Selective inhibitory action of Biginelli-type dihydropyrimidines on depolarization-induced arterial smooth muscle contraction

Abstract

Abstract Objectives 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. Methods 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. Key findings 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 Emax), indicating a more selective action on L-type calcium channel than nifedipine with 75% inhibition of noradrenaline Emax at 10−4m nifedipine). Conclusions 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.