Characterization of a novel nonpeptide vasopressin V(2)-agonist, OPC-51803, in cells transfected human vasopressin receptor subtypes.
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.
Nakamura
S
S
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
Yamamura
Y
Y
Itoh
S
S
Hirano
T
T
Tsujimae
K
K
Aoyama
M
M
Kondo
K
K
Ogawa
H
H
Shinohara
T
T
Kan
K
K
Tanada
Y
Y
Teramoto
S
S
Sumida
T
T
Nakayama
S
S
Sekiguchi
K
K
Kambe
T
T
Tsujimoto
G
G
Mori
T
T
Tominaga
M
M
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
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