CONSTRUCTION OF A MOLECULAR SHAPE-ANALYSIS 3-DIMENSIONAL QUANTITATIVESTRUCTURE-ANALYSIS RELATIONSHIP FOR AN ANALOG SERIES OF PYRIDOBENZODIAZEPINONE INHIBITORS OF MUSCARINIC-2 AND MUSCARINIC-3 RECEPTORS

A generalized three-dimensional (3D) quantitative structure-property r elationship (QSPR) formalism, based upon molecular shape analysis (MSA ), has been applied to an analog series of pyridobenzodiazepinone inhi bitors of muscarinic 2 (M2) and 3 (M3) receptors. The fundamental goal of this application is to establish MSA-3D-QSARs (P = A = inhibition activity) that are based upon identifying the active conformations of these flexible analogs. The repetitive use of partial least squares (P LS) analysis permits the construction of the MSA-3D-QSARs. In addition to molecular shape, the identification of the properties of a lipophi lic binding site and specific nonallowed steric receptor sites govern the MSA-3D-QSARs. The M2 and M3 QSARs suggest receptor subtype specifi city might be realized by targeting upon a specific nonallowed steric receptor site. One conformation, common to both M2 and M3 receptors, e merges as dominant in the optimum MSA-3D-QSARs. However, other similar conformations are also found to yield meaningful MSA-3D-QSARs.