Three-dimensional quantitative structure-activity relationships of mazindol analogues at the dopamine transporter

A three-dimensional quantitative structure−activity relationship (3D-QSAR) study was performed on a series of mazindol analogues using the comparative molecular field analysis (CoMFA) method with their corresponding binding affinities for the displacement of [3H]WIN 35 428 from rat caudate putamen tissue. The cross-validated CoMFA models were derived from a training set of 50 compounds, and the predictive ability of the resulting CoMFA models was evaluated against a test set of 21 compounds. A set of alignment rules was derived to superimpose these compounds onto a template structure, mazindol (1). These CoMFA models yielded significant cross-validated r2cv values. Inclusion of additional descriptors did not improve the significance of the CoMFA models; thus, steric and electrostatic fields are the relevant descriptors for these compounds. The best QSAR model was selected on the basis of the predictive ability of the activity on the external test set of compounds. The analysis of coefficient contour maps ...