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Defining the Putative Inhibitory Site for a Selective Negative Allosteric Modulator of Human α4β2 Neuronal Nicotinic Receptors

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Division of Biology, California Institute of Technology, Pasadena, California 91125, United States
Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States
§ Biophysics Graduate Program, The Ohio State University, Columbus, Ohio 43210, United States
Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States
Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210, United States
# Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio 45701, United States
Cite this: ACS Chem. Neurosci. 2012, 3, 9, 682–692
Publication Date (Web):May 25, 2012
https://doi.org/10.1021/cn300035f
Copyright © 2012 American Chemical Society

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    Abstract

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    Neuronal nicotinic receptors (nAChRs) have been implicated in several diseases and disorders such as autism spectrum disorders, Alzheimer’s disease, Parkinson’s disease, epilepsy, and nicotine addiction. To understand the role of nAChRs in these conditions, it would be beneficial to have selective molecules that target specific nAChRs in vitro and in vivo. Our laboratory has previously identified a novel allosteric site on human α4β2 nAChRs using a series of computational and in vitro approaches. At this site, we have identified negative allosteric modulators that selectively inhibit human α4β2 nAChRs, a subtype implicated in nicotine addiction. This study characterizes the allosteric site via site-directed mutagenesis. Three amino acids (Phe118, Glu60, and Thr58) on the β2 subunit were shown to participate in the inhibitory properties of the selective antagonist KAB-18 and provided insights into its antagonism of human α4β2 nAChRs. SAR studies with KAB-18 analogues and various mutant α4β2 nAChRs also provided information concerning how different physiochemical features influence the inhibition of nAChRs through this allosteric site. Together, these studies identify the amino acids that contribute to the selective antagonism of human α4β2 nAChRs at this allosteric site. Finally, these studies define the physiochemical features of ligands that influence interaction with specific amino acids in this allosteric site.

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    Effects of KAB-18 on [3H]epibatidine to nAChRs; concentration–response effects of KAB-18 on WT and mutant transiently transfected Hα4β2 nAChRs; and the method used for [3H]epibatidine binding to native and recombinant nAChRs. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cited By

    This article is cited by 9 publications.

    1. Catriona J Miller, Evgeniia Golovina, Joerg S Wicker, Jessie C Jacobsen, Justin M O’Sullivan. De novo network analysis reveals autism causal genes and developmental links to co-occurring traits. Life Science Alliance 2023, 6 (10) , e202302142. https://doi.org/10.26508/lsa.202302142
    2. Dina Manetti, Silvia Dei, Hugo R. Arias, Laura Braconi, Alessio Gabellini, Elisabetta Teodori, Maria Novella Romanelli. Recent Advances in the Discovery of Nicotinic Acetylcholine Receptor Allosteric Modulators. Molecules 2023, 28 (3) , 1270. https://doi.org/10.3390/molecules28031270
    3. R. Thomas Boyd. Function and pharmacology of neuronal nAChRs. 2023, 41-69. https://doi.org/10.1016/B978-0-12-819958-9.00002-5
    4. Skylar Y. Cooper, Austin T. Akers, Velvet Blair Journigan, Brandon J. Henderson. Novel Putative Positive Modulators of α4β2 nAChRs Potentiate Nicotine Reward-Related Behavior. Molecules 2021, 26 (16) , 4793. https://doi.org/10.3390/molecules26164793
    5. Max Epstein, Karan Bali, Thomas J. Piggot, A. Christopher Green, Christopher M. Timperley, Mike Bird, John E.H. Tattersall, Isabel Bermudez, Philip C. Biggin. Molecular determinants of binding of non-oxime bispyridinium nerve agent antidote compounds to the adult muscle nAChR. Toxicology Letters 2021, 340 , 114-122. https://doi.org/10.1016/j.toxlet.2021.01.013
    6. Mark M. Levandoski, Sivaramakrishna Koganti. Allosteric Modulation of Neuronal Nicotinic Acetylcholine Receptors. 2016, 334-359. https://doi.org/10.1039/9781782629276-00334
    7. Brandon J. Henderson, Henry A. Lester. Inside-out neuropharmacology of nicotinic drugs. Neuropharmacology 2015, 96 , 178-193. https://doi.org/10.1016/j.neuropharm.2015.01.022
    8. Ayman K. Hamouda, Ze-Jun Wang, Deirdre S. Stewart, Atul D. Jain, Richard A. Glennon, Jonathan B. Cohen. Desformylflustrabromine (dFBr) and [ 3 H]dFBr-Labeled Binding Sites in a Nicotinic Acetylcholine Receptor. Molecular Pharmacology 2015, 88 (1) , 1-11. https://doi.org/10.1124/mol.115.098913
    9. Stephen P. Arneric, Emanuele Sher. Current and Future Trends in Drug Discovery and Development Related to Nicotinic Receptors. 2014, 435-461. https://doi.org/10.1007/978-1-4939-1167-7_21

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