biostudies-literatureHenderson BJNIDA NIH HHS1797-813https://www.ebi.ac.uk/biostudies/studies/S-EPMC3274641biostudies-literatureUnknown22(4)Subtype selective molecules for ?4?2 neuronal nicotinic acetylcholine receptors (nAChRs) have been sought as novel therapeutics for nicotine cessation. ?4?2 nAChRs have been shown to be involved in mediating the addictive properties of nicotine while other subtypes (i.e., ?3?4 and ?7) 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 ?4?2 nAChRs and human ?3?4 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 ?4?2 nAChRs.Bioorganic & medicinal chemistry letters3D-QSAR and 3D-QSSR models of negative allosteric modulators facilitate the design of a novel selective antagonist of human ?4?2 neuronal nicotinic acetylcholine receptors.PMC3274641DA029433R21 DA029433-01S1R21 DA029433-01R21 DA029433Bergmeier SCMaciagiewicz IHenderson BJOrac CMMcKay DBfalse3D-QSAR and 3D-QSSR models of negative allosteric modulators facilitate the design of a novel selective antagonist of human ?4?2 neuronal nicotinic acetylcholine receptors.Subtype selective molecules for ?4?2 neuronal nicotinic acetylcholine receptors (nAChRs) have been sought as novel therapeutics for nicotine cessation. ?4?2 nAChRs have been shown to be involved in mediating the addictive properties of nicotine while other subtypes (i.e., ?3?4 and ?7) 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 ?4?2 nAChRs and human ?3?4 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 ?4?2 nAChRs.2012-01-01T00:00:00Z2012 Feb2020-10-29T14:20:54Z2019-03-27T00:48:54ZS-EPMC32746412228594210.1016/j.bmcl.2011.11.051