A-740003

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. IC50 & 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].