Pharmacological characterization of a novel centrally permeable P2X7 receptor antagonist: JNJ-47965567
Pharmacological characterization of a novel centrally permeable P2X7 receptor antagonist: JNJ-47965567
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DOI：
10.1111/bph.12314
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发表时间：
2013-10-01
影响因子：
7.3
通讯作者：
Letavic, Michael A.
中科院分区：
文献类型：
--
作者：
Bhattacharya, Anindya;Wang, Qi;Letavic, Michael A.
背景与目的越来越多的证据表明，中枢神经系统嘌呤能受体P2X，配体门控离子通道7 （P2X7）可能在神经精神病学、神经变性和慢性疼痛中起关键作用。在这项研究中，我们鉴定了JNJ-47965567，一种具有中心渗透性、高亲和力、选择性的P2X7拮抗剂。实验方法我们在重组和天然系统中使用了体外测定（钙通量，放射性配体结合，电生理，IL-1释放）的组合。通过体外受体结合放射自显像和体内阻断Bz-ATP诱导的大鼠脑IL-1释放，证实JNJ-47965567与靶标结合。最后，在抑郁、躁狂和神经性疼痛标准模型中检验JNJ-47965567的疗效。jnj -47965567是强效高亲和力（pK(i) 7.9 0.07）的选择性人P2X7拮抗剂，未观察到明显的物种形成。在天然系统中，化合物减弱IL-1释放的效价为6.7 +/- 0.07（人血液），7.5 +/- 0.07（人单核细胞）和7.1 +/- 0.1（大鼠小胶质细胞）。JNJ-47965567在大鼠脑中表现出靶向作用，脑EC50为78 +/- 19ngmL(-1) （P2X7受体放射自显影），Bz-ATP诱导IL-1释放功能阻滞。JNJ-47965567 （30mgkg(-1)）减轻了安非他明引起的多动症，并在神经性疼痛大鼠模型中表现出适度但显著的疗效。强迫游泳试验未见疗效。结论与意义jnj -47965567是一种具有中枢通透性、高亲和力的P2X7拮抗剂，可用于探讨中枢P2X7在啮齿动物中枢神经系统病理生理模型中的作用。
Background and PurposeAn increasing body of evidence suggests that the purinergic receptor P2X, ligand-gated ion channel, 7 (P2X7) in the CNS may play a key role in neuropsychiatry, neurodegeneration and chronic pain. In this study, we characterized JNJ-47965567, a centrally permeable, high-affinity, selective P2X7 antagonist.Experimental ApproachWe have used a combination of in vitro assays (calcium flux, radioligand binding, electrophysiology, IL-1 release) in both recombinant and native systems. Target engagement of JNJ-47965567 was demonstrated by ex vivo receptor binding autoradiography and in vivo blockade of Bz-ATP induced IL-1 release in the rat brain. Finally, the efficacy of JNJ-47965567 was tested in standard models of depression, mania and neuropathic pain.Key ResultsJNJ-47965567 is potent high affinity (pK(i) 7.9 0.07), selective human P2X7 antagonist, with no significant observed speciation. In native systems, the potency of the compound to attenuate IL-1 release was 6.7 +/- 0.07 (human blood), 7.5 +/- 0.07 (human monocytes) and 7.1 +/- 0.1 (rat microglia). JNJ-47965567 exhibited target engagement in rat brain, with a brain EC50 of 78 +/- 19ngmL(-1) (P2X7 receptor autoradiography) and functional block of Bz-ATP induced IL-1 release. JNJ-47965567 (30mgkg(-1)) attenuated amphetamine-induced hyperactivity and exhibited modest, yet significant efficacy in the rat model of neuropathic pain. No efficacy was observed in forced swim test.Conclusion and ImplicationsJNJ-47965567 is centrally permeable, high affinity P2X7 antagonist that can be used to probe the role of central P2X7 in rodent models of CNS pathophysiology.