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Research ArticleNeuropharmacology

Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432

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
Journal of Pharmacology and Experimental Therapeutics December 2014, 351 (3) 628-641; DOI: https://doi.org/10.1124/jpet.114.218487
Brian Lord
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.)
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Leah Aluisio
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.)
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James R. Shoblock
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.)
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Robert A. Neff
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.)
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Elena I. Varlinskaya
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.)
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Marc Ceusters
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.)
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Timothy W. Lovenberg
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.)
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Nicholas Carruthers
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.)
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Pascal Bonaventure
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.)
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Michael A. Letavic
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.)
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Terrence Deak
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.)
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Wilhelmus Drinkenburg
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.)
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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.)
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Abstract

In 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.

Footnotes

    • Received July 21, 2014.
    • Accepted September 29, 2014.
  • B.L. and L.A. contributed equally to this work.

  • This research was supported by Janssen Research & Development, LLC. All authors except T.D. and E.I.V. are full-time employees of Janssen Research & Development, LLC.

  • dx.doi.org/10.1124/jpet.114.218487.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 351 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 351, Issue 3
1 Dec 2014
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Research ArticleNeuropharmacology

Brain-Penetrant P2X7 Antagonist JNJ-42253432

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
Journal of Pharmacology and Experimental Therapeutics December 1, 2014, 351 (3) 628-641; DOI: https://doi.org/10.1124/jpet.114.218487

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Research ArticleNeuropharmacology

Brain-Penetrant P2X7 Antagonist JNJ-42253432

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
Journal of Pharmacology and Experimental Therapeutics December 1, 2014, 351 (3) 628-641; DOI: https://doi.org/10.1124/jpet.114.218487
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