Diarylamidines: High affinity inhibitors of acid-sensing ion channels
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1
University of Toronto, Department of Physiology, Canada
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2
Legacy Research, Robert S. Dow Neurobiology Laboratories, United States
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3
University of Toronto, Sunnybrook Health Sciences Centre, Canada
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4
University of Toronto, Department of Aesthesia, Canada
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5
University of Western Ontario, Robarts Research Institute, Canada
Acid-sensing ion channels (ASICs) are proton-gated cation channels that are predominantly and widely expressed in the peripheral and central nervous systems. ASICs are involved in a number of neurological diseases such as pain, seizure, stroke and multiple sclerosis but few agents are available to target these channels and provide probes for their physiological functions. Here we report that the antiprotozoal diarylamidines: diminazene, hydroxystilbamidine (HSB) and pentamidine potently inhibit ASIC currents in primary cultured hippocampal neurons with apparent affinities of 0.3 µM, 1.5 µM and 38 µM, respectively. 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 revealed diarylamidines likely bind to ASIC in a groove-shaped region formed by the beta-ball and the palm domain. This study indicates diarylamidines represent a novel class of non-diuretic ASIC blockers and suggests that diarylamidines or agents based on a similar structure maybe developed as therapeutic agents to target ASIC-involved diseases.
Conference:
B.R.A.I.N. platform in Physiology poster day 2009, Toronto, ON, Canada, 16 Dec - 16 Dec, 2009.
Presentation Type:
Poster Presentation
Topic:
Poster presentations
Citation:
Chen
X,
Qiu
L,
Li
M,
Xiong
Z,
Orser
B and
MacDonald
JF
(2009). Diarylamidines: High affinity inhibitors of acid-sensing ion channels.
Front. Neurosci.
Conference Abstract:
B.R.A.I.N. platform in Physiology poster day 2009.
doi: 10.3389/conf.neuro.03.2009.17.007
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Received:
16 Dec 2009;
Published Online:
16 Dec 2009.
*
Correspondence:
Xuanmao Chen, University of Toronto, Department of Physiology, Toronto, Canada, xuanmao.chen@utoronto.ca