Pharmacological characterization of YM087, a potent, nonpeptide human vasopressin V1A and V2 receptor antagonist

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 (Kd) of 0.67 nM, 0.28 nM and 2.14 nM and a maximum receptor density (Bmax) of 2180 fmol/mg protein, 369 fmol/mg protein and 2660 fmol/mg protein, respectively. YM087 showed high affinity for AVP V1A and V2 receptors with Ki values of 6.3 and 1.1 nM, 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 14.3 nM, 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 1.95 nM. 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.

Paraneoplastic Syndromes: An Approach to Diagnosis and Treatment

“…which is administered intravenously; in 2009, tolvaptan, an oral agent, was approved. 21,22 It is important to note that much of the clinical experience with these agents comes from use in patients with more common causes of hyponatremia, such as chronic heart failure. 7 Adverse effects of conivaptan include infusion site reactions, nausea and vomiting, and diarrhea.…”

An l -RNA-based aquaretic agent that inhibits vasopressin in vivo

“…With respect to the low dissociation constant, NOX-F37 might be even more effective in inhibiting AVP signaling via the V 1a receptor than the receptor antagonist conivaptan. For conivaptan, a K i of 6.3 nM has been reported (44). Moreover, the IC 50 value in a cell culture assay is higher for conivaptan (44) than for NOX-F37 (14.3 nM vs. 6.1 nM), which is further strengthened by the fact that the IC 50 of NOX-F37 was determined in an Ϸ4-fold less-sensitive cell assay (EC 50 Ϸ 5 nM) compared with conivaptan (EC 50 Ϸ 1.3 nM; ref.…”

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“…Each is a potent antagonist of the targeted receptors as demonstrated in binding assays and in the expected physiologic responses observed in animal studies. [21][22][23][24][25][26][27] Any of the agents possessing V 2 receptor antagonist activity would be expected to be useful in treating the hyponatremia of CHF.…”