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Research ArticleNeuropharmacology

Pharmacological Characterization of JNJ-40068782, a New Potent, Selective, and Systemically Active Positive Allosteric Modulator of the mGlu2 Receptor and Its Radioligand [3H]JNJ-40068782

Hilde Lavreysen, Xavier Langlois, Abdel Ahnaou, Wilhelmus Drinkenburg, Paula te Riele, Ilse Biesmans, Ilse Van der Linden, Luc Peeters, Anton Megens, Cindy Wintmolders, Jose Maria Cid, Andrés A. Trabanco, Jose Ignacio Andrés, Frank M. Dautzenberg, Robert Lütjens, Gregor Macdonald and John R. Atack
Journal of Pharmacology and Experimental Therapeutics September 2013, 346 (3) 514-527; DOI: https://doi.org/10.1124/jpet.113.204990
Hilde Lavreysen
Janssen Research and Development, Beerse, Belgium (H.L., X.L., A.A., W.D., P.t.R., I.B., I.V.d.L., L.P., A.M., C.W., F.M.D., G.M., J.R.A.); Janssen Research and Development, Toledo, Spain (J.M.C., A.A.T., J.I.A.); and Addex Therapeutics, Geneva, Switzerland (R.L.)
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Xavier Langlois
Janssen Research and Development, Beerse, Belgium (H.L., X.L., A.A., W.D., P.t.R., I.B., I.V.d.L., L.P., A.M., C.W., F.M.D., G.M., J.R.A.); Janssen Research and Development, Toledo, Spain (J.M.C., A.A.T., J.I.A.); and Addex Therapeutics, Geneva, Switzerland (R.L.)
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Abdel Ahnaou
Janssen Research and Development, Beerse, Belgium (H.L., X.L., A.A., W.D., P.t.R., I.B., I.V.d.L., L.P., A.M., C.W., F.M.D., G.M., J.R.A.); Janssen Research and Development, Toledo, Spain (J.M.C., A.A.T., J.I.A.); and Addex Therapeutics, Geneva, Switzerland (R.L.)
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Wilhelmus Drinkenburg
Janssen Research and Development, Beerse, Belgium (H.L., X.L., A.A., W.D., P.t.R., I.B., I.V.d.L., L.P., A.M., C.W., F.M.D., G.M., J.R.A.); Janssen Research and Development, Toledo, Spain (J.M.C., A.A.T., J.I.A.); and Addex Therapeutics, Geneva, Switzerland (R.L.)
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Paula te Riele
Janssen Research and Development, Beerse, Belgium (H.L., X.L., A.A., W.D., P.t.R., I.B., I.V.d.L., L.P., A.M., C.W., F.M.D., G.M., J.R.A.); Janssen Research and Development, Toledo, Spain (J.M.C., A.A.T., J.I.A.); and Addex Therapeutics, Geneva, Switzerland (R.L.)
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Ilse Biesmans
Janssen Research and Development, Beerse, Belgium (H.L., X.L., A.A., W.D., P.t.R., I.B., I.V.d.L., L.P., A.M., C.W., F.M.D., G.M., J.R.A.); Janssen Research and Development, Toledo, Spain (J.M.C., A.A.T., J.I.A.); and Addex Therapeutics, Geneva, Switzerland (R.L.)
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Ilse Van der Linden
Janssen Research and Development, Beerse, Belgium (H.L., X.L., A.A., W.D., P.t.R., I.B., I.V.d.L., L.P., A.M., C.W., F.M.D., G.M., J.R.A.); Janssen Research and Development, Toledo, Spain (J.M.C., A.A.T., J.I.A.); and Addex Therapeutics, Geneva, Switzerland (R.L.)
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Luc Peeters
Janssen Research and Development, Beerse, Belgium (H.L., X.L., A.A., W.D., P.t.R., I.B., I.V.d.L., L.P., A.M., C.W., F.M.D., G.M., J.R.A.); Janssen Research and Development, Toledo, Spain (J.M.C., A.A.T., J.I.A.); and Addex Therapeutics, Geneva, Switzerland (R.L.)
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Anton Megens
Janssen Research and Development, Beerse, Belgium (H.L., X.L., A.A., W.D., P.t.R., I.B., I.V.d.L., L.P., A.M., C.W., F.M.D., G.M., J.R.A.); Janssen Research and Development, Toledo, Spain (J.M.C., A.A.T., J.I.A.); and Addex Therapeutics, Geneva, Switzerland (R.L.)
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Cindy Wintmolders
Janssen Research and Development, Beerse, Belgium (H.L., X.L., A.A., W.D., P.t.R., I.B., I.V.d.L., L.P., A.M., C.W., F.M.D., G.M., J.R.A.); Janssen Research and Development, Toledo, Spain (J.M.C., A.A.T., J.I.A.); and Addex Therapeutics, Geneva, Switzerland (R.L.)
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Jose Maria Cid
Janssen Research and Development, Beerse, Belgium (H.L., X.L., A.A., W.D., P.t.R., I.B., I.V.d.L., L.P., A.M., C.W., F.M.D., G.M., J.R.A.); Janssen Research and Development, Toledo, Spain (J.M.C., A.A.T., J.I.A.); and Addex Therapeutics, Geneva, Switzerland (R.L.)
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Andrés A. Trabanco
Janssen Research and Development, Beerse, Belgium (H.L., X.L., A.A., W.D., P.t.R., I.B., I.V.d.L., L.P., A.M., C.W., F.M.D., G.M., J.R.A.); Janssen Research and Development, Toledo, Spain (J.M.C., A.A.T., J.I.A.); and Addex Therapeutics, Geneva, Switzerland (R.L.)
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Jose Ignacio Andrés
Janssen Research and Development, Beerse, Belgium (H.L., X.L., A.A., W.D., P.t.R., I.B., I.V.d.L., L.P., A.M., C.W., F.M.D., G.M., J.R.A.); Janssen Research and Development, Toledo, Spain (J.M.C., A.A.T., J.I.A.); and Addex Therapeutics, Geneva, Switzerland (R.L.)
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Frank M. Dautzenberg
Janssen Research and Development, Beerse, Belgium (H.L., X.L., A.A., W.D., P.t.R., I.B., I.V.d.L., L.P., A.M., C.W., F.M.D., G.M., J.R.A.); Janssen Research and Development, Toledo, Spain (J.M.C., A.A.T., J.I.A.); and Addex Therapeutics, Geneva, Switzerland (R.L.)
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Robert Lütjens
Janssen Research and Development, Beerse, Belgium (H.L., X.L., A.A., W.D., P.t.R., I.B., I.V.d.L., L.P., A.M., C.W., F.M.D., G.M., J.R.A.); Janssen Research and Development, Toledo, Spain (J.M.C., A.A.T., J.I.A.); and Addex Therapeutics, Geneva, Switzerland (R.L.)
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Gregor Macdonald
Janssen Research and Development, Beerse, Belgium (H.L., X.L., A.A., W.D., P.t.R., I.B., I.V.d.L., L.P., A.M., C.W., F.M.D., G.M., J.R.A.); Janssen Research and Development, Toledo, Spain (J.M.C., A.A.T., J.I.A.); and Addex Therapeutics, Geneva, Switzerland (R.L.)
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John R. Atack
Janssen Research and Development, Beerse, Belgium (H.L., X.L., A.A., W.D., P.t.R., I.B., I.V.d.L., L.P., A.M., C.W., F.M.D., G.M., J.R.A.); Janssen Research and Development, Toledo, Spain (J.M.C., A.A.T., J.I.A.); and Addex Therapeutics, Geneva, Switzerland (R.L.)
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Abstract

Modulation of the metabotropic glutamate type 2 (mGlu2) receptor is considered a promising target for the treatment of central nervous system diseases such as schizophrenia. Here, we describe the pharmacological properties of the novel mGlu2 receptor positive allosteric modulator (PAM) 3-cyano-1-cyclopropylmethyl-4-(4-phenyl-piperidin-1-yl)-pyridine-2(1H)-one (JNJ-40068782) and its radioligand [3H]JNJ-40068782. In guanosine 5′-O-(3-[35S]thio)triphosphate binding, JNJ-40068782 produced a leftward and upward shift in the glutamate concentration-effect curve at human recombinant mGlu2 receptors. The EC50 of JNJ-40068782 for potentiation of an EC20-equivalent concentration of glutamate was 143 nM. Although JNJ-40068782 did not affect binding of the orthosteric antagonist [3H]2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid (LY-341495), it did potentiate the binding of the agonist [3H](2S,2′R,3′R)-2-(2′,3′-dicarboxylcyclopropyl)glycine (DCG-IV), demonstrating that it can allosterically affect binding at the agonist recognition site. The binding of [3H]JNJ-40068782 to human recombinant mGlu2 receptors in Chinese hamster ovary cells and rat brain receptors was saturable with a KD of ∼10 nM. In rat brain, the anatomic distribution of [3H]JNJ-40068782 was consistent with mGlu2 expression previously described and was most abundant in cortex and hippocampus. The ability of structurally unrelated PAMs to displace [3H]JNJ-40068782 suggests that PAMs may bind to common determinants within the same site. It is noteworthy that agonists also increased the binding affinity of [3H]JNJ-40068782. JNJ-40068782 influenced rat sleep-wake organization by decreasing rapid eye movement sleep with a lowest active dose of 3 mg/kg PO. In mice, JNJ-40068782 reversed phencyclidine-induced hyperlocomotion with an ED50 of 5.7 mg/kg s.c. Collectively, the present data demonstrate that JNJ-40068782 has utility in investigating the potential of mGlu2 modulation for the treatment of diseases characterized by disturbed glutamatergic signaling and highlight the value of [3H]JNJ-40068782 in exploring allosteric binding.

Footnotes

    • Received March 21, 2013.
    • Accepted June 12, 2013.
  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • dx.doi.org/10.1124/jpet.113.204990.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 346 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 346, Issue 3
1 Sep 2013
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Research ArticleNeuropharmacology

Pharmacological Characterization of JNJ-40068782, an mGlu2 Receptor PAM

Hilde Lavreysen, Xavier Langlois, Abdel Ahnaou, Wilhelmus Drinkenburg, Paula te Riele, Ilse Biesmans, Ilse Van der Linden, Luc Peeters, Anton Megens, Cindy Wintmolders, Jose Maria Cid, Andrés A. Trabanco, Jose Ignacio Andrés, Frank M. Dautzenberg, Robert Lütjens, Gregor Macdonald and John R. Atack
Journal of Pharmacology and Experimental Therapeutics September 1, 2013, 346 (3) 514-527; DOI: https://doi.org/10.1124/jpet.113.204990

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Research ArticleNeuropharmacology

Pharmacological Characterization of JNJ-40068782, an mGlu2 Receptor PAM

Hilde Lavreysen, Xavier Langlois, Abdel Ahnaou, Wilhelmus Drinkenburg, Paula te Riele, Ilse Biesmans, Ilse Van der Linden, Luc Peeters, Anton Megens, Cindy Wintmolders, Jose Maria Cid, Andrés A. Trabanco, Jose Ignacio Andrés, Frank M. Dautzenberg, Robert Lütjens, Gregor Macdonald and John R. Atack
Journal of Pharmacology and Experimental Therapeutics September 1, 2013, 346 (3) 514-527; DOI: https://doi.org/10.1124/jpet.113.204990
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