Targeting metabotropic glutamate receptors for novel treatments of schizophrenia

Abstract

Support for the N-methyl-d-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia has led to increasing focus on restoring proper glutamatergic signaling as an approach for treatment of this devastating disease. The ability of metabotropic glutamate (mGlu) receptors to modulate glutamatergic neurotransmission has thus attracted considerable attention for the development of novel antipsychotics. Consisting of eight subtypes classified into three groups based on sequence homology, signal transduction, and pharmacology, the mGlu receptors provide a wide range of targets to modulate NMDAR function as well as glutamate release. Recently, allosteric modulators of mGlu receptors have been developed that allow unprecedented selectivity among subtypes, not just groups, facilitating the investigation of the effects of subtype-specific modulation. In preclinical animal models, positive allosteric modulators (PAMs) of the group I mGlu receptor mGlu5 have efficacy across all three symptom domains of schizophrenia (positive, negative, and cognitive). The discovery and development of mGlu5 PAMs that display unique signal bias suggests that efficacy can be retained while avoiding the neurotoxic effects of earlier compounds. Interestingly, mGlu1 negative allosteric modulators (NAMs) appear efficacious in positive symptom models of the disease but are still in early preclinical development. While selective group II mGlu receptor (mGlu2/3) agonists have reached clinical trials but were unsuccessful, specific mGlu2 or mGlu3 receptor targeting still hold great promise. Genetic studies implicated mGlu2 in the antipsychotic effects of group II agonists and mGlu2 PAMs have since entered into clinical trials. Additionally, mGlu3 appears to play an important role in cognition, may confer neuroprotective effects, and thus is a promising target to alleviate cognitive deficits in schizophrenia. Although group III mGlu receptors (mGlu4/6/7/8) have attracted less attention, mGlu4 agonists and PAMs appear to have efficacy across all three symptoms domains in preclinical models. The recent discovery of heterodimers comprising mGlu2 and mGlu4 may explain the efficacy of mGlu4 selective compounds but this remains to be determined. Taken together, compounds targeting mGlu receptors, specifically subtype-selective allosteric modulators, provide a compelling alternative approach to fill the unmet clinical needs for patients with schizophrenia.

Glutamate hypothesis in schizophrenia

“…These receptors are expressed presynaptically as autoreceptors, activated by astrocytic glutamate release or glutamate overflow from the synapse during excessive glutamate release. mGlu 3 is also found postsynaptically as well as on astrocytes where it mediates neuroprotective effects and participates in astrocytic‐neuronal communication . Group II mGlu receptors also have a reciprocal relationship with 5‐HT 2A receptors.…”

Atypical Antipsychotic Drug Olanzapine Deregulates Hepatic Lipid Metabolism and Aortic Inflammation and Aggravates Atherosclerosis

“…Schizophrenia is a persistent and disabling psychotic disorder that may be attributed to multiple factors including genetic and environmental aspects and social processes [1,2]. Schizophrenic patients may display abnormal social behavior and be out of touch with reality [1,2].…”

“…Schizophrenic patients may display abnormal social behavior and be out of touch with reality [1,2]. The most common symptoms of schizophrenia include delusions, hallucinations and disorganized thoughts, which are divided into three categories: positive, negative, and cognitive [3].…”

Control of neuronal excitability by Group I metabotropic glutamate receptors

“…The development and characterization of selective agonists and antagonists for mGlu receptors has greatly facilitated the study of their role in physiological and pathological responses (Hovelsø et al 2012;Maksymetz et al 2017;Nicoletti et al 2011;Niswender and Conn 2010;Zou et al 2017). Metabotropic glutamate receptors have binding sites for two classes of ligands.…”