title: 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.
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 [(3)H]JNJ-40068782. In guanosine 5'-O-(3-[(35)S]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 [(3)H]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 [(3)H](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 [(3)H]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 [(3)H]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 [(3)H]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 [(3)H]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 [(3)H]JNJ-40068782 in exploring allosteric binding.
authors.affiliation: Janssen Research and Development, Beerse, Belgium. hlavrey1@its.jnj.com
authors.forename: Hilde
authors.initials: H
authors.lastname: Lavreysen
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.forename: Abdel
authors.initials: A
authors.lastname: Ahnaou
authors.forename: Wilhelmus
authors.initials: W
authors.lastname: Drinkenburg
authors.forename: Paula
authors.initials: P
authors.lastname: te Riele
authors.forename: Ilse
authors.initials: I
authors.lastname: Biesmans
authors.forename: Ilse
authors.initials: I
authors.lastname: Van der Linden
authors.forename: Luc
authors.initials: L
authors.lastname: Peeters
authors.forename: Anton
authors.initials: A
authors.lastname: Megens
authors.forename: Cindy
authors.initials: C
authors.lastname: Wintmolders
authors.forename: Jose Maria
authors.initials: JM
authors.lastname: Cid
authors.forename: Andrés A
authors.initials: AA
authors.lastname: Trabanco
authors.forename: Jose Ignacio
authors.initials: JI
authors.lastname: Andrés
authors.forename: Frank M
authors.initials: FM
authors.lastname: Dautzenberg
authors.forename: Robert
authors.initials: R
authors.lastname: Lütjens
authors.forename: Gregor
authors.initials: G
authors.lastname: Macdonald
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive / Q000187:drug effects; D001923:Brain Chemistry; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003521:Cyclopropanes / Q000378:metabolism; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007553:Isotope Labeling; D008024:Ligands; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects*; D012890:Sleep / Q000187:drug effects; D014316:Tritium; D014966:Xanthenes / Q000378:metabolism
chemical_list: C584080:3-cyano-1-cyclopropylmethyl-4-(4-phenylpiperidin-1-yl)-pyridine-2(1H)-one; D000596:Amino Acids; D003521:Cyclopropanes; D018683:Excitatory Amino Acid Agents; D018690:Excitatory Amino Acid Agonists; C114624:LY 341495; D008024:Ligands; D010880:Piperidines; D011728:Pyridones; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; D014316:Tritium; C082313:2-(2,3-dicarboxycyclopropyl)glycine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002118:Calcium; D005998:Glycine