Henderson_2012_Bioorg.Med.Chem.Lett_22_1797

Subtype selective molecules for alpha4beta2 neuronal nicotinic acetylcholine receptors (nAChRs) have been sought as novel therapeutics for nicotine cessation. alpha4beta2 nAChRs have been shown to be involved in mediating the addictive properties of nicotine while other subtypes (i.e., alpha3beta4 and alpha7) 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 alpha4beta2 nAChRs and human alpha3beta4 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 alpha4beta2 nAChRs.