摘要
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.
摘要译文
在这里，我们考察NS383，酸传感离子通道的一种新颖的小分子抑制剂的药理学（ASIC）中ASIC方法抑制NS383是其特征在于，膜片钳电studiesAnalgesic性疼痛四个大鼠行为模型进行评估结果NS383抑制^ h SUP + / SUP从大鼠的同聚ASIC1a，ASIC3记录激活的电流，异ASIC1a + 3与IC 50值从0℃至2糓然而，NS383是在含有AISC2a同聚ASIC2aHeteromeric受体如ASIC1a + 2a和ASIC2a阳性神经元+3完全失活，只有部分抑制，大概是作为化学计量依赖性bindingNS383（10鈥毫克/公斤，我并，阿米洛利（50鈥毫克/公斤，我并，对乙酰氨基酚（100鈥毫克/公斤，我并和的结果吗啡（3鈥毫克/公斤，我并）所有剂量依赖性减弱在大鼠福尔马林测试nocifensive行为，颠倒在完全弗氏佐剂发炎的大鼠病理炎性痛觉过敏，和在神经性painHowever的慢性挤压伤模型逆转机械超敏，而相比之下，对乙酰氨基酚和吗啡，运动功能不受NS383剂量至少8倍比那些是有效的疼痛模型更大，而镇痛剂量阿米洛利被认为是有毒的结论NS383是含有1a和/或3 subunitsIt大鼠的ASIC一个强有力的和独特的选择性抑制剂的耐受性良好，并且能够逆转病理painlike行为，想必通过外周作用，但也可能通过中枢性疼痛电路中的动作
Gordon Munro[1,*]; Jeppe K. Christensen[1]; Helle K. Erichsen[1]; Tino Dyhring[1,2]; Joachim Demnitz[1]; Eva Dam[1] and Philip K. Ahring[1,2,3];. NS383 Selectively Inhibits Acid-Sensing Ion Channels Containing 1a and 3 Subunits to Reverse Inflammatory and Neuropathic Hyperalgesia in Rats[J]. CNS Neuroscience & Therapeutics, 2016,22(2): 135-145