Optical-Controlled Kinetic Switch: Fine-Tuning of the Residence Time of an Antagonist Binding to the Vasopressin V2 Receptor in In Vitro, 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 V₂ receptor (V₂R), a validated target for autosomal dominant polycystic kidney disease (ADPKD). We adapted the photoswitching trait of azobenzene to the parent V₂R antagonist lixivaptan (LP) to generate azobenzene lixivaptan derivatives (aLPs). Among them, aLPs-5g was a potential optical-controlled kinetic switch. Upon irradiation, cis-aLPs-5g displayed a 4.3-fold prolonged V₂R residence time compared to its thermally stable trans configuration. The optical-controlled kinetic variations led to distinct inhibitory effects on cellular functional readout. Furthermore, conversion of the cis/trans isomer of aLPs-5g resulted in different efficacies of inhibiting renal cystogenesis ex vivo and in vivo. Overall, aLPs-5g represents a photoswitch for precise control of ligand-receptor residence time and, consequently, the pharmacological activity.