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

• Published in: Journal of medicinal chemistry 2023-01, Vol.66 (2), p.1454-1466
• Main Authors: Gu, Xiaoke, Yuan, Haoxing, Zhao, Wenchao, Sun, Nan, Yan, Wenzhong, Jiang, Chunyu, He, Yan, Liu, Hongli, Cheng, Jianjun, Guo, Dong
• Format: Article
• Language: English
• Subjects: Antidiuretic Hormone Receptor Antagonists - pharmacology; Humans; Ligands; Polycystic Kidney, Autosomal Dominant - drug therapy; Receptors, Vasopressin - metabolism; Vasopressins - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c01625

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 (V R), a validated target for autosomal dominant polycystic kidney disease (ADPKD). We adapted the photoswitching trait of azobenzene to the parent V R antagonist lixivaptan ( ) to generate azobenzene lixivaptan derivatives ( ). Among them, was a potential optical-controlled kinetic switch. Upon irradiation, displayed a 4.3-fold prolonged V R 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.