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Varenicline Is a Potent Agonist of the Human 5-Hydroxytryptamine_3 Receptor

Lummis, S. C. R. and Thompson, A. J. and Bencherif, M. and Lester, H. A. (2011) Varenicline Is a Potent Agonist of the Human 5-Hydroxytryptamine_3 Receptor. Journal of Pharmacology and Experimental Therapeutics, 339 (1). pp. 125-131. ISSN 0022-3565. PMCID PMC3186289. doi:10.1124/jpet.111.185306.

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Varenicline, a widely used and successful smoking cessation agent, acts as a partial agonist at nicotinic acetylcholine receptors. Here, we explore the effects of varenicline at human and mouse 5-Hydroxytryptamine_3 (5-HT_3) receptors. Application of varenicline to human 5-HT_3 receptors expressed in Xenopus laevis oocytes reveal it is almost a full agonist (R_max = 80%) with an EC_50 (5.9 μM) 3-fold higher than 5-HT. At mouse 5-HT_3 receptors varenicline is a partial agonist (R_max = 35%) with an EC50 (18 μM) 20-fold higher than 5-HT. Displacement of the competitive 5-HT_3 receptor antagonist [^(3)H]granisetron reveals similar IC_50 values for varenicline at mouse and human receptors expressed in human embryonic kidney 293 cells, although studies in these cells using a membrane potential-sensitive dye show that again varenicline is a 4- or 35-fold less potent agonist than 5-HT in human and mouse receptors, respectively. Thus the data suggest that the efficacy, but not the affinity, of varenicline is greater at human 5-HT3 receptors compared with mouse. Docking studies provide a possible explanation for this difference, because they suggest distinct orientations of the ligand in the mouse versus human 5-HT_3 agonist binding sites. Additional binding selectivity studies in a broad panel of recombinant receptors and enzymes confirmed an interaction with 5-HT_3 receptors but revealed no additional interactions of varenicline. Therefore, activation of human 5-HT_3 receptors may be responsible for some of the side effects that preclude use of higher doses during varenicline treatment.

Item Type:Article
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URLURL TypeDescription CentralArticle
Lummis, S. C. R.0000-0001-9410-9805
Lester, H. A.0000-0002-5470-5255
Additional Information:© 2011 by the American Society for Pharmacology and Experimental Therapeutics. Received June 21, 2011; accepted July 11, 2011. Published online before print July 20, 2011. This work was supported by the Wellcome Trust [Grant 81925] (to A.J.T. and S.C.R.L.); the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS11756] (to H.A.L.); and the National Institutes of Health National Institute of General Medical Sciences [Grant GM19375] (to H.A.L.). S.C.R.L. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science. Authorship Contributions: Participated in research design: Lummis, Thompson, Bencherif, and Lester. Conducted experiments: Lummis and Thompson. Performed data analysis: Lummis, Thompson, and Lester. Wrote or contributed to the writing of the manuscript: Lummis, Thompson, Bencherif, and Lester.
Funding AgencyGrant Number
Wellcome Trust81925
Issue or Number:1
PubMed Central ID:PMC3186289
Record Number:CaltechAUTHORS:20111028-122557103
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:27494
Deposited By: Jason Perez
Deposited On:28 Oct 2011 23:16
Last Modified:09 Nov 2021 16:49

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