SEMIRIGID ANALOGS OF THE CALCIUM-ANTAGONIST VERAPAMIL - A MOLECULAR MODELING STUDY

In this work the rigid-analogue approach has been used to obtain infor mation on the active conformation(s) of the calcium antagonist verapam il. A series of semi-rigid analogues of verapamil were synthesized and their biological activities evaluated on guinea-pig heart and aorta. These molecules were analysed by means of molecular modelling techniqu es. On the basis of the pharmacological profile and conformational ana lysis of these compounds, two different models for negative inotropic and negative chronotropic activity are proposed. The two actions seem to be due to conformations of the molecules which differ in the orient ation of their phenylethylamino groups.