Xenical Research Today is a free monthly online journal that collates and summarizes the latest research about Xenical, including details on orlistat, side-effects, obesity, weight loss, dieting.

Development of the first potent and specific inhibitors of endocannabinoid biosynthesis.

Bisogno T, Cascio MG, Saha B, Mahadevan A, Urbani P, Minassi A, Appendino G, Saturnino C, Martin B, Razdan R, Di Marzo V

Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, C.N.R., Via Campi Flegrei, 34-80078-Pozzuoli (NA), Italy.

Enzymes for the biosynthesis and degradation of the endocannabinoid 2-arachidonoyl glycerol (2-AG) have been cloned and are the sn-1-selective-diacylglycerol lipases alpha and beta (DAGLalpha and beta) and the monoacylglycerol lipase (MAGL), respectively. Here, we used membranes from COS cells over-expressing recombinant human DAGLalpha to screen new synthetic substances as DAGLalpha inhibitors, and cytosolic fractions from wild-type COS cells to look for MAGL inhibitors. DAGLalpha and MAGL activities were assessed by using sn-1-[(14)C]-oleoyl-2-arachidonoyl-glycerol and 2-[(3)H]-arachidonoylglycerol as substrates, respectively. We screened known compounds as well as new phosphonate derivatives of oleic acid and fluoro-phosphinoyl esters of different length. Apart from the general lipase inhibitor tetrahydrolipstatin (orlistat(R)) (IC(50) approximately 60 nM), the most potent inhibitors of DAGLalpha were O-3640 [octadec-9-enoic acid-1-(fluoro-methyl-phosphoryloxymethyl)-propylester] (IC(50)=500 nM), and O-3841 [octadec-9-enoic acid 1-methoxymethyl-2-(fluoro-methyl-phosphinoyloxy)-ethyl ester] (IC(50)=160 nM). Apart from being almost inactive on MAGL, these two compounds showed high selectivity over rat liver triacylglycerol lipase, rat N-acylphosphatidyl-ethanolamine-selective phospholipase D (involved in anandamide biosynthesis), rat fatty acid amide hydrolase and human recombinant cannabinoid CB(1) and CB(2) receptors. Methylarachidonoyl-fluorophosphonate and the novel compound UP-101 [O-ethyl-O-p-nitro-phenyl oleylphosphonate] inhibited both DAGLalpha and MAGL with similar potencies (IC(50)=0.8-0.1 and 3.7-3.2 muM, respectively). Thus, we report the first potent and specific inhibitors of the biosynthesis of 2-AG that may be used as pharmacological tools to investigate the biological role of this endocannabinoid.

Published 9 February 2006 in Biochim Biophys Acta.
Full-text of this article is available online (may require subscription).

© 2004-2008 Xenical Research Today. All Rights Reserved.