Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Oct 12;60(19):8192-8200.
doi: 10.1021/acs.jmedchem.7b01072. Epub 2017 Sep 26.

Molecular Basis for Allosteric Inhibition of Acid-Sensing Ion Channel 1a by Ibuprofen

Affiliations

Molecular Basis for Allosteric Inhibition of Acid-Sensing Ion Channel 1a by Ibuprofen

Timothy Lynagh et al. J Med Chem. .

Abstract

A growing body of evidence links certain aspects of nonsteroidal anti-inflammatory drug (NSAID) pharmacology with acid-sensing ion channels (ASICs), a small family of excitatory neurotransmitter receptors implicated in pain and neuroinflammation. The molecular basis of NSAID inhibition of ASICs has remained unknown, hindering the exploration of this line of therapy. Here, we characterized the mechanism of inhibition, explored the molecular determinants of sensitivity, and sought to establish informative structure-activity relationships, using electrophysiology, site-directed mutagenesis, and voltage-clamp fluorometry. Our results show that ibuprofen is an allosteric inhibitor of ASIC1a, which binds to a crucial site in the agonist transduction pathway and causes conformational changes that oppose channel activation. Ibuprofen inhibits several ASIC subtypes, but certain ibuprofen derivatives show some selectivity for ASIC1a over ASIC2a and vice versa. These results thus define the NSAID/ASIC interaction and pave the way for small-molecule drug design targeting pain and inflammation.

Similar articles

See all similar articles

Cited by 5 articles

Publication types

MeSH terms

Substances

LinkOut - more resources

Feedback