title: Discovery of benzamide analogs as negative allosteric modulators of human neuronal nicotinic receptors: pharmacophore modeling and structure-activity relationship studies.
abstract: 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 IC₅₀ value of 6.0 (3.4-10.6) μM on human α4β2 nAChRs with a ∼5-fold preference against human α3β4 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.
authors.affiliation: Division of Pharmacology, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Bitna
authors.initials: B
authors.lastname: Yi
authors.forename: Sihui
authors.initials: S
authors.lastname: Long
authors.forename: Tatiana F
authors.initials: TF
authors.lastname: González-Cestari
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Henderson
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Pavlovicz
authors.forename: Karl
authors.initials: K
authors.lastname: Werbovetz
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.forename: Dennis B
authors.initials: DB
authors.lastname: McKay
mesh_terms: D000494:Allosteric Regulation; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D018733:Nicotinic Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic