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J Med Chem. 1994 Oct 28;37(22):3775-88.

Construction of a molecular shape analysis-three-dimensional quantitative structure-analysis relationship for an analog series of pyridobenzodiazepinone inhibitors of muscarinic 2 and 3 receptors.

Author information

1
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago 60612-7231.

Abstract

A generalized three-dimensional (3D) quantitative structure-property relationship (QSPR) formalism, based upon molecular shape analysis (MSA), has been applied to an analog series of pyridobenzodiazepinone inhibitors 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 (PLS) analysis permits the construction of the MSA-3D-QSARs. In addition to molecular shape, the identification of the properties of a lipophilic binding site and specific nonallowed steric receptor sites govern the MSA-3D-QSARs. The M2 and M3 QSARs suggest receptor subtype specificity might be realized by targeting upon a specific nonallowed steric receptor site. One conformation, common to both M2 and M3 receptors, emerges as dominant in the optimum MSA-3D-QSARs. However, other similar conformations are also found to yield meaningful MSA-3D-QSARs.

PMID:
7966137
DOI:
10.1021/jm00048a014
[Indexed for MEDLINE]

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