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An Unusual Pattern of Ligand-Receptor Interactions for the α7 Nicotinic Acetylcholine Receptor, with Implications for the Binding of Varenicline

Van Arnam, Ethan B. and Blythe, Emily E. and Lester, Henry A. and Dougherty, Dennis A. (2013) An Unusual Pattern of Ligand-Receptor Interactions for the α7 Nicotinic Acetylcholine Receptor, with Implications for the Binding of Varenicline. Molecular Pharmacology, 84 (2). pp. 201-207. ISSN 0026-895X. PMCID PMC3716316. doi:10.1124/mol.113.085795.

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The α7 nicotinic acetylcholine receptor shows broad pharmacology, complicating the development of subtype-specific nicotinic receptor agonists. Here we use unnatural amino acid mutagenesis to characterize binding to α7 by the smoking cessation drug varenicline (Chantix; Pfizer, Groton, CT), an α4β2-targeted agonist that shows full efficacy and modest potency at the α7 receptor. We find that unlike binding to its target receptor, varenicline does not form a cation-π interaction with TrpB, further supporting a unique binding mode for the cationic amine of nicotinic agonists at the α7 receptor. We also evaluate binding to the complementary face of the receptor’s binding site by varenicline, the endogenous agonist acetylcholine, and the potent nicotine analog epibatidine. Interestingly, we find no evidence for functionally important interactions involving backbone NH and CO groups thought to bind the canonical agonist hydrogen bond acceptor of the nicotinic pharmacophore, perhaps reflecting a lesser importance of this pharmacophore element for α7 binding. We also show that the Trp55 and Leu119 side chains of the binding site’s complementary face are important for the binding of the larger agonists epibatidine and varenicline, but dispensable for binding of the smaller, endogenous agonist acetylcholine.

Item Type:Article
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URLURL TypeDescription CentralArticle
Blythe, Emily E.0000-0001-6363-2644
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2013 The American Society for Pharmacology and Experimental Therapeutics. Received February 20, 2013; accepted May 16, 2013. This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS34407]; and California Tobacco-Related Disease Research Program of the University of California, Award 19XT-0102. E.E.B. was an Amgen Scholar. The authors thank Pfizer for a generous gift of varenicline. Participated in research design: Van Arnam, Blythe, Lester, Dougherty. Conducted experiments: Van Arnam, Blythe. Performed data analysis: Van Arnam, Blythe, Lester, Dougherty. Wrote or contributed to the writing of the manuscript: Van Arnam, Dougherty.
Funding AgencyGrant Number
California Tobacco-Related Disease Research Program19XT-0102
National Institute of Neurological Disorders and Stroke (NINDS)UNSPECIFIED
Issue or Number:2
PubMed Central ID:PMC3716316
Record Number:CaltechAUTHORS:20130808-161341375
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:39824
Deposited By: Jason Perez
Deposited On:09 Aug 2013 03:11
Last Modified:09 Nov 2021 23:47

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