title: Antidiuretic effects of a novel nonpeptide vasopressin V(2)-receptor agonist, OPC-51803, administered orally to dogs.
abstract: We elucidated the pharmacological properties of a novel nonpeptide vasopressin V(2)-receptor agonist, OPC-51803 ((5R)-2-[1-(2-chloro-4-(1-pyrrolidinyl)benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]-N-isopropylacetamide), via both in vitro binding experiments incorporating canine kidney and platelet membrane fractions and in vivo experiments that would determine the compound's antidiuretic effects after oral administration to water-loaded dogs. OPC-51803 displaced [(3)H]arginine vasopressin (AVP) binding to canine V(2) and V(1a) receptors, as determined by resulting K(i) values of 15.2 +/- 0.6 nM (n = 4) and 653 +/- 146 nM (n = 4), respectively. These data indicate that OPC-51803 was about 43 times more selective for V(2) receptors than for V(1a) receptors. Antidiuretic studies showed that orally administered doses of OPC-51803 (0.03 to 0.3 mg x kg(-1)) decreased urine volume and increased urinary osmolality in a dose-dependent manner in water-loaded dogs. Intravenous OPC-51803 infusions (0.3 and 3 microg x kg(-1) x min(-1)) did not affect renal or systemic hemodynamics in anesthetized dogs. Since these results confirm that OPC-51803 shows antidiuretic action in dogs, the compound may be useful for treating AVP-deficient pathophysiological states.
authors.affiliation: First Institute of New Drug Research, Otsuka Pharmaceutical Co, Ltd, Tokushima, Japan. s_nakamura@research.otsuka.co.jp
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nakamura
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hirano
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Onogawa
authors.forename: Shuji
authors.initials: S
authors.lastname: Itoh
authors.forename: Ayako
authors.initials: A
authors.lastname: Hashimoto
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Yamamura
authors.forename: Kazumi
authors.initials: K
authors.lastname: Kondo
authors.forename: Toyoki
authors.initials: T
authors.lastname: Mori
authors.forename: Toshimi
authors.initials: T
authors.lastname: Kambe
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage* / Q000494:pharmacology*; D001667:Binding, Competitive; D001792:Blood Platelets / Q000166:cytology; D002462:Cell Membrane / Q000378:metabolism; D004231:Diuresis / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D007679:Kidney Medulla / Q000166:cytology; D008297:Male; D009994:Osmolar Concentration; D011759:Pyrrolidines / Q000008:administration & dosage* / Q000494:pharmacology*; D011869:Radioligand Assay; D017483:Receptors, Vasopressin / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D001552:Benzazepines; C409942:OPC 51803; D011759:Pyrrolidines; D017483:Receptors, Vasopressin