Anandamide Carrier Proteins as Drug Targets

Anandamide 载体蛋白作为药物靶点

• 批准号: 8507699
• 负责人: Jason Jianxin Guo
• 金额: $ 13.87万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507699
• 关键词: 2-arachidonylglycerol; AM1172; AM404; Affect; Affinity; Analgesics; Attenuated; Binding; Biochemical; Biological Assay; Blood - brain barrier anatomy; Brain; Carrier Proteins; Cellular Assay; Characteristics; Chemicals; Cloning; Data; Development; Disease; Docosahexaenoic Acids; Drug Addiction; Drug Targeting; Eating; Endocannabinoids; Escherichia coli; FABP5 gene; Fatty Acids; Future; Goals; Human; Hydrogen Bonding; Inclusion Bodies; Joints; Lead; Letters; Ligands; Lipids; Maps; Mass Spectrum Analysis; Methods; Modality; Modeling; Molecular Conformation; Molecular Probes; NMR Spectroscopy; Nuclear; Nuclear Magnetic Resonance; Pain; Pharmaceutical Preparations; Pharmacotherapy; Phase; Process; Property; Protein Family; Proteins; Quantitative Structure-Activity Relationship; Recombinants; Research; Rewards; Role; Signal Transduction; Site; Structure; Structure-Activity Relationship; Substance abuse problem; System; Testing; Variant; Work; Workplace; analog; anandamide; bindin; design; drug candidate; fatty acid-binding proteins; human FABP5 protein; in vivo; inhibitor/antagonist; novel; novel therapeutics; pharmacophore; pi bond; research study; transport inhibitor; uptake

DESCRIPTION (provided by applicant): The proposed research will explore the significance of intracellular carrier proteins in the transport of endocannabinoids and will develop novel ligands that can modulate brain endocannabinoid levels. Endocannabinoids, including anandamide and 2-arachidonoyl glycerol, are neurolipids involved in cell signaling. They affect pain sensing, food intake, and reward mechanisms. Specific transporter and/or carrier protein(s) have been implicated in the transport of endocannabinoids to their intracellular inactivation sites In this proposal, we shall use nuclear magnetic resonance (NMR) spectroscopy to explore the structural and binding characteristics of two lipid carrier proteins, human brain fatty acid bindin protein (FABP7) and epidermal FABP (FABP5), to a range of selected ligands including the endocannabinoids and several widely used endocannabinoid transport inhibitors. The information will be used to derive structure activity relationships (SAR) of these two target proteins. This SAR by NMR approach will guide the development of potent FABP7 ligands as well as FABP7/5 dual inhibitors as putative drug candidates which act through the elevation of endocannabinoid levels. The conclusion of the proposed research will lead to a greater understanding of the endocannabinoid system and represent first step towards a potential new pharmacotherapy utilizing the inhibition of FABPs as a new therapeutic modality for treating pain, substance abuse/drug addiction and other disorders.

描述(申请人提供)：这项拟议的研究将探索细胞内载体蛋白在内源性大麻素运输中的意义，并将开发能够调节脑内内源性大麻素水平的新型配体。内源性大麻素，包括花生胺和2-花生四烯酸甘油，是参与细胞信号转导的神经脂类。它们影响疼痛感觉、食物摄取和奖励机制。特定的转运体和/或载体蛋白(S)参与了内源性大麻素向其细胞内失活部位的运输。在这项研究中，我们将利用核磁共振波谱来研究两种脂类载体蛋白，人脑脂肪酸结合蛋白(FABP7)和表皮FABP(FABP5)的结构和与包括内源性大麻素和几种广泛使用的内源性大麻素转运抑制剂在内的一系列配基的结合特性。这些信息将被用来推导这两个目标蛋白的结构活性关系(SAR)。这种核磁共振方法的SAR将指导开发有效的FABP7配体以及FABP7/5双重抑制剂作为假定的候选药物，这些候选药物通过提高内源性大麻素水平发挥作用。这项拟议研究的结论将使人们更好地了解内源性大麻素系统，并代表着朝着潜在的新药物疗法迈出的第一步，该药物疗法利用抑制FABP作为治疗疼痛、药物滥用/药物成瘾和其他疾病的新治疗方式。