Rationale, pharmacology and clinical efficacy of partial agonists of α4β2 nACh receptors for smoking cessation

Most smokers repeatedly fail in their attempts to stop smoking because of the addictive nature of the nicotine in tobacco products. Nicotine dependence is probably mediated through the activation of multiple subtypes of neuronal nicotinic acetylcholine receptor (nAChR), among which the mesolimbic α4β2 subtype has a pivotal role. Here, we discuss the rationale for and the design of α4β2 nAChR partial agonists as novel treatments for tobacco addiction. Such agents are expected to exhibit a dual action by sufficiently stimulating α4β2-nAChR-mediated dopamine release to reduce craving when quitting and by inhibiting nicotine reinforcement when smoking. Potent and selective α4β2 nAChR partial agonists that exhibit dual agonist and antagonist activity in preclinical models can be identified. The validity of this approach is demonstrated by the clinical efficacy of the α4β2 nAChR partial agonist varenicline, which has significantly better quit rates than do other treatments and offers a new option for smoking cessation pharmacotherapy.