Group I and group II metabotropic glutamate receptor allosteric modulators as novel potential antipsychotics

Recently, there has been a shift in the schizophrenia field focusing on restoring glutamate signaling. Extensive preclinical data suggests that mGlu(5) PAMs could have efficacy in all three symptom domains but there is concern of potential adverse effects. New insights into mechanisms underlying this toxicity may provide a path for discovery of safe mGlu(5) PAMs. Genetic mutations in mGlu(1) have been described in schizophrenics creating interest in this receptor as a therapeutic target. Preclinical data demonstrated the antipsychotic potential of mGlu(2/3) agonists but clinical trials were not successful. However, studies have suggested that mGlu(2) is the subtype mediating antipsychotic effects and selective mGlu(2) PAMs are now in clinical development. Finally, recent genetic studies suggest mGlu(3) modulators may be pro-cognitive.