NS383 Selectively Inhibits Acid‐Sensing Ion Channels Containing 1a and 3 Subunits to Reverse Inflammatory and Neuropathic Hyperalgesia in Rats

• Published in: CNS neuroscience & therapeutics 2016-02, Vol.22 (2), p.135-145
• Main Authors: Munro, Gordon, Christensen, Jeppe K., Erichsen, Helle K., Dyhring, Tino, Demnitz, Joachim, Dam, Eva, Ahring, Philip K.
• Format: Article
• Language: English
• Subjects: Acid Sensing Ion Channel Blockers - chemistry; Acid Sensing Ion Channel Blockers - pharmacology; Acid Sensing Ion Channel Blockers - therapeutic use; Acid Sensing Ion Channels - physiology; Acid‐sensing ion channel; Acid‐sensing ion channel blockers; Analgesics - chemistry; Analgesics - pharmacology; Analgesics - therapeutic use; Animals; CHO Cells; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Electrophysiology; Heterocyclic Compounds, 3-Ring - chemistry; Heterocyclic Compounds, 3-Ring - pharmacology; Heterocyclic Compounds, 3-Ring - therapeutic use; Hyperalgesia; Hyperalgesia - drug therapy; Hyperalgesia - physiopathology; Male; Morphine; Neuralgia - drug therapy; Neuralgia - physiopathology; Original; Oximes - chemistry; Oximes - pharmacology; Oximes - therapeutic use; Pain Measurement - drug effects; Pain Measurement - methods; Protein Subunits - antagonists & inhibitors; Protein Subunits - physiology; Rats
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.12487

Summary Aims 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.