A-740003

P2X7 receptor antagonist CAS# 861393-28-4

A-740003

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Chemical structure

A-740003

3D structure

Chemical Properties of A-740003

Cas No. 861393-28-4 SDF Download SDF
PubChem ID 11351968 Appearance Powder
Formula C26H30N6O3 M.Wt 474.57
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 50 mg/mL (105.36 mM; Need ultrasonic)
H2O : < 0.1 mg/mL (insoluble)
Chemical Name N-[1-[(Z)-[(cyanoamino)-(quinolin-5-ylamino)methylidene]amino]-2,2-dimethylpropyl]-2-(3,4-dimethoxyphenyl)acetamide
SMILES CC(C)(C)C(NC(=O)CC1=CC(=C(C=C1)OC)OC)N=C(NC#N)NC2=CC=CC3=C2C=CC=N3
Standard InChIKey PUHSRMSFDASMAE-UHFFFAOYSA-N
Standard InChI InChI=1S/C26H30N6O3/c1-26(2,3)24(31-23(33)15-17-11-12-21(34-4)22(14-17)35-5)32-25(29-16-27)30-20-10-6-9-19-18(20)8-7-13-28-19/h6-14,24H,15H2,1-5H3,(H,31,33)(H2,29,30,32)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of A-740003

DescriptionPotent and selective P2X7 receptor antagonist (IC50 values are 18 and 40 nM for rat and human receptors respectively). Displays selectivity over a variety of P2X and P2Y receptors up to a concentration of 100 μM. Reduces nociception in animal models of persistent neuropathic and inflammatory pain. Also reduces neuroblastoma tumor growth in mice.

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Preparing Stock Solutions of A-740003

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.1072 mL 10.5359 mL 21.0717 mL 42.1434 mL 52.6793 mL
5 mM 0.4214 mL 2.1072 mL 4.2143 mL 8.4287 mL 10.5359 mL
10 mM 0.2107 mL 1.0536 mL 2.1072 mL 4.2143 mL 5.2679 mL
50 mM 0.0421 mL 0.2107 mL 0.4214 mL 0.8429 mL 1.0536 mL
100 mM 0.0211 mL 0.1054 mL 0.2107 mL 0.4214 mL 0.5268 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on A-740003

A-740003 is a selective and competitive antagonist of P2X7 receptor with IC50 values of 40 nM and 18 nM in human and rat, respectively [1].

P2X7 receptors are members of ATP-sensitive ionotropic P2X receptor family (P2X1–P2X7). P2X7 receptors can trigger various responses such as activation of caspases, cytokine release, membrane permeabilization, apoptosis and cell proliferation, in immunologically genetic cells [1].

Activated P2X7 receptors rapidly change intracellular calcium concentrations, the release of interleukin-1β (IL-1β), and cytolytic plasma membrane pore formation. In human THP-1 cells with a macrophage phenotype that P2X7 receptors were expressed, IL-1β release and pore formation were resulted from the activation of P2X7 receptors. A-740003 potently inhibited pore formation (measured by Yo-Pro uptake) with an IC50 value of 92 nM and blocked the release of IL-1β with an IC50 value of 156 nM [1].

Homomeric P2X7 receptors were activated by 2´,3´-O-(4-benzoylbenzoyl)-ATP (BzATP) and ATP at high concentrations. This property made homomeric P2X7 receptors different from other P2 receptor superfamily members. In 1321N1 cells stably expressing P2X7 receptors, BzATP changed intracellular calcium concentrations. A-740003 potently inhibited this change with an IC50 value of 18 nM when rat P2X7 receptors were expressed, and an IC50 value of 40 nM when human P2X7 receptors were expressed. A-740003 also inhibited intracellular Yo-Pro uptake with IC50 values of 138 nM and 93 nM, when the Yo-Pro uptake was mediated by rat and human P2X7 receptors, respectively [1].

Reference:
[1].  Prisca Honore, Diana Donnelly-Roberts, Marian T. Namovic, 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. Journal of Pharmacology and Experimental Therapeutics, 2006, 319:1376-1385.

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References on A-740003

Synthesis and initial preclinical evaluation of the P2X7 receptor antagonist [(1)(1)C]A-740003 as a novel tracer of neuroinflammation.[Pubmed:24995673]

J Labelled Comp Radiopharm. 2014 Jun 30;57(8):509-16.

Neuroinflammation, in particular activation of microglia, is thought to play an important role in the progression of neurodegenerative diseases. In activated microglia, the purinergic P2X7 receptor is upregulated. A-740003, a highly affine and selective P2X7 receptor antagonist, is a promising candidate for the development of a radiotracer for imaging of neuroinflammation by positron emission tomography. For this purpose, [(11)C]A-740003 was synthesised and evaluated in vivo with respect to both tracer metabolism and biodistribution. In plasma, a moderate metabolic rate was seen. In healthy rat brain, only marginal uptake of [(11)C]A-740003 was observed and, therefore, metabolites in brain could not be determined. Whether the minimal brain uptake is due to the low expression levels of the P2X7 receptor in healthy brain or to limited transport across the blood-brain barrier has yet to be elucidated.

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.[Pubmed:16982702]

J Pharmacol Exp Ther. 2006 Dec;319(3):1376-85.

ATP-sensitive P2X(7) receptors are localized on cells of immunological origin including glial cells in the central nervous system. Activation of P2X(7) receptors leads to rapid changes in intracellular calcium concentrations, release of the proinflammatory cytokine interleukin-1beta (IL-1beta), and following prolonged agonist exposure, cytolytic plasma membrane pore formation. P2X(7) knockout mice show reduced inflammation as well as decreased nociceptive sensitivity following peripheral nerve injury. A-740003 (N-(1-{[(cyanoimino)(5-quinolinylamino) methyl] amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide) is a novel competitive antagonist of P2X(7) receptors (IC(50) values = 40 nM for human and 18 nM for rat) as measured by agonist-stimulated changes in intracellular calcium concentrations. A-740003 showed weak or no activity (IC(50) > 10 muM) at other P2 receptors and an array of other neurotransmitter and peptide receptors, ion channels, reuptake sites, and enzymes. A-740003 potently blocked agonist-evoked IL-1beta release (IC(50) = 156 nM) and pore formation (IC(50) = 92 nM) in differentiated human THP-1 cells. Systemic administration of A-740003 produced dose-dependent antinociception in a spinal nerve ligation model (ED(50) = 19 mg/kg i.p.) in the rat. A-740003 also attenuated tactile allodynia in two other models of neuropathic pain, chronic constriction injury of the sciatic nerve and vincristine-induced neuropathy. In addition, A-740003 effectively reduced thermal hyperalgesia observed following intraplantar administration of carrageenan or complete Freund's adjuvant (ED(50) = 38-54 mg/kg i.p.). A-740003 was ineffective in attenuating acute thermal nociception in normal rats and did not alter motor performance at analgesic doses. These data demonstrate that selective blockade of P2X(7) receptors in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.

The P2X7 receptor is a key modulator of the PI3K/GSK3beta/VEGF signaling network: evidence in experimental neuroblastoma.[Pubmed:25619831]

Oncogene. 2015 Oct 8;34(41):5240-51.

Neuroblastoma (NB) is an aggressive pediatric tumor, responsible for 15% of cancer-related deaths in childhood, lacking an effective treatment in its advanced stages. The P2X7 receptor for extracellular ATP was associated to NB cell proliferation and recently emerged as a promoter of tumor engraftment, growth and vascularization. In an effort to identify new therapeutic options for neuroblastoma, we studied the role of P2X7 receptor in NB biology. We first analyzed the effect of P2X7 activation or down-modulation of the main biochemical ways involved in NB progression: the PI3K/Akt/GSK3beta/MYCN and the HIF1alpha/VEGF pathways. In ACN human NB cells, P2X7 stimulation enhanced PI3K/Akt, while decreasing GSK3beta activity. In the same model, P2X7 silencing or antagonist administration reduced the activity of PI3K/Akt and increased that of GSK3beta, leading to a decrease in cellular glycogen stores. Similarly, P2X7 downmodulation caused a reduction in HIF1alpha levels and vascular endothelial growth factor (VEGF) secretion. Systemic administration of two different P2X7 antagonists (AZ10606120 or A740003) in nude/nude mice reduced ACN-derived tumor growth. An even stronger effect of P2X7 blockade was obtained in a syngeneic immune-competent neuroblastoma model: Neuro2A cells injected in AlbinoJ mice. Together with tumor regression, treatment with P2X7 antagonists caused downmodulation of the Akt/HIF1alpha axis, leading to reduced VEGF content and decreased vessel formation. Interestingly, in both experimental models, P2X7 antagonists strongly reduced the expression of the probably best-accepted oncogene in NB: MYCN. Finally, we associated P2X7 overexpression with poor prognosis in advanced-stage NB patients. Taken together, our data suggest that P2X7 receptor is an upstream regulator of the main signaling pathways involved in NB growth, metabolic activity and angiogenesis, and a promising therapeutic target for neuroblastoma treatment.

Mammalian P2X7 receptor pharmacology: comparison of recombinant mouse, rat and human P2X7 receptors.[Pubmed:19558545]

Br J Pharmacol. 2009 Aug;157(7):1203-14.

BACKGROUND AND PURPOSE: Acute activation of P2X7 receptors rapidly opens a non-selective cation channel. Sustained P2X7 receptor activation leads to the formation of cytolytic pores, mediated by downstream recruitment of hemichannels to the cell surface. Species- and single-nucleotide polymorphism-mediated differences in P2X7 receptor activation have been reported that complicate understanding of the physiological role of P2X7 receptors. Studies were conducted to determine pharmacological differences between human, rat and mouse P2X7 receptors. EXPERIMENTAL APPROACH: Receptor-mediated changes in calcium influx and Yo-Pro uptake were compared between recombinant mouse, rat and human P2X7 receptors. For mouse P2X7 receptors, wild-type (BALB/c) and a reported loss of function (C57BL/6) P2X7 receptor were also compared. KEY RESULTS: BzATP [2,3-O-(4-benzoylbenzoyl)-ATP] was more potent than ATP in stimulating calcium influx and Yo-Pro uptake at rat, human, BALB/c and C57BL/6 mouse P2X7 receptors. Two selective P2X7 receptor antagonists, A-740003 and A-438079, potently blocked P2X7 receptor activation across mammalian species. Several reported P2X1 receptor antagonists [e.g. MRS 2159 (4-[(4-formyl-5-hydroxy-6-methyl-3-[(phosphonooxy)methyl}-2-pyridinyl)azo]-benzoi c acid), PPNDS and NF279] blocked P2X7 receptors. NF279 fully blocked human P2X7 receptors, but only partially blocked BALB/c P2X7 receptors and was inactive at C57BL/6 P2X7 receptors. CONCLUSIONS AND IMPLICATIONS: These data provide new insights into P2X7 receptor antagonist pharmacology across mammalian species. P2X7 receptor pharmacology in a widely used knockout background mouse strain (C57BL/6) was similar to wild-type mouse P2X7 receptors. Several structurally novel, selective and competitive P2X7 receptor antagonists show less species differences compared with earlier non-selective antagonists.

Novel P2X7 receptor antagonists ease the pain.[Pubmed:17471176]

Br J Pharmacol. 2007 Jul;151(5):565-7.

In recent months, a series of chemically diverse antagonists has been identified for the ATP-gated P2X(7) receptor. In particular, two classes of highly-selective competitive P2X(7) antagonists have been developed by Michael Jarvis and his colleagues at Abbott Laboratories. These di-substituted tetrazole and cyanoguanidine derivatives are outstanding for a number of reasons (not least their stability, selectivity, potency and, of course, reversibility); most exciting is their near equal potency at human and rodent P2X(7) isoforms. Armed with drugs such as A740003 and newer A438079, Jarvis and colleagues have explored the role of P2X(7) receptors in the onset and persistence of chronic pain in animal models. Their findings - and applicability to the human condition - are reviewed in this current issue of British Journal of Pharmacology. This accompanying Commentary describes the progress made by Jarvis and others in developing novel P2X(7) antagonists for pain relief.

Description

A-740003 is a potent, selective and competitive P2X7 receptor antagonist with IC50 values are 18 and 40 nM for rat and human P2X7 receptors, respectively.

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