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

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.

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 (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.

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.

• Authors: Anindya Bhattacharya, Qi Wang, Hong Ao, James R Shoblock, Brian Lord, Leah Aluisio, Ian Fraser, Diane Nepomuceno, Robert A Neff, Natalie Welty, Timothy W Lovenberg, Pascal Bonaventure, Alan D Wickenden, Michael A Letavic
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 170 Issue 3 Pg. 624-40 (Oct 2013) ISSN: 1476-5381 [Electronic] England
• PMID: 23889535 (Publication Type: Journal Article)
• Copyright: © 2013 The British Pharmacological Society.

Chemical References

• Analgesics
• Antidepressive Agents
• Antimanic Agents
• Interleukin-1beta
• JNJ-47965567
• Piperazines
• Purinergic P2X Receptor Antagonists
• Receptors, Purinergic P2X7
• Niacinamide
• 3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate
• Adenosine Triphosphate

Topics

• Adenosine Triphosphate (analogs & derivatives, metabolism, pharmacology)
• Analgesics (metabolism, pharmacology)
• Animals
• Antidepressive Agents (pharmacology)
• Antimanic Agents (pharmacology)
• Behavior, Animal (drug effects)
• Binding, Competitive
• Bipolar Disorder (metabolism, prevention & control, psychology)
• Blood-Brain Barrier (metabolism)
• Brain (drug effects, metabolism)
• Calcium Signaling (drug effects)
• Capillary Permeability
• Cell Line
• Depression (metabolism, prevention & control, psychology)
• Disease Models, Animal
• Dogs
• Dose-Response Relationship, Drug
• Humans
• Interleukin-1beta (metabolism)
• Macaca
• Male
• Mice
• Mice, Inbred C57BL
• Neuralgia (metabolism, prevention & control, psychology)
• Niacinamide (analogs & derivatives, metabolism, pharmacology)
• Piperazines (metabolism, pharmacology)
• Protein Binding
• Purinergic P2X Receptor Antagonists (metabolism, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Purinergic P2X7 (drug effects, metabolism)
• Time Factors
• Transfection