Selectivity of inhibitors of endocannabinoid biosynthesis evaluated by activity-based protein profiling
Selectivity of inhibitors of endocannabinoid biosynthesis evaluated by activity-based protein profiling
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DOI：
10.1016/j.bmcl.2008.06.091
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发表时间：
2008-11-15
影响因子：
2.7
通讯作者：
Cravatt, Benjamin F.
中科院分区：
文献类型：
--
作者：
Hoover, Heather S.;Blankman, Jacqueline L.;Cravatt, Benjamin F.
基于使用 2-AG 生物合成酶二酰甘油脂肪酶 α 和 β (DAGL-α/β) 抑制剂的药理学研究，内源性大麻素 2- 花生四烯酰甘油 (2- AG) 被认为是神经系统中的关键逆行介质。在这里，我们通过基于竞争活性的蛋白质分析表明，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，其效力等于或大于其对 DAGL 酶的抑制活性。有趣的是，在 THL 和 RHC80267 中观察到靶标分布的最小重叠，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始证据。 (C) 2008 Elsevier Ltd. 保留所有权利。
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. (C) 2008 Elsevier Ltd. All rights reserved.