Chiral Me-2-arachidonoyl Glycerols: The First Potent Endocannabinoid Glyceride Templates with Stability to COX-2

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-05-28 DOI:10.1021/acsmedchemlett.4c00175

Spyros P. Nikas*, Lipin Ji, Yingpeng Liu, Markos-Orestis Georgiadis, Amey Dopeshwarkar, Alex Straiker, Shalley Kudalkar, Anastasiia V. Sadybekov, Michaela Dvorakova, Vsevolod Katritch, Ken Mackie, Lawrence Marnett and Alexandros Makriyannis*,

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Abstract

2-Arachidonoyl glycerol (2-AG) is the principal endogenously produced ligand for the cannabinoid CB1 and CB2 receptors (CBRs). The lack of potent and efficacious 2-AG ligands with resistance against metabolizing enzymes represents a significant void in the armamentarium of research tools available for studying eCB system molecular constituents and their function. Herein we report the first endocannabinoid glyceride templates with remarkably high potency and efficacy at CBRs. Two of our lead chiral 2-AG analogs, namely, (13S)- and (13R)-Me-2-AGs, potently inhibit excitatory neurotransmission via CB1 while they are endowed with excellent resistance to the oxidizing enzyme COX-2. Our SAR results are supported by docking studies of the key analog and 2-AG on the crystal structures of CB1.

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手性 Me-2-arachidonoyl 甘油：首个对 COX-2 具有稳定性的强效内源性甘油酯模板

2-Arachidonoyl glycerol (2-AG) 是大麻素 CB1 和 CB2 受体 (CBR) 的主要内源性配体。由于缺乏对代谢酶有抵抗力的强效 2-AG 配体，研究 eCB 系统分子成分及其功能的研究工具出现了重大空白。在此，我们报告了首个在 CBR 上具有显著高效力和功效的内源性大麻素甘油酯模板。我们的两种先导手性 2-AG 类似物，即 (13S)- 和 (13R)-Me-2-AGs 可通过 CB1 有效抑制兴奋性神经传递，同时它们对氧化酶 COX-2 具有极佳的抗性。关键类似物和 2-AG 与 CB1 晶体结构的对接研究支持了我们的 SAR 结果。

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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.