URB754
(Synonyms: 6-甲基-2-[(4-甲基苯基)氨基]-4H-3,1-苯并嗪-4-酮) 目录号 : GC41599A MAGL inhibitor
Cas No.:86672-58-4
Sample solution is provided at 25 µL, 10mM.
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URB754 is a potent and noncompetitive inhibitor of monoacylglycerol lipase (MAGL), exhibiting an IC50 value of 200 nM for the recombinant rat brain enzyme. However, it does not inhibit human recombinant, rat brain, or mouse brain MAGL at concentrations up to 100 µM. There is evidence that the MAGL inhibitory activity of URB754 may be attributed to the impurity bis(methylthio)mercurane (IC50 = 11.9 nM for rat recombinant MAGL) that is found in commercial preparations. URB754 inhibits rat brain fatty acyl amide hydrolase (FAAH) with an IC50 value of 32 µM and binds weakly to the rat central cannabinoid (CB1) receptor with an IC50 value of 3.8 µM. It does not inhibit COX-1 or COX-2 at concentrations up to 100 µM. Inhibition of MAGL hydrolysis of 2-arachidonoyl glycerol (2-AG) is associated with enhanced stress-induced analgesia and may represent a novel drug target in pain and stress management.
Cas No. | 86672-58-4 | SDF | |
别名 | 6-甲基-2-[(4-甲基苯基)氨基]-4H-3,1-苯并嗪-4-酮 | ||
Canonical SMILES | Cc1ccc(cc1)Nc1nc2ccc(C)cc2c(=O)o1 | ||
分子式 | C16H14N2O2 | 分子量 | 266.3 |
溶解度 | DMF: 20 mg/ml,DMSO: 10 mg/ml | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 3.7552 mL | 18.7758 mL | 37.5516 mL |
5 mM | 0.751 mL | 3.7552 mL | 7.5103 mL |
10 mM | 0.3755 mL | 1.8776 mL | 3.7552 mL |
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URB754 has no effect on the hydrolysis or signaling capacity of 2-AG in the rat brain
Chem Biol 2006 Aug;13(8):811-4.PMID:16931330DOI:10.1016/j.chembiol.2006.07.008.
Previous studies indicate that in brain tissue the endocannabinoid 2-AG is inactivated by monoglyceride lipase (MGL)-catalyzed hydrolysis, and a recent report has indicated that MGL activity could be specifically inhibited by URB754 . In the present study, URB754 failed to inhibit 2-AG hydrolysis in rat brain preparations. In addition, brain cryosections were employed to assess whether URB754 could facilitate the detection of 2-AG-stimulated G protein activity. Nevertheless, whereas pretreatment with PMSF readily allowed detection of 2-AG-stimulated G protein activity, URB754 was ineffective. In contrast to previous claims, brain FAAH activity was also resistant to URB754. Thus, in our hands URB754 was not able to block the endocannabinoid-hydrolyzing enzymes and cannot serve as a lead structure for future development of MGL-specific inhibitors.
Identification of a bioactive impurity in a commercial sample of 6-methyl-2-p-tolylaminobenzo[d][1,3]oxazin-4-one (URB754)
Ann Chim 2007 Sep;97(9):887-94.PMID:17970304DOI:10.1002/adic.200790073.
The compound URB754 was recently identified as a potent inhibitor of the endocannabinoid-deactivating enzyme monoacylglycerol lipase (MGL) by screening of a commercial chemical library. Based on HPLC/MS, NMR and EI/MS analyses, the present paper shows that the MGL-inhibitory activity attributed to URB754 is in fact due to a chemical impurity present in the commercial sample, identified as bis(methylthio)mercurane. Although this organomercurial compound is highly potent at inhibiting MGL (IC50 = 11.9 +/- 1.1 nM), its biological use is prohibited by its toxicity and target promiscuity.
Lack of selectivity of URB602 for 2-oleoylglycerol compared to anandamide hydrolysis in vitro
Br J Pharmacol 2007 Jan;150(2):186-91.PMID:17143303DOI:10.1038/sj.bjp.0706971.
Background and purpose: Two compounds, URB602 and URB754, have been reported in the literature to be selective inhibitors of monoacylglycerol lipase, although a recent study has questioned their ability to prevent 2-arachidonoyl hydrolysis by brain homogenates and cerebellar membranes. In the present study, the ability of these compounds to inhibit monoacylglycerol lipase and fatty acid amide hydrolase has been reinvestigated. Experimental approach: Homogenates and cell lines were incubated with test compounds and, thereafter, with either [(3)H]-2-oleoylglycerol or [(3)H]-anandamide. Labelled reaction products were separated from substrate using chloroform: methanol extraction. Key results: In cytosolic fractions from rat brain, URB602 and URB754 inhibited the hydrolysis of 2-oleoylglycerol with IC(50) values of 25 and 48 microM, respectively. Anandamide hydrolysis by brain membranes was not sensitive to URB754, but was inhibited by URB602 (IC(50) value 17 microM). Hydrolysis of 2-oleoylglycerol by human recombinant monoacylglycerol lipase was sensitive to URB602, but not URB754. The lack of selectivity of URB602 for 2-oleoylglycerol compared to anandamide hydrolysis was also observed for intact RBL2H3 basophilic leukaemia cells. C6 glioma expressed mRNA for monoacylglycerol lipase, and hydrolyzed 2-oleoylglycerol in a manner sensitive to inhibition by methyl arachidonoyl fluorophosphonate but not URB754 or URB597. MC3T3-E1 mouse osteoblastic cells, which did not express mRNA for monoacylglycerol lipase, hydrolyzed 2-oleoylglycerol in the presence of URB597, but the hydrolysis was less sensitive to methyl arachidonoyl fluorophosphonate than for C6 cells. Conclusions and implications: The data demonstrate that the compounds URB602 and URB754 do not behave as selective and/or potent inhibitors of monoacylglycerol lipase.
Inhibition of 2-arachidonoylglycerol catabolism modulates vasoconstriction of rat middle cerebral artery by the thromboxane mimetic, U-46619
Br J Pharmacol 2007 Nov;152(5):691-8.PMID:17891162DOI:10.1038/sj.bjp.0707468.
Background and purpose: Cerebrovascular smooth muscle cells express the CB1 cannabinoid receptor and CB1 agonists produce vasodilatation of the middle cerebral artery (MCA). The thromboxane A2 mimetic, U-46619, increased the content of the endocannabinoid, 2-arachidonoylglycerol (2-AG) in the MCA and 2-AG moderated the vasoconstriction produced by U46619 in this tissue. The purposes of this study were to examine the extent to which 2-AG is catabolized by cerebral arteries and to determine whether blockade of 2-AG inactivation potentiates its feedback inhibition of U-44619-mediated vasoconstriction. Experimental approach: The diameters of isolated, perfused MCA from male rats were measured using videomicroscopy. Key results: Exogenous 2-AG produces a CB1 receptor-dependent and concentration-related increase in the diameter of MCA constricted with 5-HT. The E (max) for 2-AG dilation is increased 4-fold in the presence of the metabolic inhibitors 3-(decylthio)-1,1,1-trifluropropan-2-one (DETFP), URB754 and URB597. To examine the role of catabolism in the effects of endogenous 2-AG, vasoconstriction induced by U-46619 was studied. DETFP and URB754, but not the fatty acid amide hydrolase inhibitor, URB597, significantly increased the EC(50) for U-46619. These data support a physiological role for endocannabinoid feedback inhibition in the effects of U-46619 and indicate that endogenously produced 2-AG is also efficiently catabolized within the MCA. Conclusions and implications: MCA express mechanisms for the efficient inactivation of 2-AG, providing further support for an endocannabinoid feedback mechanism that opposes thromboxane-mediated vasoconstriction. These data suggest that potentiation of endogenously produced 2-AG could be a novel therapeutic approach to the treatment of thrombotic stroke.