title: Pharmacological characterization of a novel centrally permeable P2X7 receptor antagonist: JNJ-47965567.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  JNJ-47965567 is potent high affinity (pKi 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 EC50 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Neuroscience Therapeutic Area, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA, USA.
authors.forename: Anindya
authors.initials: A
authors.lastname: Bhattacharya
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Ao
authors.forename: James R
authors.initials: JR
authors.lastname: Shoblock
authors.forename: Brian
authors.initials: B
authors.lastname: Lord
authors.forename: Leah
authors.initials: L
authors.lastname: Aluisio
authors.forename: Ian
authors.initials: I
authors.lastname: Fraser
authors.forename: Diane
authors.initials: D
authors.lastname: Nepomuceno
authors.forename: Robert A
authors.initials: RA
authors.lastname: Neff
authors.forename: Natalie
authors.initials: N
authors.lastname: Welty
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Lovenberg
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonaventure
authors.forename: Alan D
authors.initials: AD
authors.lastname: Wickenden
authors.forename: Michael A
authors.initials: MA
authors.lastname: Letavic
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000700:Analgesics / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D018692:Antimanic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive; D001714:Bipolar Disorder / Q000378:metabolism / Q000517:prevention & control / Q000523:psychology; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002199:Capillary Permeability; D002460:Cell Line; D003863:Depression / Q000378:metabolism / Q000517:prevention & control / Q000523:psychology; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008251:Macaca; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000378:metabolism / Q000517:prevention & control / Q000523:psychology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D058920:Purinergic P2X Receptor Antagonists / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058486:Receptors, Purinergic P2X7 / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D000700:Analgesics; D000928:Antidepressive Agents; D018692:Antimanic Agents; D053583:Interleukin-1beta; C000590736:JNJ-47965567; D010879:Piperazines; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D009536:Niacinamide; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate
keywords: P2X7; autoradiography; depression; interleukin 1β (IL-1β); mania; microdialysis; neuropathic pain; purinergic
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