Promise of mGluR2/3 activators in psychiatry

The group II metabotropic glutamate receptors (mGluRs), mGluR2 and mGluR3, have emerged as exciting and well-validated targets for novel therapeutic agents used for treating psychiatric disorders. A large number of preclinical and clinical studies provide strong evidence that mGluR2/3 agonists may provide a novel approach to treatment of anxiety disorders and schizophrenia. Group II mGluR agonists, such as LY354740 and related compounds, have robust activity in a range of animal models that predict anxiolytic (Swanson et al, 2005) and antipsychotic (Schoepp and Marek, 2002) activities. Furthermore, clinical studies reveal that group II mGluR agonists have robust efficacy in human models of panic attack and fear-potentiated startle (Swanson et al, 2005) and improve ratings for positive and negative symptoms in patients suffering from schizophrenia (Patil et al, 2007). In these trials, there were no major liabilities associated with current medications, including sedation, amnesic symptoms, withdrawal upon discontinuation of the drug, prolactin elevation, extrapyramidal symptoms, or weight gain.

These exciting clinical findings represent a major breakthrough and could ultimately lead to the introduction of mGluR2/3 activators as a novel approach to treatment of anxiety disorders and/or schizophrenia. However, it is not yet clear whether orthosteric agonists of these receptors will reach the market for broad clinical use. Also, these agonists activate both mGluR2 and mGluR3 and do not provide insights into which of these group II mGluR subtypes is most important for the clinical efficacy. Recently, a novel class of compounds, known as positive allosteric modulators (PAMs), that are selective for mGluR2 have shown exciting potential as an alternative approach to mGluR2/3 agonists. Unlike the mGluR2/3 agonists, these compounds do not activate mGluR2 directly but bind to a site distinct from the glutamate-binding site to increase responses of mGluR2 to glutamate. Multiple mGluR2 PAMs have been identified, all of which are structurally related to two prototypical mGluR2 PAMs, termed LY487379 (Johnson et al, 2003; Galici et al, 2005) and BINA (Galici et al, 2006). These compounds are highly selective for mGluR2 relative to mGluR3 or any other mGluR subtype and have robust effects in potentiating responses to group II mGluR agonists at several glutamatergic synapses (Johnson et al, 2003; Galici et al, 2006). Interestingly, psychomimetic agents increase activity of glutamatergic synapses in the prefrontal cortex (PFC) and this has been postulated to be critical in the pathophysiology of schizophrenia. Effects of psychomimetic agents on glutamatergic transmission in the PFC are blocked by group II mGluR agonists and by the mGluR2 PAMs. Furthermore, multiple structurally distinct mGluR2-selective PAMs have efficacy in animal models that predict both antipsychotic (Galici et al, 2005, 2006) and anxiolytic (Johnson et al, 2003; Galici et al, 2005) activities, which are very similar to those observed with the mGluR2/3 orthosteric agonists. These studies raise the exciting possibility that selective mGluR2 PAMs may provide a novel approach to treatment of schizophrenia and anxiety disorders that could be devoid of the adverse effects associated with currently available drugs.