3D-QSAR studies of 2,2-diphenylpropionates to aid discovery of novel potent muscarinic antagonists

Muscarinic acetylcholine receptors (mAChRs) consisting of five known subtypes, are widely distributed in both central and peripheral nervous systems for regulation of a variety of critical functions. The present theoretical study describes correlations between experimental and calculated molecular properties of 15 alpha-substituted 2,2-diphenylpropionate antimuscarinics using quantum chemical and pharmacophore generation methods to characterize the drug mAChR properties and design new therapeutics. The calculated stereoelectronic properties, such as total energies, bond distances, valence angles, torsion angles, HOMO-LUMO energies, reactivity indices, vibrational frequencies of ether and carbonyl moieties, and nitrogen atom proton affinity were found to be well correlated when compared with experimentally determined inhibition constants from the literature using three muscarinic receptor assays: [H-3]NMS receptor binding, alpha-amylase release from rat pancreas, and guinea pig ileum contraction. In silico predicted toxicity on rat oral LD50 values correlated well with the [H-3] NMS binding in N4TG1 cells and alpha-amylase release assays, but not the ileum contraction assay. Next, to explore the functional requirements for potent activity of the compounds, we developed a preliminary 3D pharmacophore model using the in silico techniques. The resulting model contained a hydrogen bond acceptor site on the carbonyl oxygen atom and a ring aromatic feature on one of the two aromatic rings in these compounds. This model was used as a template to search an in-house database for novel analogs. We found compounds equal in inhibition potency to atropine and, importantly, six not reported before as antimuscarinics. These results demonstrate that this QSAR approach not only provides a basis for understanding the molecular mechanism of action but a pharmacophore to aid in the discovery and design of novel potent muscarinic antagonists. (C) 2009 Elsevier Ltd. All rights reserved.