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Molecular Pharmacology

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Research ArticleArticle

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

Ethan B. Van Arnam, Emily E. Blythe, Henry A. Lester and Dennis A. Dougherty
Molecular Pharmacology August 2013, 84 (2) 201-207; DOI: https://doi.org/10.1124/mol.113.085795
Ethan B. Van Arnam
Division of Chemistry and Chemical Engineering (E.B.V., E.E.B., D.A.D.) and Division of Biology (H.A.L.), California Institute of Technology, Pasadena, California
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Emily E. Blythe
Division of Chemistry and Chemical Engineering (E.B.V., E.E.B., D.A.D.) and Division of Biology (H.A.L.), California Institute of Technology, Pasadena, California
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Henry A. Lester
Division of Chemistry and Chemical Engineering (E.B.V., E.E.B., D.A.D.) and Division of Biology (H.A.L.), California Institute of Technology, Pasadena, California
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Dennis A. Dougherty
Division of Chemistry and Chemical Engineering (E.B.V., E.E.B., D.A.D.) and Division of Biology (H.A.L.), California Institute of Technology, Pasadena, California
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Abstract

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.

Footnotes

    • 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.

  • dx.doi.org/10.1124/mol.113.085795.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 84 (2)
Molecular Pharmacology
Vol. 84, Issue 2
1 Aug 2013
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Research ArticleArticle

Ligand-Receptor Interactions for the α7 nAChR

Ethan B. Van Arnam, Emily E. Blythe, Henry A. Lester and Dennis A. Dougherty
Molecular Pharmacology August 1, 2013, 84 (2) 201-207; DOI: https://doi.org/10.1124/mol.113.085795

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Research ArticleArticle

Ligand-Receptor Interactions for the α7 nAChR

Ethan B. Van Arnam, Emily E. Blythe, Henry A. Lester and Dennis A. Dougherty
Molecular Pharmacology August 1, 2013, 84 (2) 201-207; DOI: https://doi.org/10.1124/mol.113.085795
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