title: Characterization of a novel nonpeptide vasopressin V(2)-agonist, OPC-51803, in cells transfected human vasopressin receptor subtypes.
abstract: 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.
authors.affiliation: Second Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co. Ltd., 463-10, Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan. s_nakamura@research.otsuka.co.jp
authors.forename: S
authors.initials: S
authors.lastname: Nakamura
authors.forename: Y
authors.initials: Y
authors.lastname: Yamamura
authors.forename: S
authors.initials: S
authors.lastname: Itoh
authors.forename: T
authors.initials: T
authors.lastname: Hirano
authors.forename: K
authors.initials: K
authors.lastname: Tsujimae
authors.forename: M
authors.initials: M
authors.lastname: Aoyama
authors.forename: K
authors.initials: K
authors.lastname: Kondo
authors.forename: H
authors.initials: H
authors.lastname: Ogawa
authors.forename: T
authors.initials: T
authors.lastname: Shinohara
authors.forename: K
authors.initials: K
authors.lastname: Kan
authors.forename: Y
authors.initials: Y
authors.lastname: Tanada
authors.forename: S
authors.initials: S
authors.lastname: Teramoto
authors.forename: T
authors.initials: T
authors.lastname: Sumida
authors.forename: S
authors.initials: S
authors.lastname: Nakayama
authors.forename: K
authors.initials: K
authors.lastname: Sekiguchi
authors.forename: T
authors.initials: T
authors.lastname: Kambe
authors.forename: G
authors.initials: G
authors.lastname: Tsujimoto
authors.forename: T
authors.initials: T
authors.lastname: Mori
authors.forename: M
authors.initials: M
authors.lastname: Tominaga
mesh_terms: D001127:Arginine Vasopressin / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology*; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D006367:HeLa Cells; D006490:Hemostatics / Q000494:pharmacology; D006801:Humans; D011759:Pyrrolidines / Q000494:pharmacology*; D017483:Receptors, Vasopressin / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014667:Vasopressins / Q000378:metabolism
chemical_list: D001552:Benzazepines; D006490:Hemostatics; C409942:OPC 51803; D011759:Pyrrolidines; D017483:Receptors, Vasopressin; D014667:Vasopressins; D001127:Arginine Vasopressin; D000242:Cyclic AMP; D003894:Deamino Arginine Vasopressin; D002118:Calcium