Received for publication July 27, 2006.
Revised September 11, 2006.
Accepted for publication September 14, 2006.

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

Abstract

Adenosine triphosphate (ATP)-sensitive P2X₇ receptors are localized on cells of immunological origin including glial cells in the CNS. Activation of P2X₇ receptors leads to rapid changes in intracellular calcium concentrations, release of the pro-inflammatory cytokine IL-1, and following prolonged agonist exposure, cytolytic plasma membrane pore formation. P2X₇ knockout mice show reduced inflammation as well as decreased nociceptive sensitivity following peripheral nerve injury. A-740003 is a novel competitive antagonist of P2X₇ receptors (IC₅₀ 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 (IC₅₀ > 10 µM) 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-1 release (IC₅₀ = 40 nM) and pore formation (IC₅₀ = 60 nM) in differentiated human THP-1 cells. Systemic administration of A-740003 produced dose-dependent antinociception in a spinal nerve ligation model (ED₅₀ = 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 (ED₅₀ = 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 P2X₇ receptors in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.

Key words: allodynia, hyperalgesia, inflammation, pain, purine receptors, purines

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