Vol. 282, Issue 1, 301-308, 1997

Pharmacological Profile of YM087, A Novel Potent Nonpeptide Vasopressin V_1A and V₂ Receptor Antagonist, in Vitro and in Vivo

Atsuo Tahara, Yuichi Tomura, Koh-Ichi Wada, Toshiyuki Kusayama, Junko Tsukada, Masahiro Takanashi, Takeyuki Yatsu, Wataru Uchida and Akihiro Tanaka

Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305, Japan

The biochemical and pharmacological profile of YM087, 4-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)-carbonyl]-2-phenylbenzanilide monohydrochloride, a newly synthesized nonpeptide vasopressin (AVP) antagonist, was investigated in several in vitro and in vivo studies. YM087 showed high affinity for V_1A receptors from rat liver and V₂ receptors from rat kidney with K_i values of 0.48 and 3.04 nM, respectively. YM087 also inhibited [³H]oxytocin (OT) binding to rat uterus (OT receptors) plasma membranes with a K_i value of 44.4 nM, and at 100 µM did not affect the binding of [³H]AVP to anterior pituitary (V_1B receptors) plasma membranes, which indicated that it had less affinity for these OT and V_1B receptors. YM087 had no effect on cytosolic free calcium concentration ([Ca⁺⁺]_i) itself, but suppressed AVP-induced increase in [Ca⁺⁺]_i of cultured vascular smooth muscle cells at the same concentrations as the binding affinities. Furthermore, YM087 potently blocked AVP-induced cAMP production of cultured renal epithelium cells concentration dependently and had no agonistic activities. In in vivo studies, intravenous administration of YM087 inhibited the pressor response to exogenous AVP in pithed rats and produced an aquaretic effect in dehydrated conscious rats in a dose-dependent manner. These results demonstrate that YM087 is a potent and nonpeptide dual AVP V_1A and V₂ receptors antagonist and can be used in future studies to help clarify the physiological and pathophysiological roles of AVP.