http://www.cnr.it/ontology/cnr/individuo/prodotto/ID15317
Development of the first potent and specific inhibitors of endocannabinoid biosynthesis (Articolo in rivista)
- Type
- Label
- Development of the first potent and specific inhibitors of endocannabinoid biosynthesis (Articolo in rivista) (literal)
- Anno
- 2006-01-01T00:00:00+01:00 (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
- 10.1016/j.bbalip.2005.12.009 (literal)
- Alternative label
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
- Tiziana Bisogno; Maria Grazia Cascio; Bijali Saha; Anu Mahadevan; Paolo Urbani;
Alberto Minassi; Giovanni Appendino; Carmela Saturnino; Billy Martin;
Raj Razdan; Vincenzo Di Marzo (literal)
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- http://ac.els-cdn.com/S1388198105003021/1-s2.0-S1388198105003021-main.pdf?_tid=49266d662dee05592141ca2fa5a910a5&acdnat=1334935905_06645b494358d184e3c6aae7f2363cc5 (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
- Rivista
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroFascicolo
- Note
- Scopu (literal)
- ISI Web of Science (WOS) (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
- Istituto di Chimica Biomolecolare, C.N.R., Via Campi Flegrei, 34-80078-Pozzuoli (NA), Italy
Organix, Inc., Woburn, MA, USA
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, Via Ponte Don Melillo, 84084 Fisciano, Salerno, Italy
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università del Piemonte Orientale, Viale Ferrucci 33,
28100 Novara, Italy
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Medical College of Virginia, Richmond 23298-0613, USA (literal)
- Titolo
- Development of the first potent and specific inhibitors of endocannabinoid biosynthesis (literal)
- Abstract
- 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 a and ß (DAGLa and ß) and the monoacylglycerol lipase (MAGL), respectively. Here, we used membranes
from COS cells over-expressing recombinant human DAGLa to screen new synthetic substances as DAGLa inhibitors, and cytosolic fractions
from wild-type COS cells to look for MAGL inhibitors. DAGLa and MAGL activities were assessed by using sn-1-[14C]-oleoyl-2-
arachidonoyl-glycerol and 2-[3H]-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®)
(IC50~60 nM), the most potent inhibitors of DAGLa were O-3640 [octadec-9-enoic acid-1-(fluoro-methyl-phosphoryloxymethyl)-propylester]
(IC50=500 nM), and O-3841 [octadec-9-enoic acid 1-methoxymethyl-2-(fluoro-methyl-phosphinoyloxy)-ethyl ester] (IC50=160 nM). Apart
from being almost inactive on MAGL, these two compounds showed high selectivity over rat liver triacylglycerol lipase, rat Nacylphosphatidyl-
ethanolamine-selective phospholipase D (involved in anandamide biosynthesis), rat fatty acid amide hydrolase and human
recombinant cannabinoid CB1 and CB2 receptors. Methylarachidonoyl-fluorophosphonate and the novel compound UP-101 [O-ethyl-O-p-nitrophenyl
oleylphosphonate] inhibited both DAGLa and MAGL with similar potencies (IC50=0.8-0.1 and 3.7-3.2 µM, 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. (literal)
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