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Structure-activity relationship of a series of inhibitors of monoacylglycerol hydrolysis-comparison with effects upon fatty acid amide hydrolase
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
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2007 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 50, no 20, 5012-5023 p.Article in journal (Refereed) PublishedText
Abstract [en]

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 an-tide 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,l 11Z,14Z)-icosa-5,8,11,14-tetraenoate (1) and tetrahydro-2H-pyran-2-ylmethyl (5Z,8Z,11Z,14z)-icosa5,8,11,14-tetraenoate (5). They inhibited cytosolic 2-oleoylglycerol (2-OG) hydrolysis completely (IC50 values of 4.5 and 5.6 mu M, respectively). They also blocked, albeit less potently, 2-OG hydrolysis in membrane fractions (IC50 values of 19 and 26,mu M, respectively) and anandamide hydrolysis (IC50 values of 12 and 51 mu M, 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.

Place, publisher, year, edition, pages
Washington: American Chemical Society (ACS), 2007. Vol. 50, no 20, 5012-5023 p.
Keyword [en]
cannabinoid receptor-ligand, rat cerebellar membranes, endocannabinoid system, monoglyceride lipase, anandamide hydrolysis, side-chain, in vitro, 2-arachidonoylglycerol, enzyme, brain
National Category
Pharmacology and Toxicology Social and Clinical Pharmacy
URN: urn:nbn:se:umu:diva-118189DOI: 10.1021/jm070642yISI: 000249871300020PubMedID: 17764163OAI: diva2:920594
Available from: 2016-04-18 Created: 2016-03-14 Last updated: 2016-04-18Bibliographically approved

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Vandevoorde, SeverineOrtega-Gutierrez, SilviaFowler, Christopher JLopez-Rodriguez, Maria L
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Department of Pharmacology and Clinical Neuroscience
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