RT Journal Article
SR Electronic
T1 A-740003 [<em>N</em>-(1-{[(Cyanoimino)(5-quinolinylamino) methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a Novel and Selective P2X<sub>7</sub> Receptor Antagonist, Dose-Dependently Reduces Neuropathic Pain in the Rat
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1376
OP 1385
DO 10.1124/jpet.106.111559
VO 319
IS 3
A1 Honore, Prisca
A1 Donnelly-Roberts, Diana
A1 Namovic, Marian T.
A1 Hsieh, Gin
A1 Zhu, Chang Z.
A1 Mikusa, Joe P.
A1 Hernandez, Gricelda
A1 Zhong, Chengmin
A1 Gauvin, Donna M.
A1 Chandran, Prasant
A1 Harris, Richard
A1 Medrano, Arturo Perez
A1 Carroll, William
A1 Marsh, Kennan
A1 Sullivan, James P.
A1 Faltynek, Connie R.
A1 Jarvis, Michael F.
YR 2006
UL http://jpet.aspetjournals.org/content/319/3/1376.abstract
AB ATP-sensitive P2X7 receptors are localized on cells of immunological origin including glial cells in the central nervous system. Activation of P2X7 receptors leads to rapid changes in intracellular calcium concentrations, release of the proinflammatory cytokine interleukin-1β (IL-1β), 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 (N-(1-{[(cyanoimino)(5-quinolinylamino) methyl] amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide) 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 &gt; 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-1β release (IC50 = 156 nM) and pore formation (IC50 = 92 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.