Welcome to the new version of CaltechAUTHORS. Login is currently restricted to library staff. If you notice any issues, please email coda@library.caltech.edu
Published August 2019 | Accepted Version + Supplemental Material
Journal Article Open

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

Abstract

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).

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.

Attached Files

Accepted Version - mol.119.116244.full.pdf

Supplemental Material - 116244_Blunt_and_Dougherty_SI.pdf

Files

mol.119.116244.full.pdf
Files (625.7 kB)
Name Size Download all
md5:4931e51f4b63d30cf0fc0b27aa46a714
514.3 kB Preview Download
md5:0c585f279ee0c32bf6c1428d4946a145
111.4 kB Preview Download

Additional details

Created:
August 22, 2023
Modified:
October 20, 2023