PHARMACOLOGICAL PROFILE OF YM087, A NOVEL POTENT NONPEPTIDE VASOPRESSIN V-1A AND V-2 RECEPTOR ANTAGONIST, IN-VITRO AND IN-VIVO

The biochemical and pharmacological profile of YM087, d][1]benzazepin- 6-yl-carbonyl]-2-phenylbenzanilide monohydrochloride, a newly synthesi zed nonpeptide vasopressin (AVP) antagonist, was investigated in sever al in vitro and in vivo studies. YM087 showed high affinity for V-1A r eceptors from rat liver and V-2 receptors from rat kidney with K value s of 0.48 and 3.04 nM, respectively. YM087 also inhibited [H-3]oxytoci n (OT) binding to rb uterus (OT receptors) plasma membranes with a K-i value of 44.4 nM, and at 100 mu M did not affect the binding of [H-3] AVP to anterior pituitary (V-1B receptors) plasma membranes, which ind icated that it had less affinity for these OT and V-1B receptors. YM08 7 had no effect on cytosolic free calcium concentration ([Ca++](i)) it self, but suppressed AVP-induced increase in [Ca++](i) of cultured vas cular smooth muscle cells at the same concentrations as the binding af finities. Furthermore, YM087 potently blocked AVP-induced cAMP product ion of cultured renal epithelium cells concentration dependently and h ad no agonistic activities. In in vivo studies, intravenous administra tion of YM087 inhibited the;presser response to exogenous AVP in pithe d rats and produced an aquaretic effect in dehydrated conscious rats i n a dose-dependent manner. These results demonstrate that YM087 is a p otent and nonpeptide dual AVP V-1A and V-2 receptors antagonist and ca n be used in future studies to help clarify the physiological and path ophysiological roles of AVP.