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Binding Interactions of NS6740, a Silent Agonist of the α7 Nicotinic Acetylcholine Receptor

Blunt, Catriona E. W. and Dougherty, Dennis A. (2019) Binding Interactions of NS6740, a Silent Agonist of the α7 Nicotinic Acetylcholine Receptor. Molecular Pharmacology, 96 (2). pp. 212-218. ISSN 0026-895X. doi:10.1124/mol.119.116244.

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The α7 nicotinic acetylcholine receptor (nAChR) is a potential drug target for the treatment of a number of neurologic and inflammatory disorders. Silent agonists are an emerging class of drugs that bind to the receptor but do not open the channel. Instead they shift the receptor to a desensitized state. Silent agonists may be able to target a subset of α7 nAChR–mediated signaling processes. Here we use noncanonical amino acid mutagenesis to characterize the binding to α7 by the silent agonist 1,4-diazabicyclo[3.2.2]nonan-4-yl(5-(3-(trifluoromethyl)phenyl)furan-2-yl)methanone (NS6740). We find that, like α7 agonists, NS6740 forms a cation-π interaction with Y115 (TyrA). We also showed that NS6740 makes a novel hydrogen bond to TyrA. This interaction is necessary for the silent agonist activity of NS6740; when the hydrogen bond is blocked, silent agonist NS6740 converts to a conventional partial agonist and appreciably opens the channel in the absence of a positive allosteric modulator (EC_(50) 150 nM).

Item Type:Article
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Dougherty, Dennis A.0000-0003-1464-2461
Alternate Title:Investigating the Binding Interactions of NS6740, a Silent Agonist of the Nicotinic Receptor
Additional Information:© 2019 The American Society for Pharmacology and Experimental Therapeutics. Received February 21, 2019; accepted May 28, 2019. Published on June 7, 2019. The authors thank Dr. Chris Marotta for providing constructs. Authorship Contributions: Participated in research design: Blunt and Dougherty. Conducted experiments: Blunt. Performed data analysis: Blunt. Wrote or contributed to the writing of the manuscript: Blunt and Dougherty.
Subject Keywords:Allosterism; Electrophysiology; Mutagenesis; Nicotinic cholinergic receptors
Issue or Number:2
Record Number:CaltechAUTHORS:20190617-104154028
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Official Citation:Binding of the Silent Agonist NS6740. Catriona E. W. Blunt and Dennis A. Dougherty. Molecular Pharmacology August 1, 2019, 96 (2) 212-218; DOI:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:96459
Deposited By: Tony Diaz
Deposited On:17 Jun 2019 17:54
Last Modified:16 Nov 2021 17:21

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