title: 3D-QSAR and 3D-QSSR models of negative allosteric modulators facilitate the design of a novel selective antagonist of human α4β2 neuronal nicotinic acetylcholine receptors.
abstract: Subtype selective molecules for α4β2 neuronal nicotinic acetylcholine receptors (nAChRs) have been sought as novel therapeutics for nicotine cessation. α4β2 nAChRs have been shown to be involved in mediating the addictive properties of nicotine while other subtypes (i.e., α3β4 and α7) are believed to mediate the undesired effects of potential CNS drugs. To obtain selective molecules, it is important to understand the physiochemical features of ligands that affect selectivity and potency on nAChR subtypes. Here we present novel QSAR/QSSR models for negative allosteric modulators of human α4β2 nAChRs and human α3β4 nAChRs. These models support previous homology model and site-directed mutagenesis studies that suggest a novel mechanism of antagonism. Additionally, information from the models presented in this work was used to synthesize novel molecules; which subsequently led to the discovery of a new selective antagonist of human α4β2 nAChRs.
authors.affiliation: Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA. mckay.2@osu.edu
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Henderson
authors.forename: Crina M
authors.initials: CM
authors.lastname: Orac
authors.forename: Iwona
authors.initials: I
authors.lastname: Maciagiewicz
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Bergmeier
authors.forename: Dennis B
authors.initials: DB
authors.lastname: McKay
mesh_terms: D000495:Allosteric Site; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D018733:Nicotinic Antagonists / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: D001713:Biphenyl Compounds; C572318:COB-172; C572319:COB-175; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; C403531:nicotinic receptor alpha4beta2