title: Pharmacology of a novel central nervous system-penetrant P2X7 antagonist JNJ-42253432.
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.
authors.affiliation: 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.).
authors.forename: Brian
authors.initials: B
authors.lastname: Lord
authors.affiliation: 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.).
authors.forename: Leah
authors.initials: L
authors.lastname: Aluisio
authors.affiliation: 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.).
authors.forename: James R
authors.initials: JR
authors.lastname: Shoblock
authors.affiliation: 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.).
authors.forename: Robert A
authors.initials: RA
authors.lastname: Neff
authors.affiliation: 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.).
authors.forename: Elena I
authors.initials: EI
authors.lastname: Varlinskaya
authors.affiliation: 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.).
authors.forename: Marc
authors.initials: M
authors.lastname: Ceusters
authors.affiliation: 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.).
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Lovenberg
authors.affiliation: 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.).
authors.forename: Nicholas
authors.initials: N
authors.lastname: Carruthers
authors.affiliation: 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.).
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonaventure
authors.affiliation: 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.).
authors.forename: Michael A
authors.initials: MA
authors.lastname: Letavic
authors.affiliation: 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.).
authors.forename: Terrence
authors.initials: T
authors.lastname: Deak
authors.affiliation: 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.).
authors.forename: Wilhelmus
authors.initials: W
authors.lastname: Drinkenburg
authors.affiliation: 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.) abhatta2@its.jnj.com.
authors.forename: Anindya
authors.initials: A
authors.lastname: Bhattacharya
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002491:Central Nervous System Agents / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D058920:Purinergic P2X Receptor Antagonists / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*
chemical_list: D002491:Central Nervous System Agents; D007546:Isoquinolines; C000620093:JNJ-42253432; D010879:Piperazines; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7