Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy.
Department of Integrative Medical Biology, Umeå University, Umeå, Sweden.
J Enzyme Inhib Med Chem. 2020 Dec;35(1):815-823. doi: 10.1080/14756366.2020.1743283.
Inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by non-steroidal anti-inflammatory agents such as sulindac and indomethacin in experimental animals, suggesting that a dual-action FAAH-cyclooxygenase (COX) inhibitor could have useful therapeutic properties. Here, we have investigated 12 novel amide analogues of ibuprofen as potential dual-action FAAH/COX inhibitors. -(3-Bromopyridin-2-yl)-2-(4-isobutylphenyl)propanamide (Ibu-AM68) was found to inhibit the hydrolysis of [H]anandamide by rat brain homogenates by a reversible, mixed-type mechanism of inhibition with a K value of 0.26 µM and an α value of 4.9. At a concentration of 10 µM, the compound did not inhibit the cyclooxygenation of arachidonic acid by either ovine COX-1 or human recombinant COX-2. However, this concentration of Ibu-AM68 greatly reduced the ability of the COX-2 to catalyse the cyclooxygenation of the endocannabinoid 2-arachidonoylglycerol. It is concluded that Ibu-AM68 is a dual-acting FAAH/substrate-selective COX inhibitor.
脂肪酸酰胺水解酶（FAAH）的抑制可减少在实验动物中舒林酸和吲哚美辛等非甾体抗炎药引起的胃肠道损伤，这表明双重作用的 FAAH-环氧化酶（COX）抑制剂可能具有有用的治疗特性。在这里，我们研究了布洛芬的 12 种新型酰胺类似物作为潜在的双重作用 FAAH/COX 抑制剂。发现-(3-溴吡啶-2-基）-2-（4-异丁基苯基）丙酰胺（Ibu-AM68）通过可逆的、混合类型的抑制机制抑制大鼠脑匀浆中 [H]花生四烯酸的水解，K 值为 0.26 µM，α 值为 4.9。在 10 µM 的浓度下，该化合物不抑制卵清蛋白 COX-1 或人重组 COX-2 对花生四烯酸的环氧化作用。然而，该浓度的 Ibu-AM68 大大降低了 COX-2 催化内源性大麻素 2-花生四烯酸甘油环氧化的能力。结论是，Ibu-AM68 是一种双重作用的 FAAH/底物选择性 COX 抑制剂。
