3-DIMENSIONAL MOLECULAR SHAPE ANALYSIS-QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP OF A SERIES OF CHOLECYSTOKININ-A RECEPTOR ANTAGONISTS

The three-dimensional molecular shape analysis-quantitative structure- activity relationship (3D-MSA-QSAR) technique has been applied to deve lop correlations between the calculated physicochemical properties and the in vitro activities of a series of 3-(acylamino)-5-phenyl-2H-1,4- benzodiaxepine cholecystokinin-A (CCK-A) antagonists. 3D-MSA-QSARs wer e developed for varying subsets of 53 analogs (J. Med. Chem. 1988, 31, 2235-2246). An active conformation is hypothesized for these compound s using the loss in biological activity-loss in conformational stabili ty principle. After placing all compounds in the active conformation a nd performing pairwise molecular shape analysis, it was determined tha t not any one analog serves as the best shape reference compound. Noni dentical volumes of allowed receptor space are mapped out by different antagonists. A shape reference compound that consists of selected ove rlapped structures expands the definition of the accessible receptor s pace. This type of mutant improves the predicted activity of analogs o ver the value predicted if only one compound is chosen as the referenc e. Molecular shape, as represented by common overlap steric volume and nonoverlap steric volume, is the major factor contributing to the aff inity of this class of compounds. Intramolecular conformational stabil ity, as measured by the difference in energy of the active conformatio n and the global minimum energy conformation, is also important. It is further concluded from the 3D-MSA-QSAR models that part of the bindin g pocket for the 3-amido substituent has a preference for lipophilicit y. The method used in this study of fragmenting the antagonist into sp heres of varying radii and measuring lipophilicity isolates the substr ucture with highest probability of interacting with the receptor. Two indicator variables marking the presence of an N-methyl group and an o -fluoro atom on the 5'-phenyl substituent of the benzodiazepine ring s tructure also contribute significantly to the 3D-MSA-QSAR models. The 3D-MSA-QSAR results have led to the proposal of a 3D pharmacophore mod el for the benzodiazepine CCK-A antagonists.