Fatty Acid Amide Hydrolase Inhibitors from Virtual Screening of the Endocannabinoid System

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• 作者：Susanna M. Saario ; Antti Poso ; Risto O. Juvonen ; Tomi J&auml ; rvinen ; Outi M. H. Salo-Ahen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：July 27, 2006
• 年：2006
• 卷：49
• 期：15
• 页码：4650 - 4656
• 全文大小：258K
• 年卷期：v.49,no.15(July 27, 2006)
• ISSN：1520-4804

文摘

The endocannabinoid system consists of two cannabinoid receptors (CB1 and CB2), endogenous ligands(endocannabinoids), and the enzymes involved in the metabolism of the endocannabinoids, including fattyacid amide hydrolase (FAAH) and monoglyceride lipase (MGL). In the present study, virtual screening ofMGL inhibitors was performed by utilizing a comparative model of the human MGL enzyme. All hitmolecules were tested for their potential MGL inhibitory activity, but no compounds were found capable ofinhibiting MGL-like enzymatic activity in rat cerebellar membranes. However, these compounds were alsotested for their potential FAAH inhibitory activity and five compounds (2-6) inhibiting FAAH were foundwith IC₅₀ values between 4 and 44 mages/entities/mgr.gif">M. In addition, the hit molecules from the virtual screening of CB2receptor ligands (reported previously in Salo et al. J. Med. Chem. 2005, 48, 7166) were also tested in ourFAAH assay, and four active compounds (7-10) were found with IC₅₀ values between 0.52 and 22 mages/entities/mgr.gif">M.Additionally, compound 7 inhibited MGL-like enzymatic activity with an IC₅₀ value of 31 mages/entities/mgr.gif">M.