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KMID : 0613820100200060831
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Journal of Life Science
2010 Volume.20 No. 6 p.831 ~ p.837
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Pharmacological Characterization of KR-31125, a Novel Nonpeptide AT1 Receptor Antagonist
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Lee Sung-Hou
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Abstract
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KR-31125 (2-butyl-5-dimethoxymethyl-6-phenyl-7-methyl-3-[[2"-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-3H-imidazo[4,5-b]pyridine) is a potent inhibitor of angiotensin II type 1 (AT₁) receptors in human recombinant AT₁ receptors and rabbit aorta. These in vitro studies revealed that KR-31125 inhibited specific [125I] [Sar¹, Ile?]-angiotensin II binding to human recombinant AT₁ receptors in a concentration dependent manner with an IC50 value of 19.72±2.65 nM. However, no interaction with AT₂ receptors was detected as displayed by the competition binding of [125I] CGP 42112A to human recombinant AT₂ receptor. The binding action was also confirmed as a competitive mode that was identical to the previously studied compound, losartan. In addition, KR-31125 caused a nonparallel shift to the right in the concentration response curves to angiotensin II with a 30-80% decrease in the maximum contractile responses (pKB: 7.63). Compared to the previous studies with losartan that showed a parallel right shift in the maximum contractile responses to AII (pA₂: 7.59), KR-31125 presented a different mode of action with a similar potency to losartan. These results demonstrate that KR-31125 is a highly potent and AT₁ selective angiotensin II receptor antagonist that can be applied to the fields of new diagnostic and research tools with upcoming in vivo study results.
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KEYWORD
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KR-31125, antihypertension, angiotensin, AT₁ receptor antagonist, diagnostics
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