URB602抑制单酰甘油脂肪酶，并在完整脑片中选择性阻断2-花生四烯酸甘油的降解。
URB602 inhibits monoacylglycerol lipase and selectively blocks 2-arachidonoylglycerol degradation in intact brain slices.
作者信息
King Alvin R, Duranti Andrea, Tontini Andrea, Rivara Silvia, Rosengarth Anja, Clapper Jason R, Astarita Giuseppe, Geaga Jennifer A, Luecke Hartmut, Mor Marco, Tarzia Giorgio, Piomelli Daniele
机构信息
Department of Pharmacology, University of California, Irvine, Irvine, CA 92697, USA.
出版信息
Chem Biol. 2007 Dec;14(12):1357-65. doi: 10.1016/j.chembiol.2007.10.017.
Abstract
The N-aryl carbamate URB602 (biphenyl-3-ylcarbamic acid cyclohexyl ester) is an inhibitor of monoacylglycerol lipase (MGL), a serine hydrolase involved in the biological deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). Here, we investigated the mechanism by which URB602 inhibits purified recombinant rat MGL by using a combination of biochemical and structure-activity relationship (SAR) approaches. We found that URB602 weakly inhibits recombinant MGL (IC(50) = 223 +/- 63 microM) through a rapid and noncompetitive mechanism. Dialysis experiments and SAR analyses suggest that URB602 acts through a partially reversible mechanism rather than by irreversible carbamoylation of MGL. Finally, URB602 (100 microM) elevates 2-AG levels in hippocampal slice cultures without affecting levels of other endocannabinoid-related substances. Thus, URB602 may provide a useful tool by which to investigate the physiological roles of 2-AG and explore the potential interest of MGL as a therapeutic target.
摘要
N-芳基氨基甲酸酯URB602（联苯-3-基氨基甲酸环己酯）是单酰甘油脂肪酶（MGL）的抑制剂，MGL是一种丝氨酸水解酶，参与内源性大麻素2-花生四烯酸甘油酯（2-AG）的生物失活过程。在此，我们结合生化和构效关系（SAR）方法，研究了URB602抑制纯化的重组大鼠MGL的机制。我们发现，URB602通过快速且非竞争性机制对重组MGL产生微弱抑制作用（IC(50)=223±63μM）。透析实验和SAR分析表明，URB602通过部分可逆机制发挥作用，而非通过对MGL进行不可逆的氨甲酰化作用。最后，URB602（100μM）可提高海马脑片培养物中的2-AG水平，而不影响其他内源性大麻素相关物质的水平。因此，URB602可能为研究2-AG的生理作用以及探索MGL作为治疗靶点的潜在价值提供有用工具。
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