Varenicline: An α4β2 Nicotinic Receptor Partial Agonist for Smoking Cessation
Abstract
Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued alpha4beta2 nicotinic receptor partial agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high alpha4beta2 nAChR affinity and the desired in vivo dopaminergic profile.
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Varenicline is a partial agonist of α4/β2* nAChRs but also activates α7-type nAChRs.
“Varenicline is a partial agonist of α4/β2* nAChRs (Coe et al., 2005), but also activates α7-type nAChRs (Mihalak et al., 2006).”
From It is not “either/or”: Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood (2008) · cites this paper as Coe et al., 2005
Varenicline is a potent partial agonist at α4β2 nAChRs.
“Varenicline, the most effective medication for smoking cessation currently available (Chantix; Pfizer), is a potent partial agonist for a4b2 nAChRs, as well as a weak partial agonist at a3b4 nAChRs and a full agonist at a7 nAChRs (Coe et al, 2005; Rollema et al, 2007).”
From Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal (2013) · cites this paper as Coe et al, 2005
Varenicline is a weak partial agonist at α3β4 nAChRs.
“Varenicline, the most effective medication for smoking cessation currently available (Chantix; Pfizer), is a potent partial agonist for a4b2 nAChRs, as well as a weak partial agonist at a3b4 nAChRs and a full agonist at a7 nAChRs (Coe et al, 2005; Rollema et al, 2007).”
From Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal (2013) · cites this paper as Coe et al, 2005
Varenicline is a full agonist at α7 nAChRs.
“Varenicline, the most effective medication for smoking cessation currently available (Chantix; Pfizer), is a potent partial agonist for a4b2 nAChRs, as well as a weak partial agonist at a3b4 nAChRs and a full agonist at a7 nAChRs (Coe et al, 2005; Rollema et al, 2007).”
From Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal (2013) · cites this paper as Coe et al, 2005
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 [7]
Varenicline produces moderate nicotinic acetylcholine receptor stimulation and lower sustained dopamine release, thereby replacing some effects of nicotine.
“Varenicline produces a moderate level of nAChR stimulation and lower sustained levels of dopamine release, thereby replacing some of nicotine’s effects (7).”
From Varenicline improves mood and cognition during smoking abstinence (2009) · cites this paper as [7]
Varenicline acts as a potent partial agonist at α4β2* nAChRs.
“numerous studies have shown that varenicline, a Food and Drug Administration-approved drug widely used to help people quit smoking, potently acts as a partial agonist at ␣42* nAChRs”
From Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum (2012) · cites this paper as Coe et al., 2005
Varenicline has significant effects at α7 nAChRs, α3β4* nAChRs, and 5-hydroxytryptamine type 3 receptors.
“subsequent work showed that varenicline had a significant effect at ␣7 nAChRs, ␣34* nAChRs, and 5-hydroxytryptamine type 3 receptors”
From Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum (2012) · cites this paper as Coe et al., 2005
Varenicline acts at both a4b2* and a7 subtypes.
“Varenicline, the best in class medication for smoking cessation, acts at both of these subtypes (Coe et al., 2005).”
From Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors (2014) · cites this paper as Coe et al., 2005
Varenicline is currently the best in class treatment of smoking cessation.
“Varenicline (Chantix; Pfizer, Groton, CT), a partial agonist at a4b2 nicotinic acetylcholine receptors (nAChRs) and a full agonist at a7 and a3b4 nAChRs is currently the best in class treatment of smoking cessation (Coe et al., 2005;Garrison and Dugan, 2009).”
From Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors (2014) · cites this paper as Coe et al., 2005
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“Abstract: Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano- 6H-pyrazino[2,3-h][ 3 ]benzazepine) has been identified for smoking cessation.”
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- Authors
- Coe, J. W., Brooks, P. R., Vetelino, M. G., Wirtz, M. C., Arnold, E. P., Huang, J., Sands, S. B., Davis, T. I., Lebel, L. A., Fox, C. B., Shrikhande, A., Heym, J. H., Schaeffer, E., Rollema, H., Lu, Y., Mansbach, R. S., Chambers, L. K., Rovetti, C. C., Schulz, D. W., Tingley, F. D., & O'Neill, B. T.
- Affiliations
- Pfizer (United States) (US)
- Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
- Corresponding author
- Coe, Jotham W.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2005-04-23
- Volume
- 48
- Issue
- 10
- Pages
- 3474-3477
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W1993112595
- Cited by
- 930
- References
- 71
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 26 · 2023: 29 · 2022: 26 · 2021: 29 · 2020: 35 · 2019: 34 · 2018: 30 · 2017: 32 · 2016: 44 · 2015: 54 · 2014: 62 · 2013: 65 · 2012: 70
- FWCI
- 21.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Alkaloids: synthesis and pharmacology
- Keywords
- varenicline, smoking cessation, α4β2 nicotinic acetylcholine receptor, partial agonists, nicotine dependence, dopamine, nicotine craving, withdrawal syndrome
- MeSH terms
- Varenicline, Animals, Benzazepines, Cell Line, Cerebral Cortex, Humans, Oocytes, Quinoxalines, Radioligand Assay, Receptors, Nicotinic, Xenopus laevis, Smoking Cessation, Nicotinic Agonists, Rats, In Vitro Techniques
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