1: Br J Pharmacol. 2007 Jan;150(2):186-91. Epub 2006 Dec 4.

Lack of selectivity of URB602 for 2-oleoylglycerol compared to anandamide
hydrolysis in vitro.

Vandevoorde S, Jonsson KO, Labar G, Persson E, Lambert DM, Fowler CJ.

Department of Pharmacology and Clinical Neuroscience, Umea University, Umea,
Sweden.

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.

PMID: 17143303 [PubMed - in process]

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