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.
