title: Amiloride Analogs as ASIC1a Inhibitors.
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 potency than EIPA.
  
  
  
  Addition of a benzyl group to the terminal guanidinyl group resulted in enhanced inhibitory activity on ASIC1a. On the other hand, the bulky groups added to the 5-amino residues slightly decreased the activity. Among the tested amiloride analogs, benzamil is the most potent ASIC1a inhibitor.
authors.affiliation: Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USA.
authors.forename: Tian-Dong
authors.initials: TD
authors.lastname: Leng
authors.affiliation: Anhui Medical University, School of Pharmacy, Hefei, Anhui, China.
authors.forename: Hong-Fang
authors.initials: HF
authors.lastname: Si
authors.affiliation: Anhui Medical University, School of Pharmacy, Hefei, Anhui, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA.
authors.forename: Mengyuan
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA.
authors.forename: Binghe
authors.initials: B
authors.lastname: Wang
authors.affiliation: Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USA.
authors.forename: Roger P
authors.initials: RP
authors.lastname: Simon
authors.affiliation: Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USA.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Xiong
mesh_terms: D062565:Acid Sensing Ion Channels / Q000502:physiology*; D000584:Amiloride / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001703:Biophysics; D016466:CHO Cells; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D014162:Transfection
chemical_list: D062565:Acid Sensing Ion Channels; C568268:Asic1 protein, rat; D000584:Amiloride
keywords: Acid-sensing ion channel; Amiloride; Benzamil; Neuroprotection; Stroke