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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. [ABSTRACT FROM AUTHOR]

Oxytocin is a neuropeptide critical for maternal physiology and social behavior, and is thought to be dysregulated in several neuropsychiatric disorders. Despite the biological and neurocognitive importance of oxytocin signaling, methods are lacking to activate oxytocin receptors with high spatiotemporal precision in the brain and peripheral mammalian tissues. Here we developed and validated caged analogs of oxytocin which are functionally inert until cage release is triggered by ultraviolet light. We examined how focal versus global oxytocin application affected oxytocin-driven Ca 2+ wave propagation in mouse mammary tissue. We also validated the application of caged oxytocin in the hippocampus and auditory cortex with electrophysiological recordings in vitro , and demonstrated that oxytocin uncaging can accelerate the onset of mouse maternal behavior in vivo . Together, these results demonstrate that optopharmacological control of caged peptides is a robust tool with spatiotemporal precision for modulating neuropeptide signaling throughout the brain and body., Competing Interests: Competing interests The authors declare no competing interests.