Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease

Abstract

Metabotropic glutamate (mGlu) receptors, a family of G-protein-coupled receptors, have been identified as novel therapeutic targets based on extensive research supporting their diverse contributions to cell signaling and physiology throughout the nervous system and important roles in regulating complex behaviors, such as cognition, reward, and movement. Thus, targeting mGlu receptors may be a promising strategy for the treatment of several brain disorders. Ongoing advances in the discovery of subtype-selective allosteric modulators for mGlu receptors has provided an unprecedented opportunity for highly specific modulation of signaling by individual mGlu receptor subtypes in the brain by targeting sites distinct from orthosteric or endogenous ligand binding sites on mGlu receptors. These pharmacological agents provide the unparalleled opportunity to selectively regulate neuronal excitability, synaptic transmission, and subsequent behavioral output pertinent to many brain disorders. Here, we review preclinical and clinical evidence supporting the utility of mGlu receptor allosteric modulators as novel therapeutic approaches to treat neuropsychiatric diseases, such as schizophrenia, substance use disorders, and stress-related disorders. Significance Statement Allosteric modulation of metabotropic glutamate (mGlu) receptors represents a promising therapeutic strategy to normalize dysregulated cellular physiology associated with neuropsychiatric disease. This review summarizes preclinical and clinical studies using mGlu receptor allosteric modulators as experimental tools and potential therapeutic approaches for the treatment of neuropsychiatric diseases, including schizophrenia, stress, and substance use disorders.

Identification and Characterization of ML321: A Novel and Highly Selective D2 Dopamine Receptor Antagonist with Efficacy in Animal Models That Predict Atypical Antipsychotic Activity

“…As noted above, D2R antagonism is effective for treating the positive symptoms of schizophrenia but less efficacious for treating the negative or cognitive symptoms of this illness. While other drug targets are being investigated, particularly for the treatment of negative and cognitive symptoms, − it may prove difficult to develop a single drug that has the appropriate affinity and activity/efficacy for all, including yet unknown, targets needed to treat the entirety of schizophrenic symptomatology. Thus, similar to many other diseases and disorders, a combinatorial approach (administering two or more drugs, perhaps formulated together) may become the standard of care for treating schizophrenia (e.g., see ref ), and it is likely that one of these drugs will be a D2R antagonist (or low efficacy partial agonist).…”

“…The so-called “third generation” antipsychotics have recently been developed that are low-efficacy partial D2R agonists with atypical side-effect profiles, although these exhibit an increased risk of akathisia, potentially due to D2R stimulation . While other drug targets are being evaluated for the treatment of schizophrenia, − particularly for ameliorating negative and cognitive symptoms, D2R antagonism remains the primary mechanism underlying current antipsychotic medications. Notably, however, pimavanserin, an inverse agonist at the 5-HT 2A serotonin receptor, has been approved for treating psychosis associated with Parkinson’s disease and may be effective as an adjunctive therapeutic (combined with an antipsychotic) for the treatment of negative symptoms in schizophrenia …”

Identification and Characterization of ML321: a Novel and Highly Selective D2Dopamine Receptor Antagonist with Efficacy in Animal Models that Predict Atypical Antipsychotic Activity

“…While other drug targets are being investigated, particularly for the treatment of negative and cognitive symptoms [12][13][14][15] , it may prove difficult to develop a single drug that has the appropriate affinity and activity/efficacy for all, including yet unknown, targets needed to treat the entirety of schizophrenic symptomatology. Thus, similar to many other diseases and disorders, a combinatorial approach (administering two or more drugs, perhaps formulated together) may become the standard of care for treating schizophrenia (e.g., see 17 ), and it is likely that one of these drugs will be a D2R antagonist (or low efficacy partial agonist).…”

“…It is not subject to copyright under 17 USC The copyright holder for this preprint this version posted November 16, 2022. ; https://doi.org/10.1101/2022.11.14.516475 doi: bioRxiv preprint been developed that are low-efficacy partial D2R agonists with atypical side-effect profiles, although these exhibit an increased risk of akathisia, potentially due to D2R stimulation 11 . While other drug targets are being evaluated for the treatment of schizophrenia [12][13][14][15] , particularly for ameliorating negative and cognitive symptoms, D2R antagonism remains the primary mechanism underlying current antipsychotic medications. Notably, however, pimavanserin, an inverse agonist at the 5-HT2A serotonin receptor, has been approved for treating psychosis associated with Parkinson's disease 16 and may be effective as an adjunctive therapeutic (combined with an antipsychotic) for the treatment of negative symptoms in schizophrenia 17 .…”

NMDARs mediate peripheral and central sensitization contributing to chronic orofacial pain

“…First of all, allosteric regulators have two-way regulation, including positive and negative allosteric regulators (Yang and Svensson, 2008 ). Some allosteric regulators can bind to conservative low NMDAR sites, which is beneficial to the development of drugs with subunit selectivity (Luessen and Conn, 2022 ). Typical compounds include GluN2A selective negative allosteric regulator STCN-201, GluN1/2B receptor regulator isopropylphenidil, GluN2C/D selective regulator QNZ-46, and so on (Zhu et al, 2020 ).…”