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      Discovery and development of varenicline for smoking cessation

      1 , 1
      Expert Opinion on Drug Discovery
      Informa UK Limited

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          Abstract

          <div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d9105868e106">Introduction:</h5> <p id="P1">Tobacco use causes one premature death every six seconds. Current smoking cessation aids include nicotine replacement therapies and bupropion. 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. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d9105868e111">Areas Covered:</h5> <p id="P2">The authors discuss the rationale, preclinical and clinical development of varenicline for smoking cessation. They cover the formulation of varenicline as a partial agonist at α <sub>4</sub>β <sub>2</sub> 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post-market surveillance, including contraindications in heavy machine operators, putative cardiovascular risk, and the repealed warning for adverse neuropsychiatric events. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d9105868e122">Expert opinion:</h5> <p id="P3">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. </p> </div>

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          Most cited references77

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          Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs.

          The question of whether nicotine, the neuroactive compound of tobacco, is addictive has been open to considerable scientific and public discussion. Although it can serve as a positive reinforcer in several animal species, including man, nicotine is thought to be a weak reinforcer in comparison with addictive drugs such as cocaine and heroin, and has been argued to be habit forming but not addictive. Here we report that intravenous nicotine in the rat, at doses known to maintain self-administration, stimulates local energy metabolism, as measured by 2-deoxyglucose autoradiography, and dopamine transmission, as estimated by brain microdialysis, in the shell of the nucleus accumbens. These neurochemical and metabolic effects are qualitatively similar to those of other drugs, such as cocaine, amphetamine and morphine, which have strong addictive properties. Our results provide functional and neurochemical evidence that there are specific neurobiological commonalities between nicotine and addictive drugs.
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            Nicotine activation of alpha4* receptors: sufficient for reward, tolerance, and sensitization.

            The identity of nicotinic receptor subtypes sufficient to elicit both the acute and chronic effects of nicotine dependence is unknown. We engineered mutant mice with a4 nicotinic subunits containing a single point mutation, Leu9' --> Ala9' in the pore-forming M2 domain, rendering a4* receptors hypersensitive to nicotine. Selective activation of a4* nicotinic acetylcholine receptors with low doses of agonist recapitulates nicotine effects thought to be important in dependence, including reinforcement in response to acute nicotine administration, as well as tolerance and sensitization elicited by chronic nicotine administration. These data indicate that activation of a4* receptors is sufficient for nicotine-induced reward, tolerance, and sensitization.
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              Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid.

              The preclinical pharmacology of the alpha4beta2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline, a novel smoking cessation agent is described. Varenicline binds with subnanomolar affinity only to alpha4beta2 nAChRs and in vitro functional patch clamp studies in HEK cells expressing nAChRs show that varenicline is a partial agonist with 45% of nicotine's maximal efficacy at alpha4beta2 nAChRs. In neurochemical models varenicline has significantly lower (40-60%) efficacy than nicotine in stimulating [(3)H]-dopamine release from rat brain slices in vitro and in increasing dopamine release from rat nucleus accumbens in vivo, while it is more potent than nicotine. In addition, when combined with nicotine, varenicline effectively attenuates the nicotine-induced dopamine release to the level of the effect of varenicline alone, consistent with partial agonism. Finally, varenicline reduces nicotine self-administration in rats and supports lower self-administration break points than nicotine. These data suggest that varenicline can reproduce to some extent the subjective effects of smoking by partially activating alpha4beta2 nAChRs, while preventing full activation of these receptors by nicotine. Based on these findings, varenicline was advanced into clinical development and recently shown to be an effective and safe aid for smoking cessation treatment.
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                Author and article information

                Journal
                Expert Opinion on Drug Discovery
                Expert Opinion on Drug Discovery
                Informa UK Limited
                1746-0441
                1746-045X
                April 19 2018
                July 03 2018
                March 28 2018
                July 03 2018
                : 13
                : 7
                : 671-683
                Affiliations
                [1 ] Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA
                Article
                10.1080/17460441.2018.1458090
                6179352
                29587555
                c583d757-56f4-4af4-98a6-7477133458a7
                © 2018
                History

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