ISSN:
1432-1912
Keywords:
Key words Vasopressin
;
Vasopressin V1A receptor
;
Vasopressin V2 receptor
;
Nonpeptide antagonist
;
Second messenger systems
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract The effects of YM087 (4’-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)-carbonyl]-2-phenylbenzanilide monohydrochloride), a novel nonpeptide vasopressin (AVP) receptor antagonist, on [3H]AVP binding to human AVP receptors (V1A, V1B and V2) cloned and transiently expressed in COS-1 cells generated from monkey renal tissue were studied. Scatchard analysis of saturation isotherms for the specific binding of [3H]AVP to membranes, prepared from COS-1 cells transfected with human V1A, V1B and V2 receptors, yielded an apparent equilibrium dissociation constant (K d) of 0.67nM, 0.28nM and 2.14nM and a maximum receptor density (B max) of 2180fmol/mg protein, 369fmol/mg protein and 2660fmol/mg protein, respectively. YM087 showed high affinity for AVP V1A and V2 receptors with K i values of 6.3 and 1.1nM, respectively, but had no effect on [3H]AVP binding to AVP V1B receptors. In COS-1 cells expressing either AVP V1A or V1B receptors, AVP caused a concentration-dependent increase in intracellular Ca2+ concentration ([Ca2+]i). YM087 inhibited the AVP-induced increase in [Ca2+]i in COS-1 cells expressing AVP V1A receptors in a concentration-dependent manner with an IC50 value of 14.3nM, but did not influence this increase in AVP V1B-receptor expressing cells. In contrast, stimulation of COS-1 cells expressing AVP V2 receptors resulted in an accumulation of cAMP. YM087 inhibited AVP-induced cAMP production in COS-1 cells expressing AVP V2 receptors in a concentration-dependent manner with an IC50 value of 1.95nM. In all assays used, YM087 was devoid of any agonistic activity. These results suggest that YM087 is a potent nonpeptide dual human AVP V1A and V2 receptor antagonist, and that YM087 will be a powerful tool in investigation of the physiological and pathophysiological roles of AVP.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/PL00005139
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