861393-28-4

A 438079 or A 740003 (10 μM) significantly blocks the sustained phase of the BzATP-induced response. A-740003 infusion reduces SE-induced TNF-α expression in dentate granule cells. A-740003 infusions increases SE-induced neuronal death. 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. A-740003 potently blocks agonist-evoked IL-1β release with (IC ₅₀ =156 nM) and pore formation (IC ₅₀ =92 nM) in differentiated human THP-1 cells.

Systemic administration of A-740003 produces dose-dependent antinociception in a spinal nerve ligation model (ED ₅₀ =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 (ED ₅₀ =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.