Center for Drug Discovery, Department of Pharmaceutical Sciences, and Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
AAPS J. 2013 Apr;15(2):477-82. doi: 10.1208/s12248-013-9455-9. Epub 2013 Jan 24.
It has been reported that the endocannabinoid anandamide (AEA) binds to a class of fatty acid-binding proteins and serum albumin which can serve as carrier proteins and potentiate the cellular uptake of AEA and its intracellular translocation. Here, we employed (19)F nuclear magnetic resonance spectroscopy to study the interactions of serum albumin with two inhibitors of fatty acid amide hydrolase (FAAH), the enzyme involved in the deactivation of anandamide. We found that, for both inhibitors AM5206 and AM5207, the primary binding site on serum albumin is drug site 1 located at subdomain IIA. Neither inhibitor binds to drug site 2. While AM5207 binds exclusively to drug site 1, AM5206 also interacts with other fatty acid-binding sites on serum albumin. Additionally, AM5206 has an affinity for serum albumin approximately one order of magnitude higher than that of AM5207. The data suggest that interactions of FAAH inhibitors with albumin may provide added advantages for their ability to modulate endocannabinoid levels for a range of applications including analgesia, antiemesis, and neuroprotection.
据报道，内源性大麻素大麻素（AEA）与一类脂肪酸结合蛋白和血清白蛋白结合，这些蛋白可以作为载体蛋白，增强 AEA 的细胞摄取及其细胞内转运。在这里，我们采用（19）F 核磁共振波谱法研究了血清白蛋白与两种脂肪酸酰胺水解酶（FAAH）抑制剂的相互作用，FAAH 酶参与了 AEA 的失活。我们发现，对于两种抑制剂 AM5206 和 AM5207，血清白蛋白上的主要结合位点是位于亚结构域 IIA 的药物结合位点 1。两种抑制剂都不与药物结合位点 2 结合。虽然 AM5207 仅与药物结合位点 1 结合，但 AM5206 也与血清白蛋白上的其他脂肪酸结合位点相互作用。此外，AM5206 与血清白蛋白的亲和力比 AM5207 高约一个数量级。这些数据表明，FAAH 抑制剂与白蛋白的相互作用可能为其调节内源性大麻素水平提供额外的优势，用于包括镇痛、止吐和神经保护在内的一系列应用。
