Therapeutic potential of group III metabotropic glutamate receptors

Metabotropic glutamate (mGlu) receptors have received much attention, driven by a strong belief in the potential of these modulatory glutamate receptors as drug targets. So far, major drug discovery programs have largely focused on group I (mGlu1 and 5) and II (mGlu2 and 3) mGlu receptors, which have been implicated in neuropathological and various psychiatric disorders. The four group III representatives (mGlu4, mGlu6, mGlu7 and mGlu8) are less understood, mainly due to the paucity of specific compounds. Recent advances in the identification of selective or specific compounds, and the generation of transgenic animals have, however, revealed important insights into the potential role of group III receptors in the pathophysiology of neurological and mood disorders. Activation of the mGlu4 receptor seems to be beneficial for treating Parkinson-like symptoms and a potential role in the treatment of mood disorders is slowly growing. Similarly, genetic inactivation studies and usage of relatively selective agonists strongly support the involvement of the mGlu8 receptor for anxiety disorders. In contrast, controversial data have been obtained for the mGlu7 receptor. While mGlu7 receptor-deficient animals show an anxiolytic profile in several in vivo readouts, the first selective allosteric agonist AMN082 has also been reported to improve anxiety-like behaviour despite activating the stress axis. The least investigated receptor remains the mGlu6 receptor, which is mostly based on its predominant expression in the retina.