[Targeting metabotropic glutamate receptors to develop novel antipsychotics]

Based on the glutamate hypothesis of schizophrenia, extensive studies to develop drugs acting on glutamate receptors have been conducted. Among glutamate receptors, metabotropic glutamate (mGlu) receptors, all of which are GPCRs, have 8 subtypes, and are involved in regulation of glutamate transmissions. Of these, much attention has been paid to mGlu2/3 receptors and mGlu5 receptor. mGlu2/3 receptor agonists improve behavioral abnormalities such as locomotor hyperactivity and cognitive deficits induced by NMDA receptor antagonists. In addition, mGlu2/3 receptor agonists attenuate glutamate overflow in the prefrontal cortex, and regulate dopamine release and 5-HT2A receptor activity, all of which have been presumed to be involved in antipsychotic actions of mGlu2/3 receptor agonists. Recently, LY2140023, an mGlu2/3 receptor agonists developed by Eli Lilly, has been demonstrated to be effective for the treatment of positive and negative symptoms of schizophrenic patients in a phase II study, while it did not cause unwanted side effects often observed with current antipsychotic medications. Moreover, a series of experiments has demonstrated that mGlu5 receptor potentiators exert antipsychotic effects in animal models of schizophrenia. Therefore, mGlu2/3 receptor and mGlu5 receptor may provide exciting targets for the development of novel medications for schizophrenia.