• Brian Lord, Leah Aluisio, James R Shoblock, Robert A Neff, Elena I Varlinskaya, Marc Ceusters, Timothy W Lovenberg, Nicholas Carruthers, Pascal Bonaventure, Michael A Letavic, Terrence Deak, Wilhelmus Drinkenburg, and Anindya Bhattacharya.
• Neuroscience Therapeutic Area, Janssen Research & Development, LLC, San Diego, California (B.L., L.A., J.R.S., R.A.N., T.W.L., N.C., P.B., M.A.L., A.B.); Neuroscience Therapeutic Area, Janssen Research & Development, Division of Janssen Pharmaceutica NV, Beerse, Belgium (M.C., W.D.); and Behavioral Neuroscience Program, Department of Psychology, Binghamton University-State University of New York, Binghamton, New York (E.I.V., T.D.).
• J. Pharmacol. Exp. Ther. 2014 Dec 1;351(3):628-41.

AbstractIn the central nervous system, the ATP-gated Purinergic receptor P2X ligand-gated ion channel 7 (P2X7) is expressed in glial cells and modulates neurophysiology via release of gliotransmitters, including the proinflammatory cytokine interleukin (IL)-1β. In this study, we characterized JNJ-42253432 [2-methyl-N-([1-(4-phenylpiperazin-1-yl)cyclohexyl]methyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide] as a centrally permeable (brain-to-plasma ratio of 1), high-affinity P2X7 antagonist with desirable pharmacokinetic and pharmacodynamic properties for in vivo testing in rodents. JNJ-42253432 is a high-affinity antagonist for the rat (pKi 9.1 ± 0.07) and human (pKi 7.9 ± 0.08) P2X7 channel. The compound blocked the ATP-induced current and Bz-ATP [2'(3')-O-(4-benzoylbenzoyl)adenosine-5'-triphosphate tri(triethylammonium)]-induced release of IL-1β in a concentration-dependent manner. When dosed in rats, JNJ-42253432 occupied the brain P2X7 channel with an ED50 of 0.3 mg/kg, corresponding to a mean plasma concentration of 42 ng/ml. The compound blocked the release of IL-1β induced by Bz-ATP in freely moving rat brain. At higher doses/exposure, JNJ-42253432 also increased serotonin levels in the rat brain, which is due to antagonism of the serotonin transporter (SERT) resulting in an ED50 of 10 mg/kg for SERT occupancy. JNJ-42253432 reduced electroencephalography spectral power in the α-1 band in a dose-dependent manner; the compound also attenuated amphetamine-induced hyperactivity. JNJ-42253432 significantly increased both overall social interaction and social preference, an effect that was independent of stress induced by foot-shock. Surprisingly, there was no effect of the compound on either neuropathic pain or inflammatory pain behaviors. In summary, in this study, we characterize JNJ-42253432 as a novel brain-penetrant P2X7 antagonist with high affinity and selectivity for the P2X7 channel.Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

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