Pharmacology of metabotropic glutamate receptor allosteric modulators: structural basis and therapeutic potential for CNS disorders

Abstract

The metabotropic glutamate receptors (mGlus) mediate a neuromodulatory role throughout the brain for the major excitatory neurotransmitter, glutamate. Seven of the eight mGlu subtypes are expressed within the CNS and are attractive targets for a variety of psychiatric and neurological disorders including anxiety, depression, schizophrenia, Parkinson's disease, and Fragile X syndrome. Allosteric modulation of these class C 7-transmembrane spanning receptors represents a novel approach to facilitate development of mGlu subtype-selective probes and therapeutics. Allosteric modulators that interact with sites topographically distinct from the endogenous ligand-binding site offer a number of advantages over their competitive counterparts. In particular for CNS therapeutics, allosteric modulators have the potential to maintain the spatial and temporal aspects of endogenous neurotransmission. The past 15 years have seen the discovery of numerous subtype-selective allosteric modulators for the majority of the mGlu family members, including positive, negative, and neutral allosteric modulators, with a number of mGlu allosteric modulators now in clinical trials.