Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia.
J Pharm Pharmacol. 2012 May;64(5):735-41. doi: 10.1111/j.2042-7158.2012.01466.x. Epub 2012 Feb 8.
Dihydropyridine calcium channel blockers have some disadvantages such as light sensitivity and relatively short plasma half-lives. Stability of dihydropyrimidines analogues could be of advantage, yet they remain less well characterized. We aimed to test four newly synthesized Biginelli-type dihydropyrimidines for their calcium channel blocking activity on rat isolated aorta.
Dihydropyrimidines (compounds A-D) were prepared by the Biginelli-like three-component condensation of benzaldehydes with urea/thiourea and dimethyl or diethyl acetone-1,3-dicarboxylate, and their physicochemical properties and effects on depolarization-induced and noradrenaline-induced contractions of rat isolated aorta were evaluated.
Dihydropyrimidines A and C blocked KCl-induced contraction only weakly (-log(IC50)=5.03 and 3.73, respectively), while dihydropyrimidine D (-log(IC50)=7.03) was almost as potent as nifedipine (-log(IC50)=8.14). Washout experiments revealed that dihydropyrimidine D may bind strongly to the L-type calcium channel or remains bound to membrane. All tested dihydropyrimidines only marginally inhibited noradrenaline-induced contractions of rat isolated aorta (20% reduction of noradrenaline E(max) ), indicating a more selective action on L-type calcium channel than nifedipine with 75% inhibition of noradrenaline E(max) at 10(-4) m nifedipine).
Compounds A and, particularly, D are potent calcium channel blockers in vitro, with a better selectivity in inhibiting depolarization-induced arterial smooth muscle contraction than nifedipine.
二氢吡啶类钙通道阻滞剂具有一些缺点，如对光敏感和相对较短的血浆半衰期。二氢嘧啶类似物的稳定性可能具有优势，但它们的特征仍不明确。我们旨在测试四种新合成的比格利尼型二氢嘧啶类化合物对大鼠离体主动脉的钙通道阻断活性。
通过苯甲醛与脲/硫脲和二甲基或二乙基 1,3-二羧酸二甲酯的比格利尼型三组分缩合反应制备二氢嘧啶（化合物 A-D），并评估它们的物理化学性质以及对大鼠离体主动脉去极化诱导和去甲肾上腺素诱导收缩的影响。
二氢嘧啶 A 和 C 仅弱抑制 KCl 诱导的收缩（-log(IC50)=5.03 和 3.73，分别），而二氢嘧啶 D（-log(IC50)=7.03）与硝苯地平（-log(IC50)=8.14）一样有效。洗脱实验表明，二氢嘧啶 D 可能与 L 型钙通道强烈结合或仍与膜结合。所有测试的二氢嘧啶类化合物仅轻度抑制大鼠离体主动脉去甲肾上腺素诱导的收缩（去甲肾上腺素 E(max)减少 20%），表明其对 L 型钙通道的选择性更强，而硝苯地平在 10(-4) m 硝苯地平下抑制去甲肾上腺素 E(max)的作用为 75%）。
化合物 A 特别是 D 是体外强效的钙通道阻滞剂，对抑制去极化诱导的动脉平滑肌收缩的选择性优于硝苯地平。
