Discovery and development of varenicline for smoking cessation

Abstract

Tobacco use causes one premature death every six seconds. Current smoking cessation aids include nicotine replacement therapies, bupropion, and varenicline. Although more than 70% of smokers express a desire to quit, fewer than 3% remain abstinent for more than one year, highlighting a critical need for more efficacious smoking cessation treatments. Areas covered: The authors discuss the rationale, preclinical and clinical development of varenicline for smoking cessation. They cover the development of varenicline as a partial agonist at α₄β₂ receptors, the primary neural substrate for nicotine reward. Then, they discuss evidence from preclinical studies indicating varenicline's efficacy in blocking nicotine reward, followed by clinical trials demonstrating safety and efficacy in sustaining abstinence in smokers. Finally, they cover post-market surveillance, including caution in heavy machine operators, putative cardiovascular risk, and the repealed warning for adverse neuropsychiatric events. Expert opinion: Varenicline development was based on strong theoretical rationale and preclinical evidence. Clinical studies indicate that varenicline is safe and more effective in sustaining abstinence than placebo, bupropion or nicotine replacement therapies. However, given that continuous abstinence rates across studies remain low (18 ~ 30% with varenicline; 4 ~ 10% with placebo), novel and more effective medications targeting other nicotinic or glutamate receptors for smoking cessation are required.

Keywords: Acetylcholine receptor; addiction; nicotine; smoking cessation; varenicline.

Figure 1.

The mesolimbic dopamine (DA) system (left) is comprised of ventral tegmental area (VTA) projections to the nucleus accumbens (NAc) and prefrontal cortex (PFC). Nicotine stimulates DA release in the mesolimbic system by activating pre- and post-synaptic nicotinic acetycholine receptors (nAchRs) in the VTA (right). Activation of pentameric α₄β₂ nAchRs in the VTA opens an ion pore, allowing cation (Na⁺ and Ca²⁺⁾ influx and depolarization of the VTA DA neuron.

Figure 2.

Chemical structures of nicotine, cytisine, and varenicline (top). Comparison of in vitro binding affinities of nicotine, cytisine, and varenicline at nicotinic acetylcholine receptor subtypes (nAchRs; bottom).

Figure 3.

A summarized history of varenicline discovery and development (see text for details). Note: Timeline is not presented at scale.