A-740003 (A 740003) is an effective and specific P2X7 receptor antagonist (IC50: 18/40 nM, for rat/human). It can reduce nociception in animal models of persistent neuropathic and inflammatory pain, and also reduce neuroblastoma tumor growth in mice.

P2X7 (rat):18nM, P2X7 (human):40 nM

A-438079 and A-740003 (10 μM) effectively inhibit the prolonged phase of BzATP-induced responses[1] and mitigate SE-induced TNF-α expression in dentate granule neurons while increasing SE-induced neuronal death[2]. Compared to other antagonists, both compounds exhibit superior efficacy in inhibiting P2X7 receptor activation across various species, with heightened activity in rat and human compared to mouse P2X7 receptors[3]. Specifically, A-740003 robustly inhibits agonist-induced IL-1β release (IC50=156 nM) and pore formation (IC50=92 nM) in differentiated human THP-1 cells[4].

Administering A-740003 systemically results in a dose-dependent reduction of pain (antinociception) in rats, as evidenced in a spinal nerve ligation model (ED50=19 mg/kg i.p.), indicating its potency. Furthermore, A-740003 diminishes sensitivity to touch (tactile allodynia) in models of neuropathic pain, including chronic constriction of the sciatic nerve and vincristine-induced neuropathy. It also significantly lowers increased sensitivity to heat (thermal hyperalgesia) following the intraplantar introduction of carrageenan or complete Freund's adjuvant (ED50=38-54 mg/kg i.p.). However, A-740003 does not affect acute thermal pain in healthy rats and does not impair motor skills at doses that relieve pain.