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Synthesis of Novel 2-Arachidonoylglycerol Analogs

新型2-花生四烯酸甘油类似物的合成

基本信息

批准号：
8035357
负责人：
KUMARA VADIVEL SUBRAMANIAN
金额：
$ 18.85万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8035357
关键词：
2-arachidonylglycerol Adenylate Cyclase Affect Affinity Agonist Arachidonic Acids Attention Binding Biochemical Biological Biological Assay Brain CNR1 gene CNR2 gene Calcium ion Cell Culture Techniques Cells Competitive Binding Data Desire for food Development Down-Regulation Endocannabinoids Enzymes Equilibrium Esters Feeding behaviors Future Goals Health Human Hunger Inflammation Ion Transport Ligand Binding Ligands Medical Membrane Monoacylglycerol Lipases Movement Disorders Obesity Pain Parents Pharmaceutical Preparations Physiological Processes Positioning Attribute Property Proteins Rattus Recovery Relative (related person)Research Rewards Rodent Role Series Signal Transduction Substance abuse problem System Testing Therapeutic Agents Work analog anandamide cannabinoid receptor craving design diphenyl drug discovery drug of abuse fatty acid amide hydrolase improved in vivo inhibitor/antagonist lipid metabolism migration novel novel therapeutics overexpression radioligand receptor research study tool transmission process

项目摘要

DESCRIPTION (provided by applicant): The primary goal of this proposal is to design and synthesize novel 2-arachidonoylglycerol analogs (2-AG) with improved potency and biochemical stability as pharmacological probes for key endocannabinoid targets. The most successful of the resulting new ligands will contribute our understanding of the role of 2- arachidonoylglycerol (2-AG) in endocannabinoid signaling and its influence on appetite, substance abuse, and other (patho)physiological processes. The first objective involves synthesis of metabolically stable analog of 2- AG, as endogenous 2-AG undergoes spontaneous enzymatic degradation and acyl migration. The proposed structural features include: (a) increasing stability of ester by introducing (i) steric hindrance and (ii) bioisosteres and (b) modifying chain to mimic lipophilic chain of arachidonic acid (including various substituted phenyl, biphenyls, diphenylmethane and oxydibenzene) (c) The second objective is to develop a covalent probe exploring the ligand binding motifs involved in the activation of the cannabinoid receptors (CB1 and CB2) by their endogenous ligand, 2-AG. These newly synthesized 2-AG analogs will be assayed for their affinity to the cannabinoid receptors CB1 and CB2 as well as inhibition of endocannabinoid proteins: monoacylglycerol lipase (MAGL), fatty acid amide hydrolase (FAAH), the putative endocannabinoid transporter system. The lack of stable 2-AG analogs represents a significant void in the research tools available to dissect the endocannabinoid system and study its delicate balance with lipid metabolism, calcium ion transport, inflammation, cell signaling, and reward mechanisms in the brain. The downregulation of the endocannabinoid system is particularly important for medical conditions related to overstimulation of the cannabinoid receptor including recovery from substance abuse, obesity, and movement disorders. PUBLIC HEALTH RELEVANCE: The endocannabinoid system is involved in cell signaling which affect pain, hunger, and cravings for drugs of abuse. A number of currently popular medications antagonize the endocannabinoid receptor proteins and the goal of this proposal is to design and synthesize novel 2-arachidonoylglycerol analogs (2-AG) with improved potency and biochemical stability as pharmacological probes for key endocannabinoid targets. The most successful of the resulting new ligands will contribute our understanding of the role of 2-arachidonoylglycerol (2-AG) in endocannabinoid signaling and its influence on appetite, substance abuse, and other (patho)physiological processes.

描述(申请人提供)：这项建议的主要目标是设计和合成新的2-花生烯酰甘油类似物(2-AG)，具有更好的效力和生物化学稳定性，作为关键的内源性大麻素靶标的药理探针。最成功的新配体将有助于我们理解2-花生四烯基甘油(2-AG)在内源性大麻信号转导中的作用及其对食欲、物质滥用和其他(病理)生理过程的影响。第一个目标是合成代谢稳定的2-AG类似物，因为内源2-AG经历了自发的酶降解和酰基迁移。建议的结构特征包括：(A)通过引入(I)空间位阻和(Ii)生物等位体来增加酯的稳定性，以及(B)通过修饰链来模拟花生四烯酸(包括各种取代的苯基、联苯、二苯基甲烷和氧二苯)的亲脂链(C)第二个目标是开发一种共价探针，探索通过内源配体2-AG激活大麻素受体(CB1和CB2)的配体结合基序。这些新合成的2-AG类似物将被检测它们与大麻素受体CB1和CB2的亲和力以及对内源性大麻素蛋白的抑制作用：单酰甘油脂肪酶(MAGL)，脂肪酸酰胺水解酶(FAAH)，推测的内源性大麻素转运体系统。缺乏稳定的2-AG类似物代表着可用于解剖内源性大麻素系统并研究其与大脑中脂代谢、钙离子转运、炎症、细胞信号和奖励机制的微妙平衡的研究工具的显著空白。内源性大麻素系统的下调对于与大麻素受体过度刺激相关的医学状况尤其重要，包括从药物滥用、肥胖和运动障碍中恢复过来。公共卫生相关性：内源性大麻素系统参与细胞信号传递，影响疼痛、饥饿和对滥用药物的渴望。一些目前流行的药物可以拮抗内源性大麻素受体蛋白，本方案的目的是设计和合成具有更高效力和生化稳定性的新型2-花生四烯基甘油类似物(2-AG)，作为内源性大麻素关键靶点的药理探针。最成功的新配体将有助于我们理解2-花生四烯基甘油(2-AG)在内源性大麻信号转导中的作用及其对食欲、物质滥用和其他(病理)生理过程的影响。