title: A selective allosteric potentiator of metabotropic glutamate (mGlu) 2 receptors has effects similar to an orthosteric mGlu2/3 receptor agonist in mouse models predictive of antipsychotic activity.
abstract: Recent studies suggest that agonists of group II metabotropic glutamate (mGlu) receptors (mGlu2/3) have potential utility as novel therapeutic agents for treatment of psychiatric disorders such as anxiety and schizophrenia. Agonists of mGlu2/3 receptors block amphetamine- and phencyclidine (PCP)-induced hyperlocomotor activity in rodents, two actions that may predict potential antipsychotic activity of these compounds. We now report that LY487379 [N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine], a recently described selective allosteric potentiator of mGlu2 receptor, has behavioral effects similar to mGlu2/3 receptor agonists. LY487379 and LY379268 [(-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate], an ortho-steric mGlu2/3 receptor agonist, induced similar dose-dependent reductions in PCP- and amphetamine-induced hyperlocomotor activity in C57BL6/J mice at doses that did not significantly alter spontaneous locomotor activity. These effects were blocked by the mGlu2/3 receptor antagonist LY341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid]. LY487379 had a short duration of action compared with LY379268. Furthermore, unlike the mGlu2/3 agonist, LY487379 reversed amphetamine-induced disruption of prepulse inhibition of the acoustic startle reflex. When LY379268 was given chronically, it failed to block amphetamine- and PCP-induced hyperlocomotor activity. The finding that the effects of an orthosteric mGlu2/3 receptor agonist in these models can be mimicked by a selective allosteric potentiator of mGlu2 suggests that these effects are mediated by the mGlu2 receptor subtype. Furthermore, these data raise the possibility that a selective allosteric potentiator of mGlu2 receptor could have utility as a novel approach for the treatment of schizophrenia.
authors.affiliation: Program in Translational Neuropharmacology, Department of Pharmacology, Vanderbilt University Medical Center, 23rd Avenue South at Pierce, 417-D Preston Research Building, Nashville, TN 37232-6600, USA.
authors.forename: Ruggero
authors.initials: R
authors.lastname: Galici
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Echemendia
authors.forename: Alice L
authors.initials: AL
authors.lastname: Rodriguez
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
mesh_terms: D000494:Allosteric Regulation; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D011237:Predictive Value of Tests; D011725:Pyridines / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors*; D012022:Reflex, Acoustic / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D014150:Antipsychotic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C118218:LY 379268; C476436:N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; D013449:Sulfonamides