Comparative Molecular Field Analysis on a Set of Muscarinic Agonists

A three-dimensional quantitative structure-activity relationship (3D-QSAR) was carried out on a set of 39 non-congeneric muscarinic agonists using Comparative Molecular Field Analysis (CoMFA). The compounds were tested on the M3 receptor subtype. However, since most of these ligands are reported as unspecific muscarinic agents, the proposed pharmacophore model accounts for features common to all the receptor populations (M1, M2 and M3). In order to define an alignment rule for the superimposition of the ligands, a common pharmacophore frame was derived with a preliminary conformational search performed on four typical muscarinic agonists. Both the steric and the electrostatic fields were used in CoMFA as molecular descriptors and were found relevant with almost the same statistical weight. The CoMFA coefficient contour maps revealed consistency with our postulated mechanism of interaction. Several 3D-QSARs were derived by means of the Partial Least Squares (PLS) method choosing the proper dimensionality with a cross-validation procedure.