The purinergic receptor P2X, ligand-gated ion channel, 7 (P2X7) is an ATP-gated ion channel that plays an essential role in neuropsychiatry, neurodegeneration, and chronic pain. JNJ 47965567 is a centrally permeable, high-affinity, selective P2X7 antagonist with high affinity binding at both the human (pKi=7.9±0.07) and rat (pKi=8.7±0.07) P2X7 ion channel. The potency (pIC50) of JNJ 47965567 to attenuate Bz-ATP-induced calcium flux at human, macaque, dog, rat, and mouse P2X7 was 8.3±0.08, 8.6±0.1, 8.5±0.2, 7.2±0.08, and 7.5±0.1, respectively. JNJ 47965567 reduced LPS primed BZ-ATP-induced IL-1β release with a pIC50 of 6.7±0.07 in human whole blood and a pIC50 of 7.5±0.07 in freshly isolated human monocytes from the blood. JNJ 47965567 also inhibited IL-18 release with a pIC50 value of 7.3 ± 0.1. JNJ-47965567 at a concentration of 100nM rapidly inhibited Bz-ATP-evoked currents in 1321N1 cells expressing hP2X7 (93.9% inhibition). Subcutaneous dosing of JNJ 47965567 at 100mg/kg significantly attenuated IL-1β release in rats challenged with Bz-ATP, a P2X7 agonist. In a rat model of neuropathic pain, subcutaneous administration of JNJ 47965567 at a dose of 30mg/kg resulted in a significant increase in tactile thresholds lasting from 30–60min post-administration[3].
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