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Development and profiling of mGlu₇ NAMs with a range of saturable inhibition of agonist responses in vitro.

ABSTRACT: We describe here a series of metabotropic glutamate receptor 7 (mGlu₇) negative allosteric modulators (NAMs) with a saturable range of activity in inhibiting responses to an orthosteric agonist in two distinct in vitro pharmacological assays. The range of inhibition among compounds in this scaffold provides highly structurally related ligands with differential degrees of receptor blockade that can be used to understand inhibitory efficacy profiles in native tissue or in vivo.

SUBMITTER: Reed CW

PROVIDER: S-EPMC10015594 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Development and profiling of mGlu<sub>7</sub> NAMs with a range of saturable inhibition of agonist responses in vitro.

Reed Carson W CW Rodriguez Alice L AL Kalbfleisch Jacob J JJ Seto Mabel M Jenkins Matthew T MT Blobaum Anna L AL Chang Sichen S Lindsley Craig W CW Niswender Colleen M CM

Bioorganic & medicinal chemistry letters 20220806

We describe here a series of metabotropic glutamate receptor 7 (mGlu<sub>7</sub>) negative allosteric modulators (NAMs) with a saturable range of activity in inhibiting responses to an orthosteric agonist in two distinct in vitro pharmacological assays. The range of inhibition among compounds in this scaffold provides highly structurally related ligands with differential degrees of receptor blockade that can be used to understand inhibitory efficacy profiles in native tissue or in vivo. ...[more]

PMID: 35944850

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Project description:Metabotropic glutamate (mGlu) receptors are promising targets for the treatment of affective disorders and alcohol use disorder (AUD). Nonspecific ligands for Group II (mGlu2 and mGlu3) mGlu receptors have demonstrated consistent therapeutic potential for affective disorders in preclinical models. Disentangling the specific roles of mGlu2 versus mGlu3 receptors in these effects has persisted as a major challenge, in part due to pharmacological limitations. However, the recent development of highly specific allosteric modulators for both mGlu2 and mGlu3 receptors have enabled straightforward and rigorous investigations into the specific function of each receptor. Here, we review recent experiments using these compounds that have demonstrated both similar and distinct receptor functions in behavioral, molecular, and electrophysiological measures associated with basal function and preclinical models of affective disorders. Studies using these selective drugs have demonstrated that mGlu2 is the predominant receptor subclass involved in presynaptic neurotransmitter release in prefrontal cortex. By contrast, the activation of postsynaptic mGlu3 receptors induces a cascade of cellular changes that results in AMPA receptor internalization, producing long-term depression and diminishing excitatory drive. Acute stress decreases the mGlu3 receptor function and dynamically alters transcript expression for both mGlu2 (Grm2) and mGlu3 (Grm3) receptors in brain areas involved in reward and stress. Accordingly, both mGlu2 and mGlu3 negative allosteric modulators show acute antidepressant-like effects and potential prophylactic effects against acute and traumatic stressors. The wide array of effects displayed by these new allosteric modulators of mGlu2 and mGlu3 receptors suggest that these drugs may act through improving endophenotypes of symptoms observed across several neuropsychiatric disorders. Therefore, recently developed allosteric modulators selective for mGlu2 or mGlu3 receptors show promise as potential therapeutics for affective disorders and AUD.

Dataset Information

Development and profiling of mGlu₇ NAMs with a range of saturable inhibition of agonist responses in vitro.

Publications

Development and profiling of mGlu<sub>7</sub> NAMs with a range of saturable inhibition of agonist responses in vitro.

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Dataset Information

Development and profiling of mGlu7 NAMs with a range of saturable inhibition of agonist responses in vitro.

Publications

Development and profiling of mGlu<sub>7</sub> NAMs with a range of saturable inhibition of agonist responses in vitro.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Development and profiling of mGlu₇ NAMs with a range of saturable inhibition of agonist responses in vitro.