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

ABSTRACT: 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.We 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.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-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 ± 19?ng·mL(-1) (P2X7 receptor autoradiography) and functional block of Bz-ATP induced IL-1? 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.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.

SUBMITTER: Bhattacharya A

PROVIDER: S-EPMC3792000 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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

Bhattacharya Anindya A Wang Qi Q Ao Hong H Shoblock James R JR Lord Brian B Aluisio Leah L Fraser Ian I Nepomuceno Diane D Neff Robert A RA Welty Natalie N Lovenberg Timothy W TW Bonaventure Pascal P Wickenden Alan D AD Letavic Michael A MA

British journal of pharmacology 20131001 3

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>We have used a combination of in vitro assays (calcium flux, radioligand binding, electrophysiology, IL-1β release) in both recombina ...[more]

PMID: 23889535

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Project description:JNJ-54175446 is a selective purine P2X7 receptor (P2X7R) antagonist that attenuates microglial IL-1β/IL-18 release. In healthy volunteers, JNJ-54175446 suppressed peripheral interleukin (IL)-1β release, and attenuated dexamphetamine-induced improvements of mood and (visuo)motor performance in a human dexamphetamine-challenge paradigm. In depression, P2X7R inhibition may dampen immune-related dysregulation of mood. These results suggest that the impact of P2X7R inhibition is most prominent in situations where mood regulation is disrupted. Total sleep deprivation (TSD) results in an acute emotional perturbation, which yields a transient antidepressant effect. In the current study, TSD was applied as a behavioral challenge to investigate whether such effects could be modulated by JNJ-54175446. This was a double-blind, placebo-controlled, randomized study to assess the safety and pharmacokinetics of JNJ-54175446 and explore its effects in patients with single episode and recurrent major depressive disorder (MDD) (N = 69) and baseline total Inventory of Depressive Symptomatology Clinician Rated (IDS-C) > 30. Patients were randomized to receive JNJ-54175446 throughout the 10-day treatment period, placebo for days 1-3 followed by JNJ-54175446 or placebo throughout. All patients underwent 36 h of TSD starting on day three until the evening of day four. The early start group was hypothesized to experience a reduced effect from TSD whilst the late starting group was hypothesized to experience prolonged effects from the TSD. JNJ-54175446 was well-tolerated and adverse events were mild to moderate. JNJ-54175446 reduced IL-1β release by LPS-stimulated peripheral white blood cells in the presence of the P2X receptor agonist benzyl adenosine triphosphate (BzATP). JNJ-54175446 did not have a significant effect on mood as assessed using the Hamilton Depression Rating Scale, 17 items (HDRS17) and the Self-rated Quick Inventory of Depressive Symptoms (QIDS-SR). However, JNJ-54175446 blunted an acute reduction of anhedonia that occurred as a result of TSD, assessed by the Snaith-Hamilton Pleasure Scale (SHAPS) and the Probabilistic Instrumental Learning Task (PILT).

Dataset Information

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

Publications

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

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