Title: Discovery of benzamide analogs as negative allosteric modulators of human neuronal nicotinic receptors: pharmacophore modeling and structure-activity relationship studies Yi B, Long S, Gonzalez-Cestari TF, Henderson BJ, Pavlovicz RE, Werbovetz K, Li C, McKay DB Ref: Bioorganic & Medicinal Chemistry, 21:4730, 2013 : PubMed
The present study describes our ongoing efforts toward the discovery of drugs that selectively target nAChR subtypes. We exploited knowledge on nAChR ligands and their binding site that were previously identified by our laboratory through virtual screenings and identified benzamide analogs as a novel chemical class of neuronal nicotinic receptor (nAChR) ligands. The lead molecule, compound 1 (4-(allyloxy)-N-(6-methylpyridin-2-yl)benzamide) inhibits nAChR activity with an IC(5)(0) value of 6.0 (3.4-10.6) muM on human alpha4beta2 nAChRs with a approximately 5-fold preference against human alpha3beta4 nAChRs. Twenty-six analogs of compound 1 were also either synthesized or purchased for structure-activity relationship (SAR) studies and provided information relating the chemical/structural properties of the molecules to their ability to inhibit nAChR activity. The discovery of subtype-selective ligands of nAChRs described here should contribute significantly to our understanding of the involvement of specific nAChR subtypes in normal and pathophysiological states.
        
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Yi B, Long S, Gonzalez-Cestari TF, Henderson BJ, Pavlovicz RE, Werbovetz K, Li C, McKay DB (2013) Discovery of benzamide analogs as negative allosteric modulators of human neuronal nicotinic receptors: pharmacophore modeling and structure-activity relationship studies Bioorganic & Medicinal Chemistry21: 4730-43
Yi B, Long S, Gonzalez-Cestari TF, Henderson BJ, Pavlovicz RE, Werbovetz K, Li C, McKay DB (2013) Bioorganic & Medicinal Chemistry21: 4730-43