Studies on nonpeptide vasopressin receptor antagonists

Abstract

Vasopressin (AVP) plays an important role in the regulation of cardiovascular homeostasis through V1 and V2 receptors. Stimulation of AVP receptors may contribute to the development of congestive heart failure, hypertension and renal failure. Thus, many efforts have been made to discover AVP receptor antagonists and develop them for therapeutic use. All of the antagonists developed thus far have been peptide AVP analogues, so their therapeutic use has been limited because of their low bioavailability and partial agonist activity. It is necessary to discover nonpeptide and orally effective AVP antagonists for therapeutic use. Therefore, we forcused our studies on nonpeptide AVP antagonists. We found a lead compound by means of chemical file screening, and performed optimization of the compound. Finally, we elaborated a V1 receptor selective antagonist (OPC-21268) and a V2 receptor selective antagonist (OPC-31260). The history of the development of our novel nonpeptide AVP receptor antagonists and their pharmacological effects are described herein.