Metabotropic Glutamate Receptors

Metabotropic glutamate receptors (mGluRs) comprise eight class C GPCRs, designated mGlu1 to mGlu8, that mediate the modulatory actions of glutamate throughout the central and peripheral nervous systems. They are divided into three pharmacological groups: Group I consists of mGlu1 and mGlu5, Group II comprises mGlu2 and mGlu3, and Group III includes mGlu4, mGlu6, mGlu7 and mGlu8. mGluRs possess a large extracellular Venus flytrap domain that binds glutamate and a seven-transmembrane domain responsible for G-protein coupling and intracellular signaling. Group I receptors primarily couple to Gq/11 and stimulate phospholipase C, intracellular calcium signaling and neuronal excitability, whereas Groups II and III predominantly couple to Gi/o and inhibit adenylyl cyclase and neurotransmitter release. mGluRs are widely expressed in the brain, with individual subtypes showing highly specific distributions in neurons, astrocytes and other cell types, and they regulate synaptic transmission, neuronal excitability, learning, memory and synaptic plasticity. Depending on the subtype and cellular localization, mGluRs can function either postsynaptically to modulate neuronal responses or presynaptically as autoreceptors that regulate glutamate and other neurotransmitter release. Dysregulation of mGluR signaling has been implicated in numerous neurological and psychiatric disorders, including schizophrenia, epilepsy, Parkinson’s disease, Alzheimer’s disease, anxiety, depression, autism spectrum disorders and Fragile X syndrome. A large pharmacological toolbox has been developed, including orthosteric agonists and antagonists as well as positive and negative allosteric modulators with substantially improved subtype selectivity. Several compounds have progressed into clinical development, including mGlu2/3 agonists and mGlu5 negative allosteric modulators, although many programs have been limited by insufficient efficacy, adverse effects or inadequate CNS pharmacology. An important clinically relevant example is fenobam, an mGlu5 negative allosteric modulator investigated for anxiety and Fragile X syndrome, while other mGlu5 modulators such as mavoglurant and basimglurant have been evaluated in neurological and psychiatric indications. Overall, the mGluR family represents one of the most extensively investigated GPCR families for CNS drug discovery, but despite extensive pharmacological validation, selective mGluR-targeted therapies remain limited and considerable opportunities remain for the development of safer and more effective subtype-selective modulators.