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Discovery and Characterization of Selective Negative Allosteric Modulators of Human α4β2 Neuronal Nicotinic Receptors

Henderson, Brandon J.
http://rave.ohiolink.edu/etdc/view?acc_num=osu1307647472

Abstract Details

2011, Doctor of Philosophy, Ohio State University, Pharmacy.
One of the difficulties in understanding the physiological role and connection to diseases and disorders of neuronal nicotinic acetylcholine receptors (nAChRs) lies in the distinction between the specific subtypes involved. It is of great importance to understand how specific nAChR subtypes are involved with normal physiology, diseases, and disorders. α4β2* nAChRs have been implicated in a growing number of diseases and disorders; the most prominent being nicotine addiction. The studies presented in this dissertation characterize a novel, human α4β2 (Hα4β2) selective antagonist as well as an allosteric site in which it binds. The primary contributions of this study are: 1) the discovery and characterization of the negative allosteric modulator (NAM), KAB-18, using calcium accumulation assays on recombinant Hα4β2 and Hα3β4 nAChRs, 2) the identification of the allosteric site in which KAB-18 binds using homology modeling, blind docking, and molecular dynamics (MD) simulations, 3) the validation of the allosteric site which was identified using computational modeling through the use of site-directed mutagenesis, 4) the construction of 3D models to predict the important binding interactions between this novel class of NAMs with Hα4β2 and Hα3β4 nAChRs, and 5) the identification of novel compounds that have similar “pharmacophores” as KAB-18 using ligand-based virtual screening. These studies provide much information regarding ligands that can interact selectively and potently with Hα4β2 nAChRs. These results also provide a novel mechanism for the negative allosterism of this class of NAMs on Hα4β2 and Hα3β4 nAChRs. The work presented herein provides a bridge to the design of new molecules from both a ligand based and structure based approach that preferentially bind and inhibit Hα4β2 nAChRs. This work will contribute to the field of nAChRs by providing a means to produce novel molecules; whether as molecular tools or as potential therapeutic drug candidates that target Hα4β2 nAChRs.
Dennis McKay, PhD (Advisor)
R. Thomas Boyd, PhD (Committee Member)
Chenglong Li, PhD (Committee Member)
Lane Wallace, PhD (Committee Member)
Anthony Young, PhD (Committee Member)
Vadim Utkin, PhD (Committee Member)
252 p.
Pharmacology
allosteric; modulator; negative; nicotinic receptor; addiction; nicotine; noncompetitive

Recommended Citations

Citations

  • Henderson, B. J. (2011). Discovery and Characterization of Selective Negative Allosteric Modulators of Human α4β2 Neuronal Nicotinic Receptors [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1307647472

    APA Style (7th edition)

  • Henderson, Brandon. Discovery and Characterization of Selective Negative Allosteric Modulators of Human α4β2 Neuronal Nicotinic Receptors. 2011. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1307647472.

    MLA Style (8th edition)

  • Henderson, Brandon. "Discovery and Characterization of Selective Negative Allosteric Modulators of Human α4β2 Neuronal Nicotinic Receptors." Doctoral dissertation, Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1307647472

    Chicago Manual of Style (17th edition)

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© 2011, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.