Optical-Controlled Kinetic Switch: Fine-Tuning of the Residence Time of an Antagonist Binding to the Vasopressin V Receptor in , Ex Vivo, and In Vivo Models of ADPKD.

The pharmacological activity of a small-molecule ligand is linked to its receptor residence time. Therefore, precise control of the duration for which a ligand binds to its receptor is highly desirable. Herein, we designed photoswitchable ligands targeting the vasopressin V receptor (VR), a validated target for autosomal dominant polycystic kidney disease (ADPKD). We adapted the photoswitching trait of azobenzene to the parent VR antagonist lixivaptan () to generate azobenzene lixivaptan derivatives (). Among them, was a potential optical-controlled kinetic switch. Upon irradiation, displayed a 4.3-fold prolonged VR residence time compared to its thermally stable configuration. The optical-controlled kinetic variations led to distinct inhibitory effects on cellular functional readout. Furthermore, conversion of the / isomer of resulted in different efficacies of inhibiting renal cystogenesis ex vivo and in vivo. Overall, represents a photoswitch for precise control of ligand-receptor residence time and, consequently, the pharmacological activity.