Antidiuretic effects of a novel nonpeptide vasopressin V(2)-receptor agonist, OPC-51803, administered orally to dogs
| Autor: | Toyoki Mori, Shigeki Nakamura, Kazumi Kondo, Ayako Hashimoto, Shuji Itoh, Yoshitaka Yamamura, Takahiro Hirano, Toshiyuki Onogawa, Toshimi Kambe |
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| Rok vydání: | 2004 |
| Předmět: |
Agonist
Blood Platelets Male medicine.medical_specialty Vasopressin Receptors Vasopressin Pyrrolidines Arginine medicine.drug_class Administration Oral Pharmacology Binding Competitive Radioligand Assay Dogs In vivo Oral administration Internal medicine Arginine vasopressin receptor 2 medicine Animals Receptor Kidney Medulla Dose-Response Relationship Drug Chemistry lcsh:RM1-950 Cell Membrane Osmolar Concentration Benzazepines Diuresis stomatognathic diseases Endocrinology lcsh:Therapeutics. Pharmacology nervous system Molecular Medicine Antidiuretic |
| Zdroj: | Journal of Pharmacological Sciences, Vol 94, Iss 4, Pp 426-433 (2004) |
| ISSN: | 1347-8613 |
| Popis: | We elucidated the pharmacological properties of a novel nonpeptide vasopressin V2-receptor agonist, OPC-51803 ((5R)-2-[1-(2-chloro-4-(1-pyrrolidinyl)benzoyl-2,3,4,5-tetra-hydro-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 [3H]arginine vasopressin (AVP) binding to canine V2 and V1a receptors, as determined by resulting Ki 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 V2 receptors than for V1a receptors. Antidiuretic studies showed that orally administered doses of OPC-51803 (0.03 to 0.3 mg · 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 μg · kg−1 · 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. Keywords:: OPC-51803, nonpeptide, V2 agonist, antidiuresis |
| Databáze: | OpenAIRE |
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