Discovery of CVN636: A Highly Potent, Selective, and CNS Penetrant mGluR7 Allosteric Agonist

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2023-03-02 DOI:10.1021/acsmedchemlett.2c00529

Louise Dickson*, Martin Teall, Elodie Chevalier, Toni Cheung, Gemma M. Liwicki, Stephen Mack, Anne Stephenson, Kathryn White, Richard Fosbeary, David C. Harrison, Nicola L. Brice, Kevin Doyle, Roberto Ciccocioppo, Chaobo Wu, Sarah Almond, Toshal R. Patel, Philip Mitchell, Matt Barnes, Andrew P. Ayscough, Lee A. Dawson, Mark Carlton and Roland W. Bürli,

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引用次数: 2

Abstract

The low affinity metabotropic glutamate receptor mGluR₇ has been implicated in numerous CNS disorders; however, a paucity of potent and selective activators has hampered full delineation of the functional role and therapeutic potential of this receptor. In this work, we present the identification, optimization, and characterization of highly potent, novel mGluR₇ agonists. Of particular interest is the chromane CVN636, a potent (EC₅₀ 7 nM) allosteric agonist which demonstrates exquisite selectivity for mGluR₇ compared to not only other mGluRs, but also a broad range of targets. CVN636 demonstrated CNS penetrance and efficacy in an in vivo rodent model of alcohol use disorder. CVN636 thus has potential to progress as a drug candidate in CNS disorders involving mGluR₇ and glutamatergic dysfunction.

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一种高效、选择性、CNS渗透的mGluR7变构激动剂CVN636的发现

低亲和力代谢性谷氨酸受体mGluR7与许多中枢神经系统疾病有关;然而，有效和选择性激活剂的缺乏阻碍了对该受体的功能作用和治疗潜力的充分描述。在这项工作中，我们介绍了高效的新型mGluR7激动剂的鉴定、优化和表征。特别令人感兴趣的是铬胺CVN636，这是一种有效的(EC50 7 nM)变构激动剂，与其他mglur相比，它不仅对mGluR7具有良好的选择性，而且对靶标范围也很广。CVN636在体内酒精使用障碍啮齿动物模型中显示出CNS外显性和有效性。因此，CVN636作为mGluR7和谷氨酸能功能障碍相关的中枢神经系统疾病的候选药物具有发展潜力。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.

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