Pharmacological characterization of a novel centrally permeable P2X7 receptor antagonist: JNJ-47965567.
Br J Pharmacol
; 170(3): 624-40, 2013 Oct.
Article
in En
| MEDLINE
| ID: mdl-23889535
ABSTRACT
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. EXPERIMENTALAPPROACH:
We have used a combination of in vitro assays (calcium flux, radioligand binding, electrophysiology, IL-1ß 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-1ß release in the rat brain. Finally, the efficacy of JNJ-47965567 was tested in standard models of depression, mania and neuropathic pain. KEYRESULTS:
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-1ß 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-1ß 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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Piperazines
/
Brain
/
Niacinamide
/
Receptors, Purinergic P2X7
/
Purinergic P2X Receptor Antagonists
Type of study:
Prognostic_studies
Language:
En
Journal:
Br J Pharmacol
Year:
2013
Document type:
Article
Affiliation country: