Emerging data continues to point towards a relationship between neuroinflammation and neuropsychiatric disorders. ATP-induced activation of P2X7 results in IL-1β release causing neuroinflammation and microglial activation. This study describes the in-vitro and in-vivo neuropharmacology of a novel brain-penetrant P2X7 antagonist, JNJ-55308942, currently in clinical development. JNJ-55308942 is a high-affinity, selective, brain-penetrant (brain/plasma of 1) P2X7 functional antagonist. In human blood and in mouse blood and microglia, JNJ-55308942 attenuated IL-1β release in a potent and concentration-dependent manner. After oral dosing, the compound exhibited both dose and concentration-dependent occupancy of rat brain P2X7 with an ED₅₀ of 0.07 mg/kg. The P2X7 antagonist (3 mg/kg, oral) blocked Bz-ATP-induced brain IL-1β release in conscious rats, demonstrating functional effects of target engagement in the brain. JNJ-55308942 (30 mg/kg, oral) attenuated LPS-induced microglial activation in mice, assessed at day 2 after a single systemic LPS injection (0.8 mg/kg, i.p.), suggesting a role for P2X7 in microglial activation. In a model of BCG-induced depression, JNJ-55308942 dosed orally (30 mg/kg), reversed the BCG-induced deficits of sucrose preference and social interaction, indicating for the first time a role of P2X7 in the BCG model of depression, probably due to the neuroinflammatory component induced by BCG inoculation. Finally, in a rat model of chronic stress induced sucrose intake deficit, JNJ-55308942 reversed the deficit with concurrent high P2X7 brain occupancy as measured by autoradiography. This body of data demonstrates that JNJ-55308942 is a potent P2X7 antagonist, engages the target in brain, modulates IL-1β release and microglial activation leading to efficacy in two models of anhedonia in rodents.

中文翻译：

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JNJ-55308942的神经心理药理学：在神经炎症和快感缺乏症动物模型中评估靶向P2X7离子通道的临床候选药物。

新兴数据继续指向神经炎症与神经精神疾病之间的关系。ATP诱导的P2X7活化导致IL-1β释放，引起神经炎症和小胶质细胞活化。这项研究描述了目前正在临床开发中的新型脑穿透性P2X7拮抗剂JNJ-55308942的体外和体内神经药理学。JNJ-55308942是一种高亲和力，选择性，脑渗透剂（1个脑/血浆）P2X7功能拮抗剂。在人血以及小鼠血液和小胶质细胞中，JNJ-55308942以有效且浓度依赖性的方式减弱了IL-1β的释放。口服给药后，该化合物对大鼠脑P2X7的ED ₅₀表现出剂量和浓度依赖性0.07 mg / kg。P2X7拮抗剂（3 mg / kg，口服）在有意识的大鼠中阻断了Bz-ATP诱导的脑IL-1β的释放，证明了靶标参与脑部的功能作用。JNJ-55308942（30 mg / kg，口服）在单次系统性LPS注射（0.8 mg / kg，ip）后第2天评估了LPS诱导的小鼠小胶质细胞激活的减弱，表明P2X7在小胶质细胞激活中的作用。在BCG诱发的抑郁症模型中，JNJ-55308942口服（30 mg / kg）逆转了BCG引起的蔗糖偏爱和社交互动缺失，这首次表明P2X7在BCG抑郁症模型中的作用，可能是由于BCG接种引起的神经炎症成分。最后，在慢性应激引起的蔗糖摄入不足的大鼠模型中，JNJ-55308942通过放射线照相术可逆转并发高P2X7脑占用率的缺陷。大量数据表明，JNJ-55308942是有效的P2X7拮抗剂，可与脑中的靶标接合，调节IL-1β的释放和小胶质细胞活化，从而在啮齿动物性快感缺乏症的两种模型中发挥功效。