Synthesis and receptor specificities of vasopressin antagonists.

We present some highlights of our findings on the design and synthesis of antagonists of the vascular (V1) and renal tubular (V2) responses to arginine vasopressin. The most potent of our original V1 antagonists, [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid) 2-O-methyltyrosine] arginine vasopressin [d(CH2)5Tyr(Me)AVP], and the most potent of our original V2/V1 antagonists, [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid), 2-O-ethyltyrosine, 4-valine] arginine vasopressin [d(CH2)5Tyr(Et)VAVP], have been modified at positions 1, 2, 4, and 8 and at positions 2, 4, 7, 8, and 9, respectively. A number of highly potent and highly selective arginine vasopressin (AVP) V1 and AVP V2/V1 antagonists have resulted from these studies. The in vivo antioxytocic properties of many of those antagonists are also given here, a number for the first time. We also present preliminary data on some orally active antagonists. A number of these antagonists have become valuable pharmacological tools in studies on the physiological and pathophysiological roles of AVP. In addition, the AVP V2 antagonists may be of therapeutic value for the treatment of hyponatremia resulting from the excessive secretion of AVP.