ligands (PORTLs). These BG-Azo5HTs provide rapid, reversible, repeatable optical following conjugation SNAP-tagged 5-HT2AR. Overall, this study provides foundation broad extension photopharmacology family.