Molecule of the Month

Chantix™ - the first non-nicotine-containing medication for smoking cessation. Nicotine is a highly addictive, bioactive small molecule found in tobacco (e.g., cigarettes) which produces physical dependence [1]. Despite serious tobacco-related illnesses (cancer, respiratory disease and cardiovascular disease), most smokers fail to quit due to the addictive nature of nicotine [2]. Few pharmacotherapies are available for nicotine addiction, and those that are, nicotine replacement therapy and the antidepressant bupropion, have but modest long-term success [3]. An alternative, non-nicotine-containing approach centers on neuronal nicotinic acetylcholine receptors (nAChRs), and in particular, the α4β2 nAChR is a target of interest for the development of smoking cessation therapies due to its location on presynaptic terminals in the striatum and its role in modulating dopamine release [4]. In the mid 90s, Pontieri and Corrigall reported that the reinforcing effects of nicotine are mediated by high affinity α4β2 nAChRs in the mesolimbic dopamine system [5,6]. Activation of α4β2 nAChRs triggers mesolimbic dopamine release which elicits reward signal to higher cortical centers. Repeated abuse of nicotine triggers rapid and variable increases in dopamine release, facilitating both association and learning that leads to dependence [7]. Deletion of either the α4 or β2 subunit of α4β2 nAChRs led to an attenuation of the effects of nicotine and further supported the key role of mesolimbic α4β2 nAChRs in nicotine addiction [3]. These data led to the hypothesis that a partial agonist of α4β2 nAChRs would relieve the cravings and withdrawal symptoms in smokers trying to quit as well as reducing or eliminating the reinforcing element of tobacco [3, 8].

Achieving subtype selectivity within the nAChRs, which consist of many α and β subunit combinations, is a huge challenge, and developing a selective α4β2 nAChR partial agonist through a classical HTS approach seems daunting. However, Pfizer delivered a potent partial agonist of α4β2 nAChR Chantix™, also known as varenicline tartrate, which was approved by the FDA in 2006 for the cessation of smoking [3, 9]. The origin of Chantix™ can be traced back to a small, conformationally rigid plant alkaloid known as cytosine [10-13]. Equilibrium binding assays demonstrated that cytisine was selective for the α4β2 subtype. In functional assays, cytisine showed greater potency at α4β2 receptors than any other subtype; however, it does display a wide range of efficacy at multiple subunit congeners. In fact, cytisine, while a partial agonist at α4β2, it is also a high efficacy agonist at α7 and at various β4 variant. Studies demonstrated that structural manipulations of cytisine resulted in changes in efficacy at multiple neuronal nAChRs. The structure of Chantix™ is loosely based on cytisine, and it was the partial agonist activity of cytisine that led to the development of Chantix™. Chantix™ is a orally bioavailable, partial agonist of α4β2 nAChR (EC50 = 2.3 μM, 13.4% of ACh max), but also activates other subtypes with a range of potencies and efficacies. Five separate clinical trials demonstrated the superior efficacy, tolerability and safety of Chantix™ relative to the other available pharmacotherapies. Indeed, after 12 weeks, 44% of patients taking a 1 mg dose of Chantix™ quit smoking as compared to 17% on placebo. After 52 weeks, prevalence abstinence rates were 36.7% for Chantix™ as compared to 7.9% for placebo [3, 8-13]. The development of Chantix™, exclusively for the treatment of nicotine addiction, represents a huge advance for an unmet medical need, and once again highlights how a natural product inspired and facilitated the discovery of a major new pharmaceutical agent.