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）：该提案的主要目标是设计和合成新型的2-芳基烯丙基甘油类似物（2-AG），其效力和生物化学稳定性提高了，作为关键内源性核靶靶标的药理探针。最成功的新配体将有助于我们理解2-蛛网膜化甘油（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（PATHO）生理过程的影响。第一个目标涉及合成2-Ag代谢稳定的类似物，因为内源性2-AG经历了自发的酶促降解和酰基迁移。所提出的结构特征包括：（a）通过引入（i）空间阻滞和（ii）生物酶固定剂和（b）对蛛网膜酸的模拟亲脂性链的修改链（包括各种替代苯基，二苯基苯基和氧化型的均替代苯基）（包括各种替代苯基）（包括二苯基甲基二苯二甲酸酯IS（C）AA AI ASS的替代链（C）配体结合基序与内源性配体2-Ag激活大麻素受体（CB1和CB2）激活。这些新合成的2AG类似物将通过与大麻素受体CB1和CB2的亲和力以及对内源性大麻素蛋白的抑制：单酰甘油脂肪酶（MAGL），脂肪酸酰胺水解酶（FAAH）的抑制作用，并抑制抑制大麻素受体。缺乏稳定的2-ag类似物代表了可剖析内源性大麻素系统的研究工具中的重要空隙，并研究了其与脂质代谢，钙离子传输，炎症，细胞信号传导和奖励机制的微妙平衡。内源性大麻素系统的下调对于与大麻素受体过度刺激有关的医疗状况尤为重要，包括从药物滥用，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细胞信号，影响疼痛，饥饿和对滥用药物的渴望。许多当前流行的药物会拮抗内源性大麻素受体蛋白，该提案的目的是设计和合成新型的2-芳基烯丙基甘油类似物（2-AG），并改善了效力和生物化学稳定性，作为关键内cannabinoid靶标的药理探针。最成功的新配体将有助于我们理解2-芳基烯丙基甘油（2-AG）在内源性大麻素信号中的作用及其对食欲，药物滥用和其他（PATHO）生理过程的影响。