Crystal structure of the dihydropyridine calcium antagonist felodipine. Dihydropyridine binding prerequisites assessed from crystallographic data

Abstract

The molecular structure of the dihydropyridine Ca2+ antagonist felodipine (ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxy late) has been determined by X-ray crystallographic methods. The dihydropyridine ring in this potent smooth muscle relaxant is among the flattest found in such structures. This is in qualitative agreement with previous investigations of dihydropyridine Ca2+ antagonists; deviations from planarity in the dihydropyridine ring are generally smallest in the most active compounds. Hydrogen-bonding patterns observed in the crystal lattices of several dihydropyridine Ca2+ antagonists are compared. Antiperiplanar carbonyl groups are partly shielded from forming hydrogen bonds in compounds with relatively bulky ortho phenyl substituents. Conformational prerequisites for a favorable hydrogen-bonding geometry toward a receptor site may thus involve synperiplanar carbonyl groups.