Dataset Information

Design and Synthesis of mGlu₂ NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core.

ABSTRACT: Herein, we detail the optimization of the mGlu₂ negative allosteric modulator (NAM), VU6001192, by a reductionist approach to afford a novel, simplified mGlu₂ NAM scaffold. This new chemotype not only affords potent and selective mGlu₂ inhibition, as exemplified by VU6001966 (mGlu₂ IC₅₀ = 78 nM, mGlu₃ IC₅₀ > 30 ?M), but also excellent central nervous system (CNS) penetration (K_p = 1.9, K_p,uu = 0.78), a feature devoid in all previously disclosed mGlu₂ NAMs (K_ps ? 0.3, K_p,uus ? 0.1). Moreover, this series, based on overall properties, represents an exciting lead series for potential mGlu₂ PET tracer development.

SUBMITTER: Bollinger KA

PROVIDER: S-EPMC5601377 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Publications

Design and Synthesis of mGlu2 NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core.

Bollinger Katrina A KA Felts Andrew S AS Brassard Christopher J CJ Engers Julie L JL Rodriguez Alice L AL Weiner Rebecca L RL Cho Hyekyung P HP Chang Sichen S Bubser Michael M Jones Carrie K CK Blobaum Anna L AL Niswender Colleen M CM Conn P Jeffrey PJ Emmitte Kyle A KA Lindsley Craig W CW

ACS medicinal chemistry letters 20170803 9

Herein, we detail the optimization of the mGlu2 negative allosteric modulator (NAM), VU6001192, by a reductionist approach to afford a novel, simplified mGlu2 NAM scaffold. This new chemotype not only affords potent and selective mGlu2 inhibition, as exemplified by VU6001966 (mGlu2 IC50 = 78 nM, mGlu3 IC50 > 30 μM), but also excellent central nervous system (CNS) penetration (Kp = 1.9, Kp,u ...[more]

PMID: 28947937

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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

Design and Synthesis of mGlu₂ NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core.

Publications

Design and Synthesis of mGlu<sub>2</sub> NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core.

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