CC4, a dimer of cytisine, is a selective partial agonist at α4β2/α6β2 nAChR with improved selectivity for tobacco smoking cessation

摘要: Background and Purpose Many of the addictive rewarding effects nicotine are due to its actions on neuronal nicotinic ACh receptor (nAChR) subtypes expressed in dopaminergic mesocorticolimbic cells. The partial agonists, cytisine varenicline, helpful smoking cessation aids. These drugs have a number side that limit their usefulness. aim this study was investigate preclinical pharmacology dimer1,2-bisN-cytisinylethane (CC4). Experimental Approach The CC4 nAChRs were investigated using vitro assays animal behaviours. Key Results When electrophysiologically tested heterologously human subtypes, less efficacious than α4β2, α3β4, α7 muscle-type receptors, had no effect 5-hydroxytryptamine3 receptors. Acting through α4β2 α6β2 nAChRs, is agonist nAChR-mediated striatal dopamine release and, when co-incubated with nicotine, prevented nicotine's maximal response. In addition, it low affinity for, α3β4 α7-nAChR subtypes. Like CC4-induced conditioned place preference (CPP), self-administration shows an inverted-U dose–response curve. Pretreatment non-reinforcing doses significantly reduced nicotine-induced CPP without affecting motor functions. Conclusion Implications Our vivo findings reveal selectively reduces behaviours associated addiction consistent selectivity for β2-nAChRs. results support possible development or derivatives as promising drug tobacco cessation.