RT Journal Article SR Electronic T1 Antidiuretic Effects of a Nonpeptide Vasopressin V2-Receptor Agonist, OPC-51803, Administered Orally to Rats JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 1005 OP 1011 VO 295 IS 3 A1 Shigeki Nakamura A1 Takahiro Hirano A1 Kenji Tsujimae A1 Masashi Aoyama A1 Kazumi Kondo A1 Yoshitaka Yamamura A1 Toyoki Mori A1 Michiaki Tominaga YR 2000 UL http://jpet.aspetjournals.org/content/295/3/1005.abstract AB 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 (Ki = 49.8 ± 8.1 nM) more greatly than that to V1a-receptors (Ki = 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. The American Society for Pharmacology and Experimental Therapeutics