Description
JNJ-47965567 is a selective antagonist of the purinergic receptor P2X subtype 7 (P2X
7), a ligand-gated ion channel. Activation of P2X receptors by BzATP induces calcium flux, which is reduced by JNJ-47965567 in 1321N1 cells transfected with recombinant P2X
7 human, macaque, dog, rat, or mouse protein with pIC
50s of 8.3, 8.6, 8.5, 7.2, or 7.5, respectively. JNJ-47965567 suppresses neonatal hypoxia-induced seizures in mice and has some anticonvulsant properties in rats. It also reduces spontaneous seizures in epileptic mice even after treatment is stopped.
Uses
2-(Phenylthio)-N-[[tetrahydro-4-(4-phenyl-1-piperazinyl)-2H-pyran-4-yl]methyl]-3-pyridinecarboxamide is a potent and selective human P2X7 antagonist.
Biochem/physiol Actions
JNJ-47965567 is a potent P2X7 antagonist with high affinity for the rat receptor (pKi = 8.7). It is centrally available after systemic injection with a superior brain:plasma distribution compared to other available P2X7 antagonists. JNJ-47965567 was shown to suppress epileptic seizures in a mouse model of epilepsy. It appears to have a disease modifying effect since spontaneous seizure rates did not increase once treatment with JNJ-477965567 was stopped.
in vivo
JNJ-47965567 (30-100 mg/kg; s.c.) attenuates IL-1β release induced by Bz-ATP[1].
JNJ-47965567 (30 mg/kg) attenuates amphetamine-induced hyperactivity and exhibits modest, yet significant efficacy in the rat model of neuropathic pain[1].
| Animal Model: | Male Sprague Dawley rats[1] |
| Dosage: | 30 mg/kg, 100 mg/kg |
| Administration: | Subcutaneous injection; 30 minutes prior to Bz-ATP infusion |
| Result: | Significantly attenuated IL-1β release at 100 mg/kg, with no effect at 30 mg/kg dose group. |
References
[1] ANINDYA BHATTACHARYA. Pharmacological characterization of a novel centrally permeable P2X7 receptor antagonist: JNJ-47965567[J]. British Journal of Pharmacology, 2013, 170 3: 624-640. DOI:
10.1111/bph.12314[2] NATALIA RODRIGUEZ-ALVAREZ . Effects of P2X7 receptor antagonists on hypoxia-induced neonatal seizures in mice[J]. Neuropharmacology, 2017, 116: Pages 351-363. DOI:
10.1016/j.neuropharm.2017.01.005[3] WOLFGANG FISCHER. Critical Evaluation of P2X7 Receptor Antagonists in Selected Seizure Models.[J]. PLoS ONE, 2016: e0156468. DOI:
10.1371/journal.pone.0156468[4] ALBA JIMENEZ-PACHECO. Transient P2X7 Receptor Antagonism Produces Lasting Reductions in Spontaneous Seizures and Gliosis in Experimental Temporal Lobe Epilepsy.[J]. Journal of Neuroscience, 2016, 36 22: 5920-5932. DOI:
10.1523/jneurosci.4009-15.2016
