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 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). 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.
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 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). 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.