Cited by 410Smoking Behavior and CessationNicotinic Acetylcholine Receptors StudyAlkaloids: synthesis and pharmacology

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

Rollema, Hans, Coe, Jotham W., Chambers, Leslie K., Hurst, Raymond S., Stahl, Stephen M., Williams, Kathryn E.·2007·Trends in Pharmacological Sciences

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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Crossref · 10.1016/j.tips.2007.05.003

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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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