Mahmoudian M, Mirkhani H, Nehardani Z, Ghiaee S
Department of Pharmacology, Iran University of Medical Sciences, Tehran.
J Pharm Pharmacol. 1997 Dec;49(12):1229-33. doi: 10.1111/j.2042-7158.1997.tb06075.x.
Dihydropyridine derivative calcium-channel blockers are widely used in the therapy of hypertension, angina pectoris and other cardiovascular diseases. Because the prototype of dihydropyridine derivatives, nifedipine, does not have the optimum pharmacokinetic and pharmacodynamic characteristics, attempts have been made to synthesize other drugs in this class with improved properties. The synthesis and biological activity of two new calcium-channel blockers, non-symmetrical (mebudipine) and symmetrical (dibudipine) analogues of nifedipine, is described herein. The pharmacological potencies of the compounds were evaluated by studying their effects on the contractions of isolated guinea-pig ileum and rat aortic rings. Results were compared with those obtained from nifedipine. The new analogues and nifedipine inhibited the contractile response of guinea-pig ileum to electrical stimulation and the pIC50 value of the compounds did not differ significantly from each other. The compounds also antagonized the contractile responses of K+-depolarized guinea-pig ileum to cumulative concentrations of calcium. The inhibitory effect of mebudipine was significantly higher than that of nifedipine whereas the inhibitory effects of dibudipine and nifedipine were not different. All three compounds relaxed KCl (40 mM)-treated isolated aortic rings; the pIC50 values for relaxation were: mebudipine > nifedipine > dibudipine. It is concluded that these new dihydropyridine derivatives are potent relaxants of vascular and ileal smooth muscles and therefore have high potential for use as antihypertensive and anti-anginal agents.
二氢吡啶衍生物钙通道阻滞剂广泛用于治疗高血压、心绞痛及其他心血管疾病。由于二氢吡啶衍生物的原型硝苯地平不具备最佳的药代动力学和药效学特性，因此人们尝试合成该类别的其他具有改善性质的药物。本文描述了两种新型钙通道阻滞剂，硝苯地平的非对称（美布地尔）和对称（地布地尔）类似物的合成及生物活性。通过研究这些化合物对豚鼠离体回肠和大鼠主动脉环收缩的影响来评估其药理活性。将结果与硝苯地平所得结果进行比较。新型类似物和硝苯地平均抑制豚鼠回肠对电刺激的收缩反应，且化合物的半数抑制浓度负对数（pIC50）值彼此无显著差异。这些化合物还拮抗钾离子去极化的豚鼠回肠对累积浓度钙的收缩反应。美布地尔的抑制作用显著高于硝苯地平，而地布地尔和硝苯地平的抑制作用无差异。所有三种化合物均使氯化钾（40 mM）处理的离体主动脉环舒张；舒张的pIC50值为：美布地尔>硝苯地平>地布地尔。结论是这些新型二氢吡啶衍生物是血管和回肠平滑肌的有效舒张剂，因此具有用作抗高血压和抗心绞痛药物的巨大潜力。
