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

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.