PT  - JOURNAL ARTICLE
AU  - Hilde Lavreysen
AU  - Xavier Langlois
AU  - Abdel Ahnaou
AU  - Wilhelmus Drinkenburg
AU  - Paula te Riele
AU  - Ilse Biesmans
AU  - Ilse Van der Linden
AU  - Luc Peeters
AU  - Anton Megens
AU  - Cindy Wintmolders
AU  - Jose Maria Cid
AU  - Andrés A. Trabanco
AU  - Jose Ignacio Andrés
AU  - Frank M. Dautzenberg
AU  - Robert Lütjens
AU  - Gregor Macdonald
AU  - John R. Atack
TI  - Pharmacological Characterization of JNJ-40068782, a New Potent, Selective, and Systemically Active Positive Allosteric Modulator of the mGlu2 Receptor and Its Radioligand [<sup>3</sup>H]JNJ-40068782
AID  - 10.1124/jpet.113.204990
DP  - 2013 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 514--527
VI  - 346
IP  - 3
4099  - http://jpet.aspetjournals.org/content/346/3/514.short
4100  - http://jpet.aspetjournals.org/content/346/3/514.full
SO  - J Pharmacol Exp Ther2013 Sep 01; 346
AB  - 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.