Vol. 295, Issue 3, 1005-1011, December 2000

Antidiuretic Effects of a Nonpeptide Vasopressin V₂-Receptor Agonist, OPC-51803, Administered Orally to Rats

Shigeki Nakamura, Takahiro Hirano, Kenji Tsujimae, Masashi Aoyama, Kazumi Kondo, Yoshitaka Yamamura, Toyoki Mori and Michiaki Tominaga

Second Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co. Ltd., Kagasuno Kawauchi-cho, Tokushima, Japan

OPC-51803 is the first nonpeptide vasopressin (AVP) V₂-receptor-selective agonist. Its pharmacological profile, including antidiuretic action and receptor binding, was characterized using conscious Brattleboro rats with hereditary diabetes insipidus and Sprague-Dawley rats. In membrane preparations from the liver and kidney, OPC-51803 displaced the [³H]AVP binding to V₂-receptors (K_i = 49.8 ± 8.1 nM) more greatly than that to V_1a-receptors (K_i = 1061 ± 60 nM), showing a 21 times higher affinity for V₂-receptors. At single oral doses of 0.003 to 0.3 mg/kg in female Brattleboro rats, OPC-51803 decreased urine volume (from 10.8 ± 1.1 to 0.5 ± 0.2 ml during 0-2 h postdosing) and increased urinary osmolality (from 114 ± 9 to 432 ± 114 mOsm/kg) in a dose-dependent manner. During the period of 4-week treatment with OPC-51803, significant and constant antidiuresis was observed. In male Sprague-Dawley rats with normal plasma AVP levels, OPC-51803 at 0.03 to 0.3 mg/kg also produced a dose-dependent antidiuretic action (urine volume: from 2.6 ± 0.6 to 1.1 ± 0.2 ml at 0-4 h postdosing). Few changes in urinary parameters, serum parameters, or plasma hormone levels were observed. OPC-51803 did not change blood pressure or heart rate, or inhibit AVP-induced pressor response even at 30 mg/kg p.o. These results demonstrate that OPC-51803 is a V₂-selective agonist that produces a significant antidiuretic action after single and multiple oral dosing in AVP-deficient and normal AVP states. The data suggest that OPC-51803 is a useful therapeutic drug in the treatment of hypothalamic diabetes insipidus, nocturnal enuresis, and some kinds of urinary incontinence.