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  • Title: Predictive quantitative structure-activity relationships (QSAR) analysis of beta 3-adrenergic ligands.
    Author: Blin N, Federici C, Koscielniak T, Strosberg AD.
    Journal: Drug Des Discov; 1995 Apr; 12(4):297-311. PubMed ID: 9040990.
    Abstract:
    A novel quantitative structure-activity relationships strategy was used to analyze seventeen beta-adrenergic ligands for which we had previously evaluated pharmacological properties in Chinese hamster ovary cells transfected with the human beta 1-, beta 2- or beta 3-adrenergic gene (Blin et al., 1993, Mol. Pharmacol., 44: 1094-1104). These ligands were classified into pharmacological activity categories in order to determine the extent to which molecular structural features may be involved in the selectivity of the interaction with the beta 3-AR, or to define molecular features and properties characteristic of a beta 3-AR high affinity ligand or of a potent beta 3-adrenergic agonist. Topological and physico-chemical molecular descriptors were obtained using a novel software combining calculations with multivariate statistical methods, such as principal component analysis and discriminant analysis. This study showed that beta 1/beta 2-antagonists beta 3-agonists could be differentiate from beta 1/beta 2/beta 3-agonists on the basis of their topological molecular descriptors weighted by partial atomic charge and lipophilicity logP values. Bulky lipophilic groups at the end of the alkylamine chain and an ethoxy function, extending the flexible portion of the molecule and modifying the electron density distribution, were requirements for selective agonism at the beta 3-site. Charge and logP weighted 2D-autocorrelation vectors were properties able to discriminate between classes of agonists in terms of their affinity, potency or intrinsic activity, thus emphasizing the part these molecular descriptors play in determining beta 3-adrenergic ligands. These results, in association with the powerful activity-prediction model evaluated in the test, provide a framework to rationalize the synthesis of new beta 3-AR specific compounds.
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