, Volume 235, Issue 9, pp 2479–2505 | Cite as

The contribution of agonist and antagonist activities of α4β2* nAChR ligands to smoking cessation efficacy: a quantitative analysis of literature data

  • Hans RollemaEmail author
  • Raymond S. Hurst


Rationale and objective

Two mechanisms underlie smoking cessation efficacies of α4β2* nicotinic acetylcholine receptor (nAChR) agonists: a “nicotine-like” agonist activity reduces craving by substituting for nicotine during a quit attempt, and a “nicotine-blocking” antagonist activity attenuates reinforcement by competing with inhaled nicotine during a relapse. To evaluate the contribution of each mechanism to clinical efficacy, we estimated the degree of agonist and antagonist activities of nicotine replacement therapy (NRT), varenicline, cytisine, and the discontinued nAChR agonists dianicline, ABT-418, ABT-089, CP-601927, and CP-601932, relative to the functional effects of nicotine from smoking.


Functional activities that occur in vivo with clinical doses were predicted from literature data on binding and functional potencies at the target α4β2 nAChR, as well as at α6β2* nAChRs, and from estimates of free drug exposures in human brain. Agonist activity is comprised of nAChR activation and desensitization, which were expressed as percentages of desensitization and activation by nicotine from smoking. Antagonist activity was expressed as the reduction in nAChR occupancy by nicotine during smoking in the presence of an agonist.


Comparisons with odds ratios at end of treatment suggest that extensive α4β2 and α6β2* nAChR desensitization combined with α6β2* nAChR activation at similar levels as nicotine from smoking is associated with clinical efficacy (NRT, varenicline, cytisine, ABT-418). Effective competition with inhaled nicotine for α4β2 and α6β2* nAChRs further improves clinical efficacy (varenicline). Other discontinued nAChR agonists have lower agonist and antagonist activities at α4β2 nAChRs and are inactive or less efficacious than NRT (dianicline, ABT-089, CP-601927, CP-601932).


Three pharmacological effects appear to be key factors underlying smoking cessation efficacy: the degree of activation of α6β2* nAChRs, desensitization of α4β2 and α6β2* nAChRs (agonist activity), and the reduction of nicotine occupancy at α4β2 and α6β2* nAChRs (antagonist activity). No single activity is dominant, and the level of smoking cessation efficacy depends on the profile of these activities achieved at clinical doses. While adequate agonist activity alone seems sufficient for a clinical effect (e.g., NRT, cytisine), clinical efficacy is improved with substantial competitive antagonism of α4β2 nAChRs, i.e., if the drug has a dual agonist-antagonist mechanism of action (e.g., varenicline).


α4β2 nAChR agonists α6β2* nAChR agonists nAChR activation and desensitization Agonist-antagonist activities Smoking cessation NRT Varenicline Cytisine 



The authors thank Drs. David Lawrence and Sarah Dubrava (Pfizer, New York and Groton, USA) for conducting the meta-analyses, Dr. Ellen Wang (Pfizer, New York, USA) for reviewing the pharmacokinetic sections, and Dr. Jotham Coe (Pfizer, Groton, CT, USA) and Dr. Daniel Bertrand (HiQScreen, Geneva, Switzerland) for sharing unpublished data on discontinued nAChR agonists.

Compliance with ethical standards

Conflict of interest

HR and RSH are former employees of Pfizer Inc., the manufacturer of varenicline.

HR received financial support for this publication from Pfizer. RSH declares no conflict of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Rollema Biomedical ConsultingMysticUSA
  2. 2.Hurst Neuropharmacology ConsultingWaylandUSA
  3. 3.Concert Pharmaceuticals, Inc.LexingtonUSA

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