Anandamide Carrier Proteins as Drug Targets

描述（由申请人提供）：拟进行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，并将开发可以调节脑内源性大麻素水平的新型配体。内源性大麻素，包括阿南达胺和2-花生四烯醇甘油，是参与细胞信号传导的神经脂类。它们影响痛觉、食物摄入和奖励机制。特定的转运蛋白和/或载体蛋白参与了内源性大麻素运输到细胞内失活位点的过程。在本研究中，我们将利用核磁共振（NMR）波谱技术探索人脑脂肪酸结合蛋白（FABP7）和表皮脂肪酸结合蛋白（FABP5）这两种脂质载体蛋白的结构和结合特性。一系列选择的配体，包括内源性大麻素和几种广泛使用的内源性大麻素运输抑制剂。这些信息将用于推导这两个目标蛋白的结构活性关系（SAR）。这种核磁共振合成SAR方法将指导有效的FABP7配体以及FABP7/5双抑制剂的开发，这些抑制剂通过提高内源性大麻素水平起作用。这项研究的结论将使人们对内源性大麻素系统有更深入的了解，并代表着利用抑制FABPs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的潜在新药物疗法的第一步。

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. PUBLIC HEALTH RELEVANCE: This research aims to increase our understanding of the role of cytosolic carrier proteins in the transport of endocannabinoids in the brain. These endocannabinoids are involved in cell signaling and affect pain sensitization, food intake, and reward mechanisms involved in drug addiction. The work set forth is intended to explore the structure and binding characteristics of two carrier proteins that belong to the fatty acid binding protein family, brain FABP (FABP7) and epidermal FABP (FABP5), and to develop selective FABP ligands as putative drug candidates for pain relief and drug addiction.