Optical-Controlled Kinetic Switch: Fine-Tuning of the Residence Time of an Antagonist Binding to the Vasopressin V 2 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 V 2 receptor (V 2 R), a validated target for autosomal dominant polycystic kidney disease (ADPKD). We adapted the photoswitching trait of azobenzene to the parent V 2 R 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 V 2 R 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.