Rationale, pharmacology and clinical efficacy of partial agonists of α4β2 nACh receptors for smoking cessation
Abstract
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 alpha(4)beta(2) subtype has a pivotal role. Here, we discuss the rationale for and the design of alpha(4)beta(2) nAChR partial agonists as novel treatments for tobacco addiction. Such agents are expected to exhibit a dual action by sufficiently stimulating alpha(4)beta(2)-nAChR-mediated dopamine release to reduce craving when quitting and by inhibiting nicotine reinforcement when smoking. Potent and selective alpha(4)beta(2) 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 alpha(4)beta(2) 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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Competitive binding at nicotinic acetylcholine receptors should theoretically reduce nicotine reward.
“Further, competitive nAChR binding should, theoretically, reduce nicotine reward (7, 8).”
From Varenicline improves mood and cognition during smoking abstinence (2009) · cites this paper as [8]
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- Authors
- Rollema, H., Coe, J. W., Chambers, L. K., Hurst, R. S., Stahl, S. M., & Williams, K. E.
- Affiliations
- Pfizer (United States) (US)
- University of California San Diego (US)
- Corresponding author
- Rollema, Hans
- Venue
- Trends in Pharmacological Sciences
- Publisher
- Elsevier BV
- Published
- 2007-07
- Volume
- 28
- Issue
- 7
- Pages
- 316-325
- ISSN
- 0165-6147 (ISSN-L)
- OpenAlex
- W1997437727
- Cited by
- 400
- References
- 65
- Citations by year
- 2026: 8 · 2025: 2 · 2024: 8 · 2023: 3 · 2022: 9 · 2021: 8 · 2020: 169 · 2019: 6 · 2018: 8 · 2017: 11 · 2016: 5 · 2015: 15 · 2014: 16 · 2013: 16 · 2012: 17
- FWCI
- 2.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Trends in Pharmacological Sciences (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Alkaloids: synthesis and pharmacology
- Keywords
- α4β2 nicotinic acetylcholine receptor, partial agonists, smoking cessation, nicotine dependence, varenicline, dopamine release, nicotine reinforcement, craving reduction, mesolimbic system
- MeSH terms
- Varenicline, Animals, Benzazepines, Humans, Quinoxalines, Receptors, Nicotinic, Tobacco Use Disorder, Drug Design, Smoking Cessation, Treatment Outcome, Nicotinic Agonists
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