Anandamide Carrier Proteins as Drug Targets

描述（由申请人提供）：拟议的研究将探索细胞内载体蛋白在内源性大麻素转运中的意义，并将开发可调节脑内源性大麻素水平的新型配体。内源性大麻素，包括花生四烯酸和2-花生四烯酸甘油，是参与细胞信号传导的神经脂质。它们影响疼痛感测、食物摄入和奖励机制。特异性转运蛋白和/或载体蛋白参与内源性大麻素向其细胞内失活位点的转运。在本研究中，我们将使用核磁共振（NMR）光谱来探索两种脂质载体蛋白，人脑脂肪酸结合蛋白（FABP 7）和表皮脂肪酸结合蛋白（FABP 5）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转运抑制剂。这些信息将用于推导这两种靶蛋白的结构活性关系（SAR）。这种NMR方法的SAR将指导开发有效的FABP 7配体以及FABP 7/5双重抑制剂作为推定的候选药物，其通过提高内源性大麻素水平起作用。拟议研究的结论将导致对内源性大麻素系统的更深入了解，并代表了利用FABPs抑制作为治疗疼痛，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.