Compounds in Nicotine-free Tobacco Smoke Condensates Bind Allosterically to the α3β4α5 Neuronal Nicotinic Acetylcholine Receptor

Abstract

Cigarette smoking is a leading health concern worldwide due to accessibility of cigarettes and the adverse health affects that smoking has on the body. Several of the health risks associated with cigarette smoking are due to the addictive properties of nicotine. Nicotine affects the body by binding to neuronal nicotinic acetylcholine receptors (nAChR) and causing downstream effects that trigger reward pathways. Diversity in composition of neuronal nicotinic acetylcholine receptors affects binding of nicotine. In particular, the a3B4a5 neuronal nAChR has shown differences in nicotine binding affinity which this study hypothesized to be affected by allosteric binding of non-nicotine components of tobacco smoke. The cellular membrane affinity chromatography column technique was used to immobilize a3B4a5 receptors onto columns for screening of nicotine-free tobacco smoke condensates. In this study, we were able to detect allosteric binding of compounds in nicotine-free tobacco smoke condensates by testing competition with 3- hydroximorphinan, a known ligand that binds to the allosteric site of the a3B4a5 neuronal nAChR. We were able to identify a group of compounds from the nicotine-free tobacco smoke condensate sample that bind allosterically to a3B4a5 neuronal nAChRs. Binding of these compound to the allosteric site of the a3B4a5 neuronal nAChRs has potential to moderate binding affinity of nicotine and may lead to potential therapeutics for smoking cessation.