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Synthesis and evaluation of paracetamol esters as novel fatty acid amide hydrolase inhibitors.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
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2010 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 5, 2286-2298 p.Article in journal (Refereed) Published
Abstract [en]

Fatty acid amide hydrolase (FAAH) is the key hydrolytic enzyme for the endogenous cannabinoid receptor ligand anandamide. The synthesis and evaluation for their FAAH inhibitory activities of a series of 18 paracetamol esters are described. Structure-activity relationship studies indicated that the ester (33) with a 2-(4-(2-(trifluoromethyl)pyridin-4-ylamino)phenyl)acetic acid substituent was the most potent analogue in this series. The compound inhibited FAAH activity in a competitive manner with a K(i) value of 0.16 microM. The compound was also able to inhibit the FAAH activity in rat basophilic leukemia cells as assessed by measuring either the hydrolysis of anandamide, the FAAH-dependent cellular accumulation of anandamide, or the FAAH-dependent recycling of tritium to the cell membranes. The compound also inhibited the activity of monoacylglycerol lipase (MGL), the enzyme responsible for the hydrolysis of the endogenous cannabinoid receptor ligand 2-arachidonoylglycerol, with an IC(50) value of 1.9 microM. It is concluded that the compound may be a useful template for the design of potent novel inhibitors of FAAH.

Place, publisher, year, edition, pages
ACS Publications , 2010. Vol. 53, no 5, 2286-2298 p.
National Category
Pharmacology and Toxicology
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URN: urn:nbn:se:umu:diva-35628DOI: 10.1021/jm901891pISI: 000275087000034PubMedID: 20143779OAI: oai:DiVA.org:umu-35628DiVA: diva2:345715
Available from: 2010-08-26 Created: 2010-08-26 Last updated: 2017-12-12Bibliographically approved

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Björklund, EmmelieHempel, FranziskaSöderström, EmmaFowler, Christopher J
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CiteExportLink to record
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