https://dx.doi.org/10.1016/j.neuropharm.2010.01.011">
 

Abstract

Acid-sensing ion channels (ASICs) are proton-gated cation channels that are predominantly expressed in the nervous system. ASICs are involved in a number of neurological diseases such as pain, ischemic stroke and multiple sclerosis but limited tools are available to target these channels and provide probes for their physiological functions. Here we report that the anti-protozoal diarylamidines, 4′,6-diamidino-2-phenylindole (DAPI), diminazene, hydroxystilbamidine (HSB) and pentamidine potently inhibit ASIC currents in primary cultured hippocampal neurons with apparent affinities of 2.8 μM, 0.3 μM, 1.5 μM and 38 μM, respectively. These four compounds (100 μM) failed to block ENaC channels expressed in oocytes. Sub-maximal concentrations of diminazene also strongly accelerated desensitization of ASIC currents in hippocampal neurons. Diminazene blocked ASIC1a, -1b -2a, and -3 currents expressed in CHO cells with a rank order of potency 1b > 3 > 2a ≥ 1a. Patchdock computational analysis suggested a binding site of diarylamidines on ASICs. This study indicates diarylamidines constitute a novel class of non-amiloride ASIC blockers and suggests that diarylamidines may be developed as therapeutic agents in treatment of ASIC-involved diseases.

Publication Date

1-28-2010

Journal Title

Neuropharmacology

Publisher

Elsevier

Digital Object Identifier (DOI)

https://dx.doi.org/10.1016/j.neuropharm.2010.01.011

Document Type

Article

Rights

© 2010 Published by Elsevier Ltd. All rights reserved.

Comments

This is an Accepted Manuscript of an article published by Elsevier in Neuropharmacology in 2010, available online: https://dx.doi.org/10.1016/j.neuropharm.2010.01.011.

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