JNJ-47965567
目录号 : GC43931
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。
Cas No.:1428327-31-4
Sample solution is provided at 25 µL, 10mM.
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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]。
| Cell experiment [1]: | |
Cell lines | Neural progenitor cells (NPCs) |
Preparation Method | Control hiPSC-derived Neural progenitor cells (NPCs) were cultured on 96-well plates at 90,000 cells/cm2 density and treated with different concentrations of ATP and BzATP and incubated at standard cultivation conditions for 24h. Cells were pretreated with 1µM JNJ-47965567 for 30min. Viability of the cultures was assessed using PrestoBlueTM Cell Viability Reagent. |
Reaction Conditions | 1µM; 30min |
Applications | The viability of the cells treated with lower concentrations of BzATP was not different from the untreated control, but the JNJ-47965567 pre-treated cells showed decreased viability. The viability of the cells treated with higher concentrations of BzATP was significantly decreased, and pre-treatment with JNJ-47965567 had no effect on the measured viability. |
| Animal experiment [2]: | |
Animal models | Sprague-Dawley rats |
Preparation Method | On day 1 of the experiment, animals were acclimated to the procedure room for at least 1 hour and then each cage was placed onto a MotorMonitor rack, which surrounded each animal cage by a grid of photobeams (7 beams along the width of the cage and 15 beams along the length). The photobeams allowed for tracking the distance traveled by each animal. After 1h, rats were injected subcutaneously with either vehicle (30% sulfobutylether beta-cyclodextrin) or JNJ-47965567 (30mg/kg) and locomotor activity was recorded for an additional hour. All animals then received an injection of d-amphetamine sulfate (2mg/kg, i.p.) and locomotor activity was recorded for 2 additional hours. On day 2-5, the The experiment was repeated in the same manner, with the same treatments provided each day. After 2 days of drug-withdrawal, the same procedure was repeated again on day 8 with another amphetamine challenge. |
Dosage form | 30mg/kg; s.c. |
Applications | JNJ-47965567 show significant effect on attenuating the sensitization of amphetamine induced locomotion. |
References: | |
| Cas No. | 1428327-31-4 | SDF | |
| Canonical SMILES | O=C(C1=CC=CN=C1SC2=CC=CC=C2)NCC3(CCOCC3)N(CC4)CCN4C5=CC=CC=C5 | ||
| 分子式 | C28H32N4O2S | 分子量 | 488.6 |
| 溶解度 | DMF: 30 mg/mL,DMSO: 30 mg/mL,DMSO:PBS(pH 7.2) (1:3): 0.25 mg/mL,Ethanol: 12.5 mg/mL | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.0467 mL | 10.2333 mL | 20.4666 mL |
| 5 mM | 0.4093 mL | 2.0467 mL | 4.0933 mL |
| 10 mM | 0.2047 mL | 1.0233 mL | 2.0467 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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计算结果:
工作液浓度： mg/ml；
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- Purity: >99.00%
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