Comparative QSAR studies on vasodilatory and negative inotropic properties of ring-varied verapamil congeners

In the present study quantitative structure-activity relationships (QSAR) for the vasodilator properties of verapamil have been derived: Potency of ring-varied verapamil congeners on the phasic and tonic component of K+-contractures has been measured in aortic rings of the cat. Potency of verapamil derivatives on the phasic component significantly correlates with lipophilic properties of the compounds. Inhibition of the tonic component best correlates with a parameter combination of steric and electronic properties (MV, sigma). These results contrast with investigations with dihydropyridine derivatives where identical SAR have been found for both response components. Furthermore, SAR analyses yield disparate results in comparison to investigations in heart muscle where primarily electronic and secondarily steric parameters best explain the potency of verapamil derivatives. The postulate of chemically differing binding sites for verapamil congeners in heart and smooth muscle is substantiated by calculating binding energies to the hypothetical binding site arginine. While negative inotropic potency of verapamil derivatives significantly correlates with binding energy to the model binding site arginine, this correlation fails in case of aortic ring. These results obtained for verapamil congeners contrast with observations with dihydropyridine derivatives where the chemistry of binding sites in heart and smooth muscle seems to be identical.