Positive allosteric modulators (PAMs) of the group II metabotropic glutamate receptors: Design, synthesis, and evaluation as ex-vivo tool compounds,Bioorganic & Medicinal Chemistry Letters

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Positive allosteric modulators (PAMs) of the group II metabotropic glutamate receptors: Design, synthesis, and evaluation as ex-vivo tool compounds
Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2021-08-27 , DOI: 10.1016/j.bmcl.2021.128342
Yousuke Yamada ₁ , Kristen Gilliland ₂ , Zixiu Xiang ₂ , Daniel Haymer ₂ , Katherine E Crocker ₂ , Matthew T Loch ₂ , Michael L Schulte ₂ , Alice L Rodriguez ₂ , Colleen M Niswender ₃ , P Jeffrey Conn ₃ , Craig W Lindsley ₄ , Bruce J Melancon ₂

Affiliation

Warren Center for Neuroscience Drug Discovery at Vanderbilt University, Vanderbilt University, Nashville, TN 37232, USA.
Warren Center for Neuroscience Drug Discovery at Vanderbilt University, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Warren Center for Neuroscience Drug Discovery at Vanderbilt University, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Warren Center for Neuroscience Drug Discovery at Vanderbilt University, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

This letter describes synthesis and evaluation of two series of dual mGlu₂/mGlu₃ positive allosteric modulators with moderate mGlu₃ potency and robust mGlu₂ potency in thallium flux assays. These compounds were profiled their ability to modulate mGlu₃-mediated signaling in central neurons by co-application of a selective mGlu₂ NAM to isolate mGlu₃-selective effects. Using acute mouse brain slices from the prefrontal cortex, potentiation of group II mGlu receptor agonist Ca²⁺ signaling in PFC pyramidal cells with either the dual mGlu₂/mGlu₃ PAM 16e or 23d demonstrated effects mediated selectively via mGlu₃.

中文翻译：

II 组代谢型谷氨酸受体的正变构调节剂 (PAM)：作为离体工具化合物的设计、合成和评估

这封信描述了在铊通量测定中具有中等 mGlu ₃效力和强大 mGlu ₂效力的两个系列双 mGlu ₂ /mGlu ₃正变构调节剂的合成和评估。通过共同应用选择性mGlu ₂ NAM 以分离mGlu ₃选择性作用，分析了这些化合物调节中枢神经元中mGlu ₃介导的信号传导的能力。利用从前额皮质急性小鼠脑切片，组II组mGlu受体激动剂的Ca的增强²⁺在PFC锥体细胞与双组mGlu信令₂ /组mGlu ₃ PAM 16E或图23d证明了通过mGlu ₃选择性介导的效果。

更新日期：2021-08-31

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