A-317491, a novel potent and selective nonnucleotide antagonist of P2X3 and P2X2/3 receptors, reduces chronic inflammatory and neuropathic pain in the rat
A-317491, a novel potent and selective nonnucleotide antagonist of P2X3 and P2X2/3 receptors, reduces chronic inflammatory and neuropathic pain in the rat
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DOI：
10.1073/pnas.252537299
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发表时间：
2002-12-24
影响因子：
11.1
通讯作者：
Faltynek, C
中科院分区：
文献类型：
--
作者：
Jarvis, MF;Burgard, EC;Faltynek, C
P2X(3) 和 P2X(2/3) 受体高度定位于感觉传入神经的外周和中枢过程，这些通道的激活有助于 ATP 的促伤害作用。 A-317491 是一种新型非核苷酸拮抗剂，可激活 P2X3 和 P2X2/3 受体。 A-317491 可有效阻断重组人和大鼠 P2X(3) 和 P2X(2/3) 受体介导的钙通量 (K-i = 22-92 nM)，并且对其他 P2 受体和其他神经递质受体、离子通道和酶具有高度选择性 (IC50 > 10 muM)。 A-317491 还阻断大鼠背根神经节神经元中的天然 P2X3 和 P2X2/3 受体。含有 P2X3 的通道的阻断是立体特异性的，因为 A-317491 的 R 对映体 (A-317344) 对 P2X3 和 P2X2/3 受体的活性显着降低。 A-317491 剂量依赖性（ED50 = 30 mumol/kg s.c.）可减少大鼠中完全弗氏佐剂诱导的热痛觉过敏。 A-317491 在减轻慢性神经收缩损伤后的热痛觉过敏和机械异常性疼痛方面最有效（ED50 = 10-15 mumol/kg s.c.）。 R-对映体 A-317344 在这些慢性疼痛模型中没有活性。尽管在慢性疼痛模型中具有活性，但 A-317491 在减少急性疼痛、术后疼痛和内脏痛动物模型中的结节感觉方面无效（ED50 > 100 [μmol/kg s.c.）。目前的数据表明，P2X（3）和P2X（2/3）受体的有效和选择性拮抗剂可有效减少神经损伤和慢性炎症伤害感受，但P2X（3）和P2X（2/3）受体激活可能不是急性、急性炎症或内脏痛的主要介质。
P2X(3) and P2X(2/3) receptors are highly localized on peripheral and central processes of sensory afferent nerves, and activation of these channels contributes to the pronociceptive effects of ATP. A-317491 is a novel non-nucleotide antagonist of P2X3 and P2X2/3 receptor activation. A-317491 potently blocked recombinant human and rat P2X(3) and P2X(2/3) receptor-mediated calcium flux (K-i = 22-92 nM) and was highly selective (IC50 > 10 muM) over other P2 receptors and other neurotransmitter receptors, ion channels, and enzymes. A-317491 also blocked native P2X3 and P2X2/3 receptors in rat dorsal root ganglion neurons. Blockade of P2X3 containing channels was stereospecific because the R-enantiomer (A-317344) of A-317491 was significantly less active at P2X3 and P2X2/3 receptors. A-317491 dosedependently (ED50 = 30 mumol/kg s.c.) reduced complete Freund's adjuvant-induced thermal hyperalgesia in the rat. A-317491 was most potent (ED50 = 10-15 mumol/kg s.c.) in attenuating both thermal hyperalgesia and mechanical allodynia after chronic nerve constriction injury. The R-enantiomer, A-317344, was inactive in these chronic pain models. Although active in chronic pain models, A-317491 was ineffective (ED50 > 100 [mumol/kg s.c.) in reducing nodception in animal models of acute pain, postoperative pain, and visceral pain. The present data indicate that a potent and selective antagonist of P2X(3) and P2X(2/3) receptors effectively reduces both nerve injury and chronic inflammatory nociception, but P2X(3) and P2X(2/3) receptor activation may not be a major mediator of acute, acute inflammatory, or visceral pain.