Inhibition of rabbit aortic angiotensin II (AII) receptor by CV-11974, a new nonpeptide AII antagonist
The angiotensin II (AII) antagonistic action of CV-11974 (2-ethoxy-1-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid) was investigated in an AII-receptor binding assay using rabbit aortic membranes and an AII-induced contraction assay using rabbit aortic strips. A s...
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Published in | Biochemical pharmacology Vol. 46; no. 2; pp. 311 - 318 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York, NY
Elsevier Inc
20.07.1993
Elsevier Science |
Subjects | |
Online Access | Get full text |
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Summary: | The angiotensin II (AII) antagonistic action of CV-11974 (2-ethoxy-1-[[2'-(1
H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid) was investigated in an AII-receptor binding assay using rabbit aortic membranes and an AII-induced contraction assay using rabbit aortic strips. A single class of [
125I]AII-(Sar
1,Ile
8) binding sites was found in the membranes with a dissociation constant (
K
d
) of 0.15 nM and a receptor concentration (
B
max) of 86.9 fmol/mg protein. CV-11974 markedly reduced
K
d
without affecting
B
max. The specific binding of [
125I]AII-(Sar
1,Ile
8) in this preparation was inhibited competely by CV-11974 [the inhibition constant (
K
i
) = 0.64 nM], DuP 753 [an angiotensin II type I (at
1) receptor-selective antagonist] (
K
i
= 51 nM) and EXP3174 (an active metabolite of DuP 753) (
K
i
= 6.8 nM), but was not affected by PD123177 (an AT
2 receptor-selective antagonist). These results suggest that the single binding site in rabbit aortic membranes is an AT
1 receptor subtype. The affinity of CV-11974 to these AT
1 receptors was approximately 80 and 10 times higher than that of DuP 753 and EXP3174, respectively. CV-11974 showed no appreciable affinity for the AT
2 receptors found in bovine cerebellum. In the
in vitro functional study, CV-11974 markedly reduced the AII-induced maximal contractile response of rabbit aortic strips (pD'
2 = 9.97). In contrast. Compound 7-H, which lacks the carboxyl group at the benzimidazole ring of CV-11974, inhibited the contraction in a competitive manner. The inhibition by CV-11974 was long lasting. These results suggest that CV-11974 is a potent and long-acting AT
1 receptor-selective, competitive antagonist. The carboxyl group at the benzimidazole ring plays an important role in the interaction between CV-11974 and the AT
1 receptor. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0006-2952 1873-2968 |
DOI: | 10.1016/0006-2952(93)90420-2 |