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首页> 美国卫生研究院文献>The Journal of Pharmacology and Experimental Therapeutics >N-Arachidonyl Maleimide Potentiates the Pharmacological and Biochemical Effects of the Endocannabinoid 2-Arachidonylglycerol through Inhibition of Monoacylglycerol Lipase
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N-Arachidonyl Maleimide Potentiates the Pharmacological and Biochemical Effects of the Endocannabinoid 2-Arachidonylglycerol through Inhibition of Monoacylglycerol Lipase

机译：N-花生四烯酸马来酰亚胺通过抑制单酰基甘油脂酶增强内源性大麻素2-花生四烯酸甘油的药理和生化作用

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Inhibition of the metabolism of the endocannabinoids, anandamide (AEA) and 2-arachidonyl glycerol (2-AG), by their primary metabolic enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively, has the potential to increase understanding of the physiological functions of the endocannabinoid system. To date, selective inhibitors of FAAH, but not MAGL, have been developed. The purpose of this study was to determine the selectivity and efficacy of N-arachidonyl maleimide (NAM), a putative MAGL inhibitor, for modulation of the effects of 2-AG. Our results showed that NAM unmasked 2-AG activity in a tetrad of in vivo tests sensitive to the effects of cannabinoids in mice. The efficacy of 2-AG (and AEA) to produce hypothermia was reduced compared with Δ9-tetrahydrocannabinol; however, 2-AG differed from AEA by its lower efficacy for catalepsy. All tetrad effects were partially CB1 receptor-mediated because they were attenuated (but not eliminated) by SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-H-pyrazole-3-carboxamide HCl] and in CB1−/− mice. In vitro, NAM increased endogenous levels of 2-AG in the brain. Furthermore, NAM raised the potency of 2-AG, but not AEA, in agonist-stimulated guanosine 5′-O-(3-[35S]thio)triphosphate binding assay, a measure of G-protein activation. These results suggest that NAM is an MAGL inhibitor with in vivo and in vitro efficacy. NAM and other MAGL inhibitors are valuable tools to elucidate the biological functions of 2-AG and to examine the consequences of dysregulation of this endocannabinoid. In addition, NAM's unmasking of 2-AG effects that are only partially reversed by SR141716A offers support for the existence of non-CB1, non-CB2 cannabinoid receptors.
机译：通过其主要的代谢酶脂肪酸酰胺水解酶（FAAH）和单酰基甘油脂酶（MAGL）分别抑制内源性大麻素，an南酰胺（AEA）和2-花生四烯酸甘油酯（2-AG）的代谢具有增加的潜力了解内源性大麻素系统的生理功能。迄今为止，已经开发出FAAH而不是MAGL的选择性抑制剂。本研究的目的是确定N-花生四烯酸马来酰亚胺（NAM）（一种公认的MAGL抑制剂）对2-AG的调节作用的选择性和功效。我们的结果表明，NAM在对大麻素对小鼠的影响敏感的体内试验中揭示了2-AG活性。与Δ 9 -四氢大麻酚相比，2-AG（和AEA）产生体温过低的功效降低了；然而，2-AG与AEA的区别在于其对僵直症的功效较低。所有四联体效应均部分受CB1受体介导，因为它们被SR141716A [N-（哌啶-1-基）-5-（4-氯苯基）-1-（2,4-二氯苯基）-4减弱（但没有消除） -甲基-H-吡唑-3-羧酰胺盐酸盐]和CB1 -/-小鼠中。在体外，NAM可增加大脑中2-AG的内源性水平。此外，NAM在激动剂刺激的鸟苷5'-O-（3-[ 35 S]硫基）三磷酸结合磷酸酶（一种G-的测量方法）中提高了2-AG的效力，但没有提高AEA的效力。蛋白质激活。这些结果表明NAM是具有体内和体外功效的MAGL抑制剂。 NAM和其他MAGL抑制剂是阐明2-AG的生物学功能并检查这种内源大麻素失调后果的有价值的工具。此外，NAM对2-AG效应的掩盖作用仅被SR141716A所部分逆转，这为存在非CB1，非CB2大麻素受体提供了支持。

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