Dataset Information

Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu₃ NAMs.

ABSTRACT: Herein, we detail the optimization of the mGlu₃ NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu₃ NAM scaffold that engenders potent and selective mGlu₃ inhibition (mGlu₃ IC₅₀ = 245 nM, mGlu₂ IC₅₀ > 30 ?M) with excellent central nervous system penetration (rat brain/plasma K_p = 1.2, K_p,uu = 0.40). Moreover, this new chemotype, exemplified by VU6010572, requires only four synthetic steps and displays improved physiochemical properties and in vivo efficacy in a mouse tail suspension test (MED = 3 mg/kg i.p.).

SUBMITTER: Engers JL

PROVIDER: S-EPMC5601378 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs.

Engers Julie L JL Bollinger Katrina A KA Weiner Rebecca L RL Rodriguez Alice L AL Long Madeline F MF Breiner Megan M MM Chang Sichen S Bollinger Sean R SR Bubser Michael M Jones Carrie K CK Morrison Ryan D RD Bridges Thomas M TM Blobaum Anna L AL Niswender Colleen M CM Conn P Jeffrey PJ Emmitte Kyle A KA Lindsley Craig W CW

ACS medicinal chemistry letters 20170815 9

Herein, we detail the optimization of the mGlu3 NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu3 NAM scaffold that engenders potent and selective mGlu3 inhibition (mGlu3 IC50 = 245 nM, mGlu2 IC50 > 30 μM) with excellent central nervous system penetration (rat brain/plasma Kp = 1.2, Kp,uu = 0.40). Moreover, this new chemotype, exemplified by VU6010572, re ...[more]

PMID: 28947938

Similar Datasets

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

Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu₃ NAMs.

Publications

Design and Synthesis of <i>N</i>-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu<sub>3</sub> NAMs.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets