A-740003

Names

[ Name ]:
A-740003

[Synonym ]:
N-{1-[N''-Cyano-N'-(quinolin-5-yl)carbamimidamido]-2,2-dimethylpropyl}-2-(3,4-dimethoxyphenyl)acetamide
N-(1-{(E)-[(Cyanoamino)(5-quinolinylamino)methylene]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide
cc-516
UNII:532OV6WA05
Benzeneacetamide, N-[1-[[(1E)-(cyanoamino)(5-quinolinylamino)methylene]amino]-2,2-dimethylpropyl]-3,4-dimethoxy-
CS-0297
A-740003

Biological Activity

[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.

[Related Catalog]:

Signaling Pathways >> Membrane Transporter/Ion Channel >> P2X Receptor

Research Areas >> Neurological Disease

[Target]

IC50: 18 nM (rat P2X7 receptor), 40 nM (human P2X7 receptor)

[In Vitro]

A 438079 or A 740003 (10 μM) significantly blocks the sustained phase of the BzATP-induced response[1]. A-740003 infusion reduces SE-induced TNF-α expression in dentate granule cells. A-740003 infusions increases SE-induced neuronal death[2]. A-740003 and A-438079 show significantly greater potency in blocking P2X7 receptor activation across all species compared with other antagonists. A-740003 and A-438079 show greater activity at rat and human, as compared with mouse P2X7 receptors[3]. A-740003 potently blocks agonist-evoked IL-1β release with (IC50=156 nM) and pore formation (IC50=92 nM) in differentiated human THP-1 cells[4].

[In Vivo]

Systemic administration of A-740003 produces dose-dependent antinociception in a spinal nerve ligation model (ED50=19 mg/kg i.p.) in the rat. A-740003 also attenuates 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 reduces thermal hyperalgesia observed following intraplantar administration of carrageenan or complete Freund's adjuvant (ED50=38-54 mg/kg i.p.). A-740003 is ineffective in attenuating acute thermal nociception in normal rats and does not alter motor performance at analgesic doses[4].

[Animal admin]

The response to acute thermal stimulation is determined using a commercially available paw thermal stimulator. Rats are placed individually in Plexiglas cubicles mounted on a glass surface maintained at 30°C and allowed a 30-min habituation period. A thermal stimulus, in the form of radiant heat emitted from a focused projection bulb, is then applied to the plantar surface of each hind paw. In each test session, each rat is tested in three sequential trials at approximately 5-min intervals. Paw-withdrawal latencies (PWLs) are calculated as the median of the two shortest latencies. An assay cut off is set at 20.5 s. A-740003 is injected i.p. 30 min before testing for acute thermal pain.

[References]

[1]. Grol MW, et al. P2X?-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.

[2]. Kim JE, et al. 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.

[3]. Donnelly-Roberts DL, et al. Mammalian P2X7 receptor pharmacology: comparison of recombinant mouse, rat and human P2X7 receptors.Br J Pharmacol. 2009 Aug;157(7):1203-14. Epub 2009 Jun 22.

[4]. Honore P, 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. Epub 2006 Sep 18.

[5]. Y. H. Gao, et al. Effect of electroacupuncture on the cervicospinal P2X7 receptor/fractalkine/CX3CR1 signaling pathway in a rat neck-incision pain model. Purinergic Signal. 2017 Jun;13(2):215-225.

[Related Small Molecules]

Adenosine 5'-triphosphate disodium salt | KN-62 | A 438079 | af-353 | AZD9056 hydrochloride | PSB-12062 | A-317491 | A 804598 | A 839977 | Gefapixant | GW791343 | Lappaconitine | CE-224535 | JNJ-54175446

Chemical & Physical Properties

[ Density]:
1.2±0.1 g/cm3

[ Molecular Formula ]:
C₂₆H₃₀N₆O₃

[ Molecular Weight ]:
474.555

[ Exact Mass ]:
474.237946

[ PSA ]:
120.66000

[ LogP ]:
2.77

[ Index of Refraction ]:
1.597

[ Storage condition ]:
2-8℃

MSDS

Click to get detail MSDS

Safety Information

[ Symbol ]:

GHS06

[ Signal Word ]:
Danger

[ Hazard Statements ]:
H301

[ Precautionary Statements ]:
P301 + P310

[ RIDADR ]:
UN 2811 6.1 / PGIII

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

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