Diarylamidines: High potency inhibitors of acid-sensing ion channels

Xuanmao Chen, Liyan Qiu, Minghua Li, Stefan Dürrnagel, Beverley A. Orser, Zhi Gang Xiong, John F. MacDonald

Research output: Contribution to journalArticlepeer-review

99 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1045-1053
Number of pages9
Issue number7
StatePublished - Jun 2010
Externally publishedYes


  • ASIC
  • Channel blockers
  • Diarylamidines
  • Pain

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience


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