Selective inhibitory action of Biginelli-type dihydropyrimidines on depolarization-induced arterial smooth muscle contractionCernecka, H., Veizerova, L., Mensikova, L., Svetlik, J. & Krenek, P., May-2012, In : Journal of Pharmacy and Pharmacology. 64, 5, p. 735-741 7 p.
Research output: Contribution to journal › Article › Academic › peer-review
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.
|Number of pages||7|
|Journal||Journal of Pharmacy and Pharmacology|
|Publication status||Published - May-2012|
- Animals, Aorta, Calcium Channel Blockers, Calcium Channels, L-Type, Dihydropyridines, Male, Muscle Contraction, Muscle, Smooth, Vascular, Nifedipine, Norepinephrine, Potassium Chloride, Rats, Rats, Wistar, Vasoconstriction, Vasoconstrictor Agents