Ortar Giorgio, Bisogno Tiziana, Ligresti Alessia, Morera Enrico, Nalli Marianna, Di Marzo Vincenzo
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, piazzale Aldo Moro 5, 00185 Roma, Italy.
J Med Chem. 2008 Nov 13;51(21):6970-9. doi: 10.1021/jm800978m. Epub 2008 Oct 3.
A series of 21 analogues of tetrahydrolipstatin (THL, 1) were synthesized and tested as inhibitors of the formation or hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG). Three of the novel compounds, i.e., 11, 13, and 15, inhibited 2-AG formation via the diacylglycerol lipase alpha (DAGLalpha) with IC 50 values lower than 50 nM (IC 50 of THL = 1 microM) and were between 23- and 375-fold selective vs 2-AG hydrolysis by monoacylglycerol lipase (MAGL) as well as vs cannabinoid CB 1 and CB 2 receptors and anandamide hydrolysis by fatty acid amide hydrolase (FAAH). Three other THL analogues, i.e., 14, 16, and 18, were slightly more potent than THL against DAGLalpha and appreciably selective vs MAGL, CB receptors, and FAAH (15-26-fold). One compound, i.e., 8, was a potent inhibitor of MAGL-like activity (IC 50 = 0.41 microM), and relatively ( approximately 7-fold) selective vs the other targets tested.
合成了一系列21种四氢脂抑素（THL，1）类似物，并作为内源性大麻素2-花生四烯酸甘油酯（2-AG）形成或水解的抑制剂进行了测试。三种新型化合物，即11、13和15，通过二酰基甘油脂肪酶α（DAGLα）抑制2-AG的形成，IC50值低于50 nM（THL的IC50 = 1 μM），并且相对于单酰基甘油脂肪酶（MAGL）催化的2-AG水解以及相对于大麻素CB1和CB2受体以及脂肪酸酰胺水解酶（FAAH）催化的花生四烯酸乙醇胺水解，具有23至375倍的选择性。另外三种THL类似物，即14、16和18，对DAGLα的活性略强于THL，并且相对于MAGL、CB受体和FAAH具有明显的选择性（15至26倍）。一种化合物，即8，是MAGL样活性的有效抑制剂（IC50 = 0.41 μM），并且相对于其他测试靶点具有相对（约7倍）的选择性。
