Biological response as a function of conformation,chirality, and electronic characteristics: A catecholamine study

The hypothesis is introduced, that nonrigid drug molecules interact with biological receptors in a well-defined but unknown conformation that need not belong to an energy minimum. A verification of this assumption has to include a match of conformation and chirality. Even the different action of pairs of nonrigid enantiomers allow one to recognize uniquely the important role of conformations because flexible molecules are partially able to avoid wrong attachment to the receptor. According to a simple model, a monotonic relation between biological activity and rotational barriers (and/or torque constants) can be expected and, by means of rank correlation analysis of adrenergic activities, has been found, too. In order to apply the latter method, particularities concerning quantitative structure–activity analyses of nonrigid and/or chiral molecules are worked out. We optimized conformations by means of analytically calculated first partials of the energy and a quasi-Newton method. Using a convenient numerical method, it was shown that coplanar conformations of catecholamines are generally unstable. Moreover, CNDO /2 proved to be a reliable method for conformational studies, in which rotations about conjugated bonds 1] are not considered.