A-740003

A-740003 is an orally active P2X7 receptor antagonist (IC₅₀=40nM). A-740003 reduces IL-1β release and pore formation in the cell membrane by inhibiting ATP binding to the P2X7 receptor, while also alleviating neuropathic pain and inflammatory responses by blocking P2X7 receptor activation. A-740003 can be used in research related to neuropathic pain, inflammatory pain, and neuroblastoma^[1-4].

In vitro, MC3T3-E1 cells were co-treated with A-740003 (10μM), Wnt3a (20ng/ml), and BzATP (300μM) for 24 hours. A-740003 significantly inhibited the BzATP-induced potentiation of Wnt3a signaling^[5]. MC3T3-E1 or UMR-106 cells were incubated with A-740003 (10μM), and proton efflux was measured immediately. A-740003 had no significant effect on basal proton efflux but significantly blocked the sustained phase of the BzATP-induced response in both cell types^[6].

In vivo, A-740003 (10μM; 0.5μl/hour) was intracerebroventricularly infused into rats with pilocarpine-induced status epilepticus (SE) for 2 weeks. A-740003 increased the number of Fluoro-Jade B (FJB)-positive neurons in the CA3 region of the hippocampus^[7]. A-740003 (100nmol; 0.3μl; single) was injected intracerebroventricularly (into the vlPAG) in a rat model of bone cancer pain. A-740003 antagonized the analgesic effect of tramadol^[8].

References:
[1] Janssen B, Vugts DJ, Funke U, et al. Synthesis and initial preclinical evaluation of the P2X7 receptor antagonist [¹¹C]A-740003 as a novel tracer of neuroinflammation. J Labelled Comp Radiopharm. 2014 Jun 30;57(8):509-16.
[2] Honore P, Donnelly-Roberts D, Namovic MT, et al. A-740003 [N-(1-{[(cyanoimino)(5-quinolinylamino) methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a novel and selective P2X7 receptor antagonist, dose-dependently reduces neuropathic pain in the rat. J Pharmacol Exp Ther. 2006 Dec;319(3):1376-85.
[3] Zhang B, Zhang P, Li T, et al. P2X7 Receptor in Microglia Contributes to Propofol-induced Unconsciousness by Regulating Synaptic Plasticity in Mice. Neuroscience. 2023 Jul 15;523:157-172.
[4] Liu Y, Liu Q, Xu Z, et al. P2X7 Receptor acts as a novel target for ameliorating Sepsis-induced skeletal muscle atrophy in mice model. Shock. 2025 Sep 5.
[5] Grol MW, Zelner I, Dixon SJ. P2X₇-mediated calcium influx triggers a sustained, PI3K-dependent increase in metabolic acid production by osteoblast-like cells. Am J Physiol Endocrinol Metab. 2012 Mar 1;302(5):E561-75.
[6] Grol MW, Brooks PJ, Pereverzev A, et al. P2X7 nucleotide receptor signaling potentiates the Wnt/β-catenin pathway in cells of the osteoblast lineage. Purinergic Signal. 2016 Sep;12(3):509-20.
[7] Kim JE, Ryu HJ, Kang TC. P2X7 receptor activation ameliorates CA3 neuronal damage via a tumor necrosis factor-α-mediated pathway in the rat hippocampus following status epilepticus. J Neuroinflammation. 2011 Jun 2;8:62.
[8] Li P, Zhang Q, Xiao Z, et al. Activation of the P2X7 receptor in midbrain periaqueductal gray participates in the analgesic effect of tramadol in bone cancer pain rats. Mol Pain. 2018 Jan-Dec;14:1744806918803039.

A-740003是一种具有口服活性的P2X7受体拮抗剂（IC₅₀=40nM）。A-740003可通过抑制ATP在P2X7受体上的结合来减少IL-1β释放和细胞膜孔隙形成，同时通过阻断P2X7受体激活来减轻神经性疼痛和炎症反应。A-740003可用于神经性疼痛、炎症性疼痛和神经母细胞瘤的相关研究^[1-4]。

在体外，A-740003（10μM）与Wnt3a（20ng/ml）和BzATP（300μM）共同处理MC3T3-E1细胞24小时。A-740003显著抑制BzATP诱导的Wnt3a信号通路增强^[5]。A-740003（10μM）孵育MC3T3-E1或UMR-106细胞，并立即检测细胞质子外流情况。A-740003对基底质子外流无显著效果，但均显著阻断了BzATP诱导反应的持续阶段^[6]。

在体内，A-740003（10μM；0.5μl/hour）通过脑室内输注，用于处理癫痫持续状态（SE）诱导的大鼠，持续2周。A-740003增加了小鼠CA3区FJB阳性神经元的数量^[7]。A-740003（100nM；0.3μl；单次）通过脑室内（vlPAG）注射于骨癌疼痛模型大鼠。A-740003拮抗了Tramadol（曲马多）的镇痛作用^[8]。