Synthesis of Novel 2-Arachidonoylglycerol Analogs

新型2-花生四烯酸甘油类似物的合成

• 批准号: 7875958
• 负责人: KUMARA VADIVEL SUBRAMANIAN
• 金额: $ 19.45万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7875958
• 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; Human; Hunger; Hydrolysis; 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; public health relevance; radioligand; receptor; research study; tool; transmission process

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（由申请人提供）：本提案的主要目标是设计和合成新型2-花生四烯酰甘油类似物（2-AG），其作为关键内源性大麻素靶标的药理学探针具有改善的效力和生化稳定性。由此产生的新配体中最成功的将有助于我们理解2-花生四烯酸甘油（2-AG）在内源性大麻素信号传导中的作用及其对食欲，药物滥用和其他（病理）生理过程的影响。第一个目标涉及合成代谢稳定的2- AG类似物，因为内源性2-AG经历自发的酶促降解和酰基迁移。建议的结构特点包括：（a）通过引入（i）空间位阻和（ii）生物电子等排体和（B）修饰链以模拟花生四烯酸的亲脂链来增加酯的稳定性（包括各种取代的苯基，联苯，（c）第二个目的是开发一种共价探针，探索参与大麻素受体活化的配体结合基序（CB 1和CB 2）通过其内源性配体2-AG。将测定这些新合成的2-AG类似物对大麻素受体CB 1和CB 2的亲和力以及对内源性大麻素蛋白的抑制：单酰基甘油脂酶（MAGL）、脂肪酸酰胺水解酶（FAAH）、推定的内源性大麻素转运系统。缺乏稳定的2-AG类似物代表了可用于解剖内源性大麻素系统并研究其与脂质代谢、钙离子转运、炎症、细胞信号传导和大脑中的奖励机制的微妙平衡的研究工具中的显著空白。内源性大麻素系统的下调对于与大麻素受体的过度刺激相关的医学病症特别重要，包括从物质滥用、肥胖和运动障碍中恢复。公共卫生相关性：内源性大麻素系统参与影响疼痛、饥饿和对滥用药物的渴望的细胞信号传导。许多目前流行的药物拮抗内源性大麻素受体蛋白，本提案的目标是设计和合成新的2-花生四烯酰甘油类似物（2-AG），其作为关键内源性大麻素靶标的药理学探针具有改善的效力和生化稳定性。由此产生的新配体中最成功的将有助于我们理解2-花生四烯酸甘油（2-AG）在内源性大麻素信号传导中的作用及其对食欲，药物滥用和其他（病理）生理过程的影响。