title: Diarylamidines: high potency inhibitors of acid-sensing ion channels.
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 microM, 0.3 microM, 1.5 microM and 38 microM, respectively. These four compounds (100 microM) 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 >or= 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.
authors.affiliation: Department of Physiology, University of Toronto, Canada.
authors.forename: Xuanmao
authors.initials: X
authors.lastname: Chen
authors.forename: Liyan
authors.initials: L
authors.lastname: Qiu
authors.forename: Minghua
authors.initials: M
authors.lastname: Li
authors.forename: Stefan
authors.initials: S
authors.lastname: Dürrnagel
authors.forename: Beverley A
authors.initials: BA
authors.lastname: Orser
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Xiong
authors.forename: John F
authors.initials: JF
authors.lastname: MacDonald
mesh_terms: D062565:Acid Sensing Ion Channels; D000578:Amidines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004133:Diminazene / Q000008:administration & dosage / Q000494:pharmacology; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000008:administration & dosage / Q000494:pharmacology*; D009865:Oocytes; D010419:Pentamidine / Q000008:administration & dosage / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism; D013266:Stilbamidines / Q000008:administration & dosage / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: C568267:ASIC1 protein, mouse; D062565:Acid Sensing Ion Channels; D000578:Amidines; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels; D007211:Indoles; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D015222:Sodium Channels; D013266:Stilbamidines; C100274:hydroxystilbamidine; C007293:DAPI; D010419:Pentamidine; D004133:Diminazene