- Structure-activity relationship of a series of inhibitors of monoacylglycerol hydrolysis - Comparison with effects upon fatty acid amide hydrolase
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A series of 32 heterocyclic analogues based on the structure of 2-arachidonoylglycerol (2-AG) were synthesized and tested for their ability to inhibit monoacylglycerol lipase and fatty acid amide hydrolase activities. The designed compounds feature a hydrophobic moiety and different heterocyclic subunits that mimic the glycerol fragment. This series has allowed us to carry out the first systematic structure-activity relationship study on inhibition of 2-AG hydrolysis. The most promising compounds were oxiran-2-ylmethyl (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate (1) and tetrahydro-2H-pyran-2- ylmethyl (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate (5). They inhibited cytosolic 2-oleoylglycerol (2-OG) hydrolysis completely (IC50 values of 4.5 and 5.6 μM, respectively). They also blocked, albeit less potently, 2-OG hydrolysis in membrane fractions (IC50 values of 19 and 26 μM, respectively) and anandamide hydrolysis (IC50 values of 12 and 51 μM, respectively). These compounds will be useful in delineating the importance of the cytosolic hydrolytic activity in the regulation of 2-AG levels and, hence, its potential as a target for drug development.
- Cisneros, José Antonio,Vandevoorde, Séverine,Ortega-Gutiérrez, Silvia,Paris, Clément,Fowler, Christopher J.,López-Rodríguez, María L.
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p. 5012 - 5023
(2008/03/12)
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- Regioselective opening of an oxirane system with trifluoroacetic anhydride. A general method for the synthesis of 2-monoacyl- and 1,3-symmetrical triacylglycerols
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A trifluoroacetic anhydride-catalyzed opening of the oxirane system of glycidyl esters with a simultaneous migration of the acyl group provides a new, efficient entry to either 2-monoacylglycerols (2-MAG) or 1,3-symmetrical triglycerides (1,3-STG) as potential prodrug frameworks.
- Stamatov, Stephan D.,Stawinski, Jacek
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p. 3659 - 3669
(2007/10/03)
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