title: NS383 Selectively Inhibits Acid-Sensing Ion Channels Containing 1a and 3 Subunits to Reverse Inflammatory and Neuropathic Hyperalgesia in Rats.
abstract: OBJECTIVE
  Here, we investigate the pharmacology of NS383, a novel small molecule inhibitor of acid-sensing ion channels (ASICs).
  
  
  METHODS
  ASIC inhibition by NS383 was characterized in patch-clamp electrophysiological studies. Analgesic properties were evaluated in four rat behavioral models of pain.
  
  
  RESULTS
  NS383 inhibited H(+)-activated currents recorded from rat homomeric ASIC1a, ASIC3, and heteromeric ASIC1a+3 with IC50 values ranging from 0.61 to 2.2 μM. However, NS383 was completely inactive at homomeric ASIC2a. Heteromeric receptors containing AISC2a, such as ASIC1a+2a and ASIC2a+3, were only partially inhibited, presumably as a result of stoichiometry-dependent binding. NS383 (10-60 mg/kg, i.p.), amiloride (50-200 mg/kg, i.p.), acetaminophen (100-400 mg/kg, i.p.), and morphine (3-10 mg/kg, i.p.) all dose-dependently attenuated nocifensive behaviors in the rat formalin test, reversed pathological inflammatory hyperalgesia in complete Freund's adjuvant-inflamed rats, and reversed mechanical hypersensitivity in the chronic constriction injury model of neuropathic pain. However, in contrast to acetaminophen and morphine, motor function was unaffected by NS383 at doses at least 8-fold greater than those that were effective in pain models, whilst analgesic doses of amiloride were deemed to be toxic.
  
  
  CONCLUSIONS
  NS383 is a potent and uniquely selective inhibitor of rat ASICs containing 1a and/or 3 subunits. It is well tolerated and capable of reversing pathological painlike behaviors, presumably via peripheral actions, but possibly also via actions within central pain circuits.
authors.affiliation: NeuroSearch A/S, Ballerup, Denmark.
authors.forename: Gordon
authors.initials: G
authors.lastname: Munro
authors.affiliation: NeuroSearch A/S, Ballerup, Denmark.
authors.forename: Jeppe K
authors.initials: JK
authors.lastname: Christensen
authors.affiliation: NeuroSearch A/S, Ballerup, Denmark.
authors.forename: Helle K
authors.initials: HK
authors.lastname: Erichsen
authors.affiliation: NeuroSearch A/S, Ballerup, Denmark.|Saniona A/S, Ballerup, Denmark.
authors.forename: Tino
authors.initials: T
authors.lastname: Dyhring
authors.affiliation: NeuroSearch A/S, Ballerup, Denmark.
authors.forename: Joachim
authors.initials: J
authors.lastname: Demnitz
authors.affiliation: NeuroSearch A/S, Ballerup, Denmark.
authors.forename: Eva
authors.initials: E
authors.lastname: Dam
authors.affiliation: NeuroSearch A/S, Ballerup, Denmark.|Saniona A/S, Ballerup, Denmark.|Faculty of Pharmacy, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Philip K
authors.initials: PK
authors.lastname: Ahring
mesh_terms: D062646:Acid Sensing Ion Channel Blockers / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D062565:Acid Sensing Ion Channels / Q000502:physiology; D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D010091:Oximes / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats
chemical_list: C568269:ASIC3 protein, rat; D062646:Acid Sensing Ion Channel Blockers; D062565:Acid Sensing Ion Channels; D000700:Analgesics; C568268:Asic1 protein, rat; D006575:Heterocyclic Compounds, 3-Ring; C000611573:NS383 compound; D010091:Oximes; D021122:Protein Subunits
keywords: Acid-sensing ion channel; Acid-sensing ion channel blockers; Electrophysiology; Hyperalgesia; Morphine