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

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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.

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Smoking and tobacco addiction

Despite broad awareness of the health risks to individuals, tobacco smoking is the leading cause of preventable mortality in industrialized countries [1]. Globally, tobacco-attributable mortality is projected to increase to 6.4 million per annum in 2015, and account for 10% of all deaths [2]. Currently available treatments for nicotine addiction, including nicotine replacement therapy (NRT) and bupropion (Zyban®), only double the placebo quit rate in clinical trials 3, 4, highlighting the unmet

Role of α4β2 nAChRs in nicotine dependence

Recent insights into the molecular mechanisms that underlie nicotine dependence have revealed unique opportunities for developing more-efficacious treatments for tobacco addiction. Upon smoking, inhaled nicotine enters the brain within seconds, reaching maximal concentrations within 2 min 14, 15, and acts on nAChRs located on DA and GABA neurons in the mesolimbic system in the ventral tegmental area (VTA) (Figure 1). Nicotine can both activate and desensitize these receptors, depending on the

Why α4β2 nAChR partial agonists for smoking cessation?

Given the central role of α4β2 nAChRs in the reinforcement and maintenance of nicotine dependence, modulating the activity of these receptors would be expected to have therapeutic benefits. Specifically, partial agonists of α4β2 nAChRs that enhance the activity of these receptors sufficiently to blunt craving and withdrawal, but without associated abuse potential, are attractive options. Furthermore, high-affinity partial agonists of α4β2 nAChRs would have the additional potential benefit of

Agonist and antagonist combinations: a proof of concept for partial agonists

Rational approaches to pharmacotherapy for nicotine addiction would include direct activation of α4β2 nAChRs with an agonist to reduce craving and withdrawal symptoms when quitting, or blockade of α4β2 nAChRs with an antagonist to reduce reinforcement and reward from smoking. The first approach, represented by nicotine replacement therapy (NRT), uses nicotine as an agonist in safe delivery forms by eliminating the smoke that causes tobacco-related illnesses. NRT is effective [3] at reducing

Design of α4β2 nAChR partial agonists: clues from nature

Cytisine (Figure 3), which is a plant alkaloid that has been used for >40 years in Eastern Europe as a smoking cessation agent (see later), provided early support for the partial agonist theory. In 1994, evidence revealed cytisine to be a partial agonist of nAChRs [30], providing a rationale for its reported efficacy. Direct chemical modifications of cytisine did not lead to viable drug candidates (Figure 3). Although entirely synthetic variations of the cytisine [3.3.1]-bicyclic framework

The discovery and neuropharmacology of α4β2 nAChR partial agonists

Although the pharmacological characteristics of partial agonists are easily formulated, the actual identification of a partial agonist with the desired profile presents a formidable challenge. The characterization of nAChR partial agonists became more practical only in the 1990s, with the application of functional in vitro assays – most notably patch clamp and fluorescence imaging plate reader (FLIPR) methodology – to ion channels expressed in oocytes or mammalian cell lines. This enabled the

Clinical efficacy: do partial agonists of α4β2 nAChRs work?

As noted, the potential benefits of dual agonist and antagonist action, as proposed by Rose and Levin [28], were originally examined by simultaneous nAChR agonist (NRT) and antagonist (mecamylamine) administration 38, 39. Two small studies showed that mecamylamine augmented the efficacy of NRT; however, there are no published data from larger studies confirming these results, and the combination has not yet become an established treatment for smoking cessation [29]. Interestingly, the

Concluding remarks

Treatment of tobacco addiction with partial agonists of α4β2 nAChRs offers a novel and well-validated pharmacotherapeutic approach. Mechanistically, these agents target the receptors that are believed to mediate the reinforcing effects of nicotine and, to some extent, mimic the agonist effects of nicotine sufficiently to reduce craving when quitting. Furthermore, partial agonists with sufficiently high receptor-binding affinity and free concentration in the brain will act as antagonists in the

Disclosure statement

Varenicline is a product of Pfizer and is marketed as CHANTIX™ (USA) and CHAMPIX™ (Europe and elsewhere). H.R., J.W.C., L.K.C., R.S.H. and K.E.W. are employees of Pfizer and own Pfizer stock. S.M.S. has received grants from and is a consultant for several pharmaceutical companies, including Pfizer, for which he is on the speakers’ bureau.

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