Structure-Activity Relationship of a Series of Inhibitors of Monoacylglycerol Hydrolysis-Comparison with Effects upon Fatty Acid Amide Hydrolase

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• 作者：José ; Antonio Cisneros ; Sé ; verine Vandevoorde ; Silvia Ortega-Gutié ; rrez ; Clé ; ment Paris ; Christopher J. Fowler ; Marí ; a L. L&oacute ; pez-Rodrí ; guez
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：October 4, 2007
• 年：2007
• 卷：50
• 期：20
• 页码：5012 - 5023
• 全文大小：288K
• 年卷期：v.50,no.20(October 4, 2007)
• ISSN：1520-4804

文摘

A series of 32 heterocyclic analogues based on the structure of 2-arachidonoylglycerol (2-AG) weresynthesized and tested for their ability to inhibit monoacylglycerol lipase and fatty acid amide hydrolaseactivities. The designed compounds feature a hydrophobic moiety and different heterocyclic subunits thatmimic the glycerol fragment. This series has allowed us to carry out the first systematic structure-activityrelationship 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 valuesof 4.5 and 5.6 M, respectively). They also blocked, albeit less potently, 2-OG hydrolysis in membranefractions (IC₅₀ values of 19 and 26 M, respectively) and anandamide hydrolysis (IC₅₀ values of 12 and 51M, respectively). These compounds will be useful in delineating the importance of the cytosolic hydrolyticactivity in the regulation of 2-AG levels and, hence, its potential as a target for drug development.