Schizophrenia is a devastating psychiatric disorder that afflicts about 1% of the world’s population, affects men and women equally, and spans all socioeconomic groups. The pharmacological regulation of metabotropic glutamate receptor 5 (mGluR5) has attracted widespread attention as a new therapeutic mechanism for the treatment of schizophrenia.
Introduction to mGluR5
Metabotropic glutamate receptors (mGluRs) are the second class of glutamate receptors, which are members of the G-protein-coupled receptor family C. They are characterized by a large extracellular agonist binding domain at the amino terminus of the receptors, which are different from all the seven transmembrane domains coupled with G proteins. Eight mGluR subtypes have been identified and cloned and divided into three groups according to sequence similarity, effect coupling and pharmacology. Among these, the activation of mGluR5 usually results in increased neuronal excitability, mainly located at the postsynaptic level, coupled with Gq and its related effectors. In the hippocampus, prefrontal cortex (PFC) and other brain regions, mGlu5 plays an important role in synaptic plasticity-in response to specific patterns of activity.
Fig.1 Localization of metabotropic glutamate receptor subtypes. (Maksymetz, 2017)
Function of mGluR5 Agonist in Schizophrenia
Evidence shows that the glutamatergic system and N-methyl-D-aspartate receptor (NMDAR) play a key role in the underlying pathophysiology of psychiatric illness. NMDAR agonists such as d-serine show therapeutic potential for the treatment of schizophrenia. mGluR5 is structurally and functionally related to NMDAR, but unlike NMDAR, it is located in a more selective brain region, where it can fine-tune glutamatergic transmission. Early pharmacological and gene deletion studies in mice indicate that mGlu5 is important in regulating specific domains of cognitive functions and behaviors related to the positive and negative symptoms of schizophrenia. It has been confirmed that mGluR5 positive allosteric modulators (PAMs) can up-regulate NMDAR function, and may treat schizophrenia-related NMDAR hypofunction. In the past two decades, more and more evidence has shown that selective mGlu5-PAMs can provide an exciting new method for the treatment of schizophrenia.
mGluR5 Agonist Development Services in Creative Biolabs
In the development of mGlu5 agonists, the discovery of biased PAMs and the presence of mGlu heterodimers with different pharmacology can provide new methods to optimize the efficacy while avoiding toxicity or other adverse effects. At present, much drug discovery work of Creative Biolabs for schizophrenia is in preclinical development stage, but we have produced several subtype selective tool compounds, which have the least side effects and good preclinical efficacy. These compounds provide an unprecedented opportunity to deepen our basic understanding of the therapeutic role of mGluR5 regulation in schizophrenia.
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Reference
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Maksymetz, J.; et al. Targeting metabotropic glutamate receptors for novel treatments of schizophrenia. Molecular brain. 2017, 10(1): 15. Distributed under Open Access license CC BY 4.0, without modification.
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