Metabotropic Glutamate 2/3 Receptor Agonists and Positive Allosteric Modulators of Metabotropic Glutamate Receptor 2 as Novel Agents for the Treatment of Schizophrenia

The origin of modern psychopharmacology can be traced to the discovery of the first clinically efficacious antipsychotic drug, chlorpromazine, in 1952. Following this watershed advance, several additional antipsychotic agents of the same (i.e., phenothiazine) class, as well as others derived from the butyrophenone scaffold (e.g., haloperidol, 1958), were discovered and widely utilized in the treatment of schizophrenia patients. Arvid Carlsson and his colleagues were the first to show that antipsychotics of both the phenothiazine and butyrophenone classes acted via blockade of dopamine (DA) receptors [1]. This hypothesis was further refined over a decade later by observations that all antipsychotic drugs potently block dopamine D2-like receptors [2, 3]. Interest in moving to mechanisms of antipsychotic action other than dopamine D2