Characterization of a novel nonpeptide vasopressin V2‐agonist, OPC‐51803, in cells transfected human vasopressin receptor subtypes

Medientyp: E-Artikel
Titel: Characterization of a novel nonpeptide vasopressin V2‐agonist, OPC‐51803, in cells transfected human vasopressin receptor subtypes
Beteiligte: Nakamura, Shigeki; Yamamura, Yoshitaka; Itoh, Shuji; Hirano, Takahiro; Tsujimae, Kenji; Aoyama, Masashi; Kondo, Kazumi; Ogawa, Hidenori; Shinohara, Tomoichi; Kan, Keizo; Tanada, Yoshihisa; Teramoto, Shuji; Sumida, Takumi; Nakayama, Sunao; Sekiguchi, Kazuo; Kambe, Toshimi; Tsujimoto, Gozoh; Mori, Toyoki; Tominaga, Michiaki
Erschienen: Wiley, 2000
Erschienen in: British Journal of Pharmacology
Sprache: Englisch
DOI: 10.1038/sj.bjp.0703221
ISSN: 0007-1188; 1476-5381
Schlagwörter: Pharmacology
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Beschreibung: <jats:p> <jats:list list-type="explicit-label"> <jats:list-item><jats:p>We discovered the first nonpeptide arginine‐vasopressin (AVP) V<jats:sub>2</jats:sub>‐receptor agonist, OPC‐51803. Pharmacological properties of OPC‐51803 were elucidated using HeLa cells expressing human AVP receptor subtypes (V<jats:sub>2</jats:sub>, V<jats:sub>1a</jats:sub> and V<jats:sub>1b</jats:sub>) and compared with those of 1‐desamino‐8‐<jats:sc>D</jats:sc>‐arginine vasopressin (dDAVP), a peptide V<jats:sub>2</jats:sub>‐receptor agonist.</jats:p></jats:list-item> <jats:list-item><jats:p>OPC‐51803 and dDAVP displaced [<jats:sup>3</jats:sup>H]‐AVP binding to human V<jats:sub>2</jats:sub>‐ and V<jats:sub>1a</jats:sub>‐receptors with <jats:italic>K</jats:italic><jats:sub><jats:italic>i</jats:italic></jats:sub> values of 91.9±10.8 n<jats:sc>M</jats:sc> (<jats:italic>n</jats:italic>=6) and 3.12±0.38 n<jats:sc>M</jats:sc> (<jats:italic>n</jats:italic>=6) for V<jats:sub>2</jats:sub>‐receptors, and 819±39 n<jats:sc>M</jats:sc> (<jats:italic>n</jats:italic>=6) and 41.5±9.9 n<jats:sc>M</jats:sc> (<jats:italic>n</jats:italic>=6) for V<jats:sub>1a</jats:sub>‐receptors, indicating that OPC‐51803 was about nine times more selective for V<jats:sub>2</jats:sub>‐receptors, similar to the selectivity of dDAVP. OPC‐51803 scarcely displaced [<jats:sup>3</jats:sup>H]‐AVP binding to human V<jats:sub>1b</jats:sub>‐receptors even at 10<jats:sup>−4</jats:sup> <jats:sc>M</jats:sc>, while dDAVP showed potent affinity to human V<jats:sub>1b</jats:sub>‐receptors with the <jats:italic>K</jats:italic><jats:sub><jats:italic>i</jats:italic></jats:sub> value of 13.7±3.2 n<jats:sc>M</jats:sc> (<jats:italic>n</jats:italic>=4).</jats:p></jats:list-item> <jats:list-item><jats:p>OPC‐51803 concentration‐dependently increased cyclic adenosine 3′, 5′‐monophosphate (cyclic AMP) production in HeLa cells expressing human V<jats:sub>2</jats:sub>‐receptors with an EC<jats:sub>50</jats:sub> value of 189±14 n<jats:sc>M</jats:sc> (<jats:italic>n</jats:italic>=6). The concentration‐response curve for cyclic AMP production induced by OPC‐51803 was shifted to the right in the presence of a V<jats:sub>2</jats:sub>‐antagonist, OPC‐31260.</jats:p></jats:list-item> <jats:list-item><jats:p>At 10<jats:sup>−5</jats:sup> <jats:sc>M</jats:sc>, OPC‐51803 did not increase the intracellular Ca<jats:sup>2+</jats:sup> concentration ([Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub>) in HeLa cells expressing human V<jats:sub>1a</jats:sub>‐receptors. On the other hand, dDAVP increased [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> in HeLa cells expressing human V<jats:sub>1a</jats:sub>‐ and V<jats:sub>1b</jats:sub>‐receptors in a concentration‐dependent fashion.</jats:p></jats:list-item> <jats:list-item><jats:p>From these results, OPC‐51803 has been confirmed to be the first nonpeptide agonist for human AVP V<jats:sub>2</jats:sub>‐receptors without agonistic activities for V<jats:sub>1a</jats:sub>‐ and V<jats:sub>1b</jats:sub>‐receptors. OPC‐51803 may be useful for the treatment of AVP‐deficient pathophysiological states and as a tool for AVP researches.</jats:p></jats:list-item> </jats:list> </jats:p><jats:p><jats:italic>British Journal of Pharmacology</jats:italic> (2000) <jats:bold>129</jats:bold>, 1700–1706; doi:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.1038/sj.bjp.0703221">10.1038/sj.bjp.0703221</jats:ext-link></jats:p>
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