Dataset Information

Evaluation of Synthetic Cytochrome P₄₅₀-Mimetic Metalloporphyrins To Facilitate "Biomimetic" Biotransformation of a Series of mGlu₅ Allosteric Ligands.

ABSTRACT: Allosteric ligands within a given chemotype can have the propensity to display a wide range of pharmacology, as well as unexpected changes in GPCR subtype selectivity, typically mediated by single-atom modifications to the ligand. Due to the unexpected nature of these "molecular switches", chemotypes with this property are typically abandoned in lead optimization. Recently, we have found that in vivo oxidative metabolism by CYP₄₅₀s can also engender molecular switches within allosteric ligands, changing the mode of pharmacology and leading to unwanted toxicity. We required a higher-throughput approach to assess in vivo metabolic molecular switches, and we turned to a "synthetic liver", a 96 well kit of biomimetic catalysts (e.g., metalloporphyrins) to rapidly survey a broad panel of synthetic CYP₄₅₀s' ability to oxidize/"metabolize" an mGlu₅ PAM (VU0403602) known to undergo an in vivo CYP₄₅₀-mediated molecular switch. While the synthetic CYP₄₅₀s did generate a number of oxidative "metabolites" at known "hot spots", several of which proved to be pure mGlu₅ PAMs comparable in potency to the parent, the known CYP₄₅₀-mediated in vivo ago-PAM metabolite, namely, VU0453103, was not formed. Thus, this technology platform has potential to identify hot spots for oxidative metabolism and produce active metabolites of small-molecule ligands in a high-throughput, scalable manner.

SUBMITTER: Presley CC

PROVIDER: S-EPMC6690571 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Publications

Evaluation of Synthetic Cytochrome P450-Mimetic Metalloporphyrins To Facilitate "Biomimetic" Biotransformation of a Series of mGlu5 Allosteric Ligands.

Presley Christopher C CC Perry Charles K CK Childress Elizabeth S ES Mulder Matthew J MJ Luscombe Vincent B VB Rodriguez Alice L AL Niswender Colleen M CM Conn P Jeffrey PJ Lindsley Craig W CW

ACS omega 20190726 7

Allosteric ligands within a given chemotype can have the propensity to display a wide range of pharmacology, as well as unexpected changes in GPCR subtype selectivity, typically mediated by single-atom modifications to the ligand. Due to the unexpected nature of these "molecular switches", chemotypes with this property are typically abandoned in lead optimization. Recently, we have found that in vivo oxidative metabolism by CYP450s can also engender molecular switches within allosteri ...[more]

PMID: 31460402

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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

Evaluation of Synthetic Cytochrome P₄₅₀-Mimetic Metalloporphyrins To Facilitate "Biomimetic" Biotransformation of a Series of mGlu₅ Allosteric Ligands.

Publications

Evaluation of Synthetic Cytochrome P<sub>450</sub>-Mimetic Metalloporphyrins To Facilitate "Biomimetic" Biotransformation of a Series of mGlu<sub>5</sub> Allosteric Ligands.

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