Pharmacological characterization of a novel centrally permeable P2X7 receptor antagonist: JNJ-47965567

Background and PurposeAn increasing body of evidence suggests that the purinergic receptor P2X, ligand-gated ion channel, 7 (P2X7) in the CNS may play a key role in neuropsychiatry, neurodegeneration and chronic pain. In this study, we characterized JNJ-47965567, a centrally permeable, high-affinity, selective P2X7 antagonist. Experimental ApproachWe have used a combination of in vitro assays (calcium flux, radioligand binding, electrophysiology, IL-1 release) in both recombinant and native systems. Target engagement of JNJ-47965567 was demonstrated by ex vivo receptor binding autoradiography and in vivo blockade of Bz-ATP induced IL-1 release in the rat brain. Finally, the efficacy of JNJ-47965567 was tested in standard models of depression, mania and neuropathic pain. Key ResultsJNJ-47965567 is potent high affinity (pK(i) 7.9 0.07), selective human P2X7 antagonist, with no significant observed speciation. In native systems, the potency of the compound to attenuate IL-1 release was 6.7 +/- 0.07 (human blood), 7.5 +/- 0.07 (human monocytes) and 7.1 +/- 0.1 (rat microglia). JNJ-47965567 exhibited target engagement in rat brain, with a brain EC50 of 78 +/- 19ngmL(-1) (P2X7 receptor autoradiography) and functional block of Bz-ATP induced IL-1 release. JNJ-47965567 (30mgkg(-1)) attenuated amphetamine-induced hyperactivity and exhibited modest, yet significant efficacy in the rat model of neuropathic pain. No efficacy was observed in forced swim test. Conclusion and ImplicationsJNJ-47965567 is centrally permeable, high affinity P2X7 antagonist that can be used to probe the role of central P2X7 in rodent models of CNS pathophysiology.