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Review ArticleReview Article

Therapeutic Targeting of α7 Nicotinic Acetylcholine Receptors

Roger L. Papke and Nicole A. Horenstein
Habibeh Khoshbouei, ASSOCIATE EDITOR
Pharmacological Reviews July 2021, 73 (3) 1118-1149; DOI: https://doi.org/10.1124/pharmrev.120.000097
Roger L. Papke
Departments of Pharmacology and Therapeutics (R.L.P) and Chemistry (N.A.H.), University of Florida, Gainesville, FL
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Nicole A. Horenstein
Departments of Pharmacology and Therapeutics (R.L.P) and Chemistry (N.A.H.), University of Florida, Gainesville, FL
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Habibeh Khoshbouei
Roles: ASSOCIATE EDITOR
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Abstract

The α7-type nicotinic acetylcholine receptor is one of the most unique and interesting of all the members of the cys-loop superfamily of ligand-gated ion channels. Since it was first identified initially as a binding site for α-bungarotoxin in mammalian brain and later as a functional homomeric receptor with relatively high calcium permeability, it has been pursued as a potential therapeutic target for numerous indications, from Alzheimer disease to asthma. In this review, we discuss the history and state of the art for targeting α7 receptors, beginning with subtype-selective agonists and the basic pharmacophore for the selective activation of α7 receptors. A key feature of α7 receptors is their rapid desensitization by standard “orthosteric” agonist, and we discuss insights into the conformational landscape of α7 receptors that has been gained by the development of ligands binding to allosteric sites. Some of these sites are targeted by positive allosteric modulators that have a wide range of effects on the activation profile of the receptors. Other sites are targeted by direct allosteric agonist or antagonists. We include a perspective on the potential importance of α7 receptors for metabotropic as well as ionotropic signaling. We outline the challenges that exist for future development of drugs to target this important receptor and approaches that may be considered to address those challenges.

Significance Statement The α7-type nicotinic acetylcholine receptor (nAChR) is acknowledged as a potentially important therapeutic target with functional properties associated with both ionotropic and metabotropic signaling. The functional properties of α7 nAChR can be regulated in diverse ways with the variety of orthosteric and allosteric ligands described in this review.

Footnotes

  • The authors are supported by National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM57481]. This grant was first funded in 2000 and bears the same title as this review.

  • No author has an actual or perceived conflict of interest with the contents of this article.

  • https://doi.org/10.1124/pharmrev.120.000097.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 73 (3)
Pharmacological Reviews
Vol. 73, Issue 3
1 Jul 2021
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Review ArticleReview Article

Therapeutic Targeting of α7 nAChR

Roger L. Papke and Nicole A. Horenstein
Pharmacological Reviews July 1, 2021, 73 (3) 1118-1149; DOI: https://doi.org/10.1124/pharmrev.120.000097

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Review ArticleReview Article

Therapeutic Targeting of α7 nAChR

Roger L. Papke and Nicole A. Horenstein
Pharmacological Reviews July 1, 2021, 73 (3) 1118-1149; DOI: https://doi.org/10.1124/pharmrev.120.000097
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  • Article
    • Abstract
    • I. Introduction
    • II. Diversity of Nicotinic Acetylcholine Receptor
    • III. α7 Receptors as Therapeutic Targets
    • IV. α7-Selective Agonists
    • V. α7-Positive Allosteric Modulators
    • VI. Silent Agonists
    • VII. α7 Antagonists
    • VIII. Discussion and Conclusions
    • Acknowledgments
    • Appendix
    • Expression in Xenopus Oocytes
    • Two-Electrode Voltage-Clamp Electrophysiology
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
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