Characterization of a novel nonpeptide vasopressin V2-agonist, OPC-51803, in cells transfected human vasopressin receptor subtypes
| Autor: | Michiaki Tominaga, Kazuo Sekiguchi, Nakayama Sunao, Hidenori Ogawa, Yoshihisa Tanada, Takumi Sumida, Shigeki Nakamura, Takahiro Hirano, Keizo Kan, Shuji Teramoto, Shuji Itoh, Kazumi Kondo, Yoshitaka Yamamura, Masashi Aoyama, Toshimi Kambe, Tsujimae Kenji, Gozoh Tsujimoto, Toyoki Mori, Shinohara Tomoichi |
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| Rok vydání: | 2000 |
| Předmět: |
Pharmacology
chemistry.chemical_classification Agonist medicine.medical_specialty Vasopressin biology medicine.drug_class Peptide Peptide hormone biology.organism_classification Adenosine Molecular biology HeLa stomatognathic diseases Endocrinology nervous system chemistry Internal medicine medicine Receptor hormones hormone substitutes and hormone antagonists Vasopressin receptor medicine.drug |
| Zdroj: | British Journal of Pharmacology. 129:1700-1706 |
| ISSN: | 0007-1188 |
| Popis: | We discovered the first nonpeptide arginine-vasopressin (AVP) V(2)-receptor agonist, OPC-51803. Pharmacological properties of OPC-51803 were elucidated using HeLa cells expressing human AVP receptor subtypes (V(2), V(1a) and V(1b)) and compared with those of 1-desamino-8-D-arginine vasopressin (dDAVP), a peptide V(2)-receptor agonist. OPC-51803 and dDAVP displaced [(3)H]-AVP binding to human V(2)- and V(1a)-receptors with K(i) values of 91.9+/-10.8 nM (n = 6) and 3.12+/-0.38 nM (n = 6) for V(2)-receptors, and 819+/-39 nM (n = 6) and 41.5+/-9.9 nM (n = 6) for V(1a)-receptors, indicating that OPC-51803 was about nine times more selective for V(2)-receptors, similar to the selectivity of dDAVP. OPC-51803 scarcely displaced [(3)H]-AVP binding to human V(1b)-receptors even at 10(-4) M, while dDAVP showed potent affinity to human V(1b)-receptors with the K(i) value of 13.7+/-3.2 nM (n = 4). OPC-51803 concentration-dependently increased cyclic adenosine 3', 5'-monophosphate (cyclic AMP) production in HeLa cells expressing human V(2)-receptors with an EC(50) value of 189+/-14 nM (n = 6). The concentration-response curve for cyclic AMP production induced by OPC-51803 was shifted to the right in the presence of a V(2)-antagonist, OPC-31260. At 10(-5) M, OPC-51803 did not increase the intracellular Ca(2+) concentration ([Ca(2+)](i)) in HeLa cells expressing human V(1a)-receptors. On the other hand, dDAVP increased [Ca(2+)](i) in HeLa cells expressing human V(1a)- and V(1b)-receptors in a concentration-dependent fashion. From these results, OPC-51803 has been confirmed to be the first nonpeptide agonist for human AVP V(2)-receptors without agonistic activities for V(1a)- and V(1b)-receptors. OPC-51803 may be useful for the treatment of AVP-deficient pathophysiological states and as a tool for AVP researches. |
| Databáze: | OpenAIRE |
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