Theoretical calculations on calcium channel drugs: Is electron transfer involved mechanistically?

Theoretical studies were done on calcium channel drugs in order to gain insight into the mode of action. Empirical force field calculations with nifedipine, a calcium channel antagonist, indicate that the E-conformation at the ring juncture is lower in energy than the Z-conformation. This energy difference is only 0.2 kcal/mol when the esters in the 3- and 5-positions of the dihydropyridine (DHP) ring are both synperiplanar (sp, sp). Molecular orbital calculations on the ground and excited states in the Z-conformation with the esters in the (ap, sp) conformation show a low lying excited state with substantial intramolecular electron transfer (ET) character. This excited state is only 1.8 eV higher in energy than the ground state and corresponds to a transfer of approximately 0.3 electron from the DHP ring to the nitrobenzene moiety. We suggest that ET may play an important role in the mechanism of action, either intramolecular or, as previously proposed, intermolecular, along with lipophilicity and steric effects.