Metabotropic Glutamate Receptors: Potential Drug Targets for Psychiatric Disorders

Abstract

Metabotropic glutamate receptors (mGlu receptors) have emerged as new therapeutic targets for psychiatric disorders, such as schizophrenia, depression and anxiety with their regulatory roles in glutamatergic transmissions. To date, several ligands selective for each mGlu receptor have been synthesized, and pharmacological significances of these ligands have been demonstrated in animal models. Among them, mGlu2/3 receptor agonists have been proven to be effective for treating schizophrenia and anxiety disorders in clinical studies, which may prove utilities of mGlu receptor ligands for the treatment of psychiatric disorders. This article reviews recent advances in development of each mGlu receptor ligands and their therapeutic potential.

Results and evaluation of a first‐in‐human study of RG7342, an mGlu5 positive allosteric modulator, utilizing Bayesian adaptive methods

“…RG7342 represents a novel, potent and selective, orally bioavailable mGlu5 positive allosteric modulator (PAM) which potentiates the activity of glutamate, with a half maximal effective concentration (EC 50 ) of 11.2 nM. In nonclinical behavioural paradigms, RG7342 shows a pro-social, procognitive and antipsychotic drug-like profile, in line with data reported for other mGlu5 PAMs [4,5].…”

Rosiglitazone treatment reversed depression- but not psychosis-like behavior of db/db diabetic mice

“…Thus, early pharmacological intervention to improve insulin sensitivity and normalize hyperglycemia helps to overcome type-2 diabetes-related selective neurobehavioral deficits such as depression. Further, glutamate (Widerlov et al, 1988), dopamine (Davis et al, 1991; Dunlop and Nemeroff, 2007), serotonin (Butler and Meegan, 2008) and neuropeptides (Yasuhara and Chaki, 2010) are the dominant mechanisms orchestrating neuropsychiatric disorders. Such alternative mechanisms may contribute to type-2 diabetes-related neurobehavioral deficits.…”

Valproic Acid Influences MTNR1A Intracellular Trafficking and Signaling in a β-Arrestin 2-Dependent Manner

“…Pathway-biased and deleterious melatonin receptor mutants have also been reported in an autism spectrum disorder population [4]. Both prospective and retrospective studies have suggested that children who are exposed to valproic acid (2-propylpentanoic acid, VPA) in utero have an increased risk of neuropsychological developmental delays and mood disorder symptoms [5][6][7]; however, the cellular basis for the action of VPA remains elusive.…”