JNJ-47965567 is a centrally permeable, high affinity, selective P2X7 antagonist with IC50 values of 5nM and 10nM for human and mouse P2X7 receptors, respectively[1]. The ATP-gated P2X7 receptor (P2X7R) is a non-selective cation channel that senses high extracellular ATP concentrations and has been considered a target for the treatment of neuroinflammatory and neurodegenerative diseases[2]. JNJ-47965567 can be used to study the role of P2X7 in central nervous system pathophysiological models[3].
In vitro, JNJ-47965567 (1µM) pre-treated human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells (NPCs) for 30min showed an inhibitory effect on cell viability at low concentrations of BzATP, but its effect was completely inhibited under the strong toxic conditions induced by high concentrations of BzATP[4].
In vivo, JNJ-47965567 (30mg/kg) was able to increase the seizure threshold in rats with a fully kindled model by subcutaneous injection, and its combination with carbamazepine significantly enhanced the anticonvulsant effect[1]. JNJ-47965567 (30mg/kg) was significantly attenuated by subcutaneous injection in SD rats by amphetamine-induced hyperactivity[5]. JNJ-47965567 (30mg/kg) was treated by intraperitoneal injection in female SOD1G93A mice, which reduced the body weight of mice and improved motor coordination and phenotypic scores[6].
References:
[1] Fischer W, Franke H, Krügel U, et al. Critical evaluation of P2X7 receptor antagonists in selected seizure models[J]. PLoS One, 2016, 11(6): e0156468.
[2] Zheng H, Liu Q, Zhou S, et al. Role and therapeutic targets of P2X7 receptors in neurodegenerative diseases[J]. Frontiers in Immunology, 2024, 15: 1345625.
[3] Bhattacharya A. Recent advances in CNS P2X7 physiology and pharmacology: focus on neuropsychiatric disorders[J]. Frontiers in Pharmacology, 2018, 9: 30.
[4] Francistiová L, Vörös K, Lovász Z, et al. Detection and functional evaluation of the P2X7 receptor in hiPSC derived neurons and microglia-like cells[J]. Frontiers in Molecular Neuroscience, 2022, 14: 793769.
[5] Bhattacharya A, Wang Q, Ao H, et al. Pharmacological characterization of a novel centrally permeable P2X7 receptor antagonist: JNJ‐47965567[J]. British journal of pharmacology, 2013, 170(3): 624-640.
[6] Ruiz-Ruiz C, García-Magro N, Negredo P, et al. Chronic administration of P2X7 receptor antagonist JNJ-47965567 delays disease onset and progression, and improves motor performance in ALS SOD1G93A female mice[J]. Disease Models & Mechanisms, 2020, 13(10): dmm045732.
JNJ-47965567是一种中枢通透性、高亲和力、选择性P2X7拮抗剂，对人和小鼠P2X7受体作用的IC50值分别为5nM和10nM[1]。ATP门控的P2X7受体（P2X7R）是一种非选择性阳离子通道，感受高细胞外ATP浓度，已被认为是治疗神经炎症和神经退行性疾病的靶标[2]。JNJ-47965567能够用于研究P2X7 在中枢神经系统病理生理模型中的作用[3]。
在体外，JNJ-47965567（1µM）预处理人类诱导性多能干细胞（hiPSC）衍生的神经祖细胞（NPCs）30min，在低浓度BzATP下表现出对细胞活性的抑制作用，但在高浓度BzATP引发的强烈毒性条件下，其作用被完全抑制[4]。
在体内，JNJ-47965567（30mg/kg）通过皮下注射治疗完全点燃模型大鼠，能够增加癫痫发作阈值，与Carbamazepine联用显著提高了抗惊厥效果[1]。JNJ-47965567（30mg/kg）通过皮下注射治疗SD大鼠，显著减弱了苯丙胺诱导的多动症[5]。JNJ-47965567（30mg/kg）通过腹膜内注射治疗雌性SOD1G93A小鼠，减轻了小鼠体重，改善了运动配位和表型得分[6]。