Drugs to tune up glutamatergic systems: Modulators of glutamate metabotropic receptors

The metabotropic glutamate (mGlu) receptors are Class C G protein-coupled receptors that offer promising potential therapeutic targets for multiple central nervous system (CNS) disorders. Dysfunction or dysregulation of the glutamatergic system, the main excitatory neurotransmitter system in the CNS, is thought to be associated with multiple CNS disorders including schizophrenia, depression, anxiety, Fragile X syndrome, Parkinson’s disease, and refractory chronic pain. Here, we describe drug discovery and development approaches for targeting mGlu receptors, with particular focus on allosteric modulation and biased agonism. Binding to allosteric sites that are topographically distinct from the endogenous binding site, allows for increased selectivity between receptor subtypes, and maintaining tonal and temporal glutamatergic responses. Biased agonism allows for further specialization, with the potential to design drugs that target desired receptor responses at the exclusion of those leading to adverse effects. Collectively, these newer paradigms of drug action offer the promise for discovery of therapeutics with favorable outcomes and minimized adverse effects within the delicate CNS environment.