Amiloride Analogs as ASIC1a Inhibitors

CNS Neuroscience & Therapeutics
Tiandong LengZhi-Gang Xiong

Abstract

ASIC1a, the predominant acid-sensing ion channels (ASICs), is implicated in neurological disorders including stroke, traumatic spinal cord injury, and ALS. Potent ASIC1a inhibitors should have promising therapeutic potential for ASIC1a-related diseases. We examined the inhibitory effects of a number of amiloride analogs on ASIC1a currents, aimed at understanding the structure-activity relationship and identifying potent ASIC1a inhibitors for stroke intervention. Whole-cell patch-clamp techniques and a mouse model of middle cerebral artery occlusion (MCAO)-induced focal ischemia were used. Surflex-Dock was used to dock the analogs into the pocket with default parameters. Amiloride and its analogs inhibit ASIC1a currents expressed in Chinese hamster ovary cells with a potency rank order of benzamil > phenamil > 5-(N,N-dimethyl)amiloride (DMA) > amiloride > 5-(N,N-hexamethylene)amiloride (HMA) ≥ 5-(N-methyl-N-isopropyl)amiloride (MIA) > 5-(N-ethyl-N-isopropyl)amiloride (EIPA). In addition, amiloride and its analogs inhibit ASIC currents in cortical neurons with the same potency rank order. In mice, benzamil and EIPA decreased MCAO-induced infarct volume. Similar to its effect on the ASIC current, benzamil showed a much higher pote...Continue Reading

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Citations

Jul 10, 2016·European Journal of Medicinal Chemistry·Shukkoor M KondengadenPeng George Wang
May 22, 2018·PloS One·Aram J KrausonMarcelo D Carattino
Mar 9, 2020·Bulletin of Experimental Biology and Medicine·E I SolntsevaV G Skrebitsky
Apr 25, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Axel SchmidtGáspár Jékely
Dec 6, 2016·CNS Neuroscience & Therapeutics·Bao-Ming WuZhi-Gang Xiong

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