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Pharmacological characterization of a novel centrally permeable P2X7 receptor antagonist: JNJ ‐47965567
Author(s) -
Bhattacharya Anindya,
Wang Qi,
Ao Hong,
Shoblock James R,
Lord Brian,
Aluisio Leah,
Fraser Ian,
Nepomuceno Diane,
Neff Robert A,
Welty Natalie,
Lovenberg Timothy W,
Bonaventure Pascal,
Wickenden Alan D,
Letavic Michael A
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12314
Subject(s) - pharmacology , antagonist , purinergic receptor , neuropathic pain , chemistry , receptor antagonist , receptor , ex vivo , in vivo , medicine , in vitro , biology , biochemistry , microbiology and biotechnology
Background and Purpose An 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 Approach We have used a combination of in vitro assays (calcium flux, radioligand binding, electrophysiology, IL ‐1β 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 ‐1β release in the rat brain. Finally, the efficacy of JNJ ‐47965567 was tested in standard models of depression, mania and neuropathic pain. Key Results JNJ ‐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 ‐1β 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 EC 50 of 78 ± 19 ng·mL −1 ( P2X7 receptor autoradiography) and functional block of Bz ‐ ATP induced IL ‐1β release. JNJ ‐47965567 (30 mg·kg −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 Implications JNJ ‐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.