Hoover Heather S, Blankman Jacqueline L, Niessen Sherry, Cravatt Benjamin F
The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Bioorg Med Chem Lett. 2008 Nov 15;18(22):5838-41. doi: 10.1016/j.bmcl.2008.06.091. Epub 2008 Jul 2.
The endocannabinoid 2-arachidonoylglycerol (2-AG) has been implicated as a key retrograde mediator in the nervous system based on pharmacological studies using inhibitors of the 2-AG biosynthetic enzymes diacyglycerol lipase alpha and beta (DAGL-alpha/beta). Here, we show by competitive activity-based protein profiling that the DAGL-alpha/beta inhibitors, tetrahydrolipstatin (THL) and RHC80267, block several brain serine hydrolases with potencies equal to or greater than their inhibitory activity against DAGL enzymes. Interestingly, a minimal overlap in target profiles was observed for THL and RHC80267, suggesting that pharmacological effects observed with both agents may be viewed as good initial evidence for DAGL-dependent events.
基于使用2-花生四烯酸甘油酯（2-AG）生物合成酶二酰基甘油脂肪酶α和β（DAGL-α/β）抑制剂的药理学研究，内源性大麻素2-花生四烯酸甘油酯（2-AG）被认为是神经系统中的一种关键逆行介质。在此，我们通过基于活性的竞争性蛋白质谱分析表明，DAGL-α/β抑制剂四氢脂抑素（THL）和RHC80267可阻断多种脑丝氨酸水解酶，其效力等于或大于它们对DAGL酶的抑制活性。有趣的是，观察到THL和RHC80267的靶点谱有最小程度的重叠，这表明用这两种药物观察到的药理作用可能被视为DAGL依赖性事件的良好初步证据。
