Nonpeptide Angiotensin II Receptor Antagonists. IV. EXP6155 and EXP6803
Nonpeptide Angiotensin II Receptor Antagonists. IV. EXP6155 and EXP6803
复制标题
非肽血管紧张素 II 受体拮抗剂。
作者：
P. Wong;W. Price;A. Chiu;M. Thoolen;J. Duncia;A. L. Johnson;P. Timmermans
EXP 6155（2-正丁基-1-[4-羧基苄基]-4-氯咪唑-5-乙酸）和EXP 6803（2-正丁基-1-[4-（2-羧基苯甲酰氨基）苯]-4-氯咪唑-5-乙酸甲酯，钠盐）被证明是新型、非肽类、抗高血压、特异性血管紧张素II受体拮抗剂。在兔主动脉中，它们竞争性抑制对血管紧张素II的收缩反应，pA 2值为6.54和7.20，并且不改变对去甲肾上腺素或KCl的反应。在豚鼠回肠，这两种药物阻断血管紧张素I和II的反应，并没有改变缓激肽和乙酰胆碱的反应。在脊髓切除大鼠模型中，体内显示了类似的特异性血管紧张素II拮抗作用。在肾动脉结扎大鼠中，高肾素高血压模型（静脉给予EXP 6155和EXP 6803）可降低血压，ED 30分别为10和11 mg/kg。当以100 mg/ kg经口给药时，两种化合物均未改变血压。与saralasin不同，静脉给予EXP 6155和EXP 6803不会引起肾动脉结扎和非血压大鼠的血压一过性升高。我们的研究结果表明，EXP 6155和EXP 6803是选择性血管紧张素II受体拮抗剂和抗高血压药物。由于这两种化合物都没有部分激动剂活性或缓激肽增强作用，分别不同于现有的肽类血管紧张素II受体拮抗剂和血管紧张素转化酶抑制剂，它们可能代表用于研究血管紧张素II的生理作用的优选探针。
EXP6155 (2-n-butyl-l-[4-carboxybenzyl]-4-chloroimidazole-5-acetic acid) and EXP6803 (methyl 2-n-butyl-l-[4-(2-carfooxybenzamido)ben2yl]-4-chloroimidazole-5-acetate, sodium salt) are shown to be novel, nonpeptide, antihypertensive, specific angiotensin II receptor antagonists. In rabbit aorta, they competitively inhibited the contractile response to angiotensin II with pA2 values of 6.54 and 7.20 and did not alter the response to norepinephrine or KC1. In guinea pig ileum, both agents blocked the responses to angiotensin I and II and did not alter the responses to bradykinin and acetylcholine. A similar specific angiotensin II antagonism was shown in vivo in the spinal pithed rat model. In renal artery-ligated rats, a high renin hypertensive model, EXP6155 and EXP6803 given intravenously, decreased blood pressure with ED30 of 10 and 11 mg/kg, respectively. Both compounds did not alter blood pressure when given orally at 100 mg/ kg. Unlike saralasin, EXP6155 and EXP6803 given intravenously did not cause a transient increase in blood pressure in the renal artery-ligated and nonnotensive rats. Our results indicate that EXP6155 and EXP6803 are selective angiotensin II receptor antagonists and antihypertensive agents. Since neither compound had partial agonist activities or bradykinin potentiation effects, unlike the existing peptide angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, respectively, they may represent preferred probes for studying the physiological roles of angiotensin II.