A series of 21 analogues of tetrahydrolipstatin (THL, 1) were synthesized and tested as inhibitors of the formation or hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG). Three of the novel compounds, i.e., 11, 13, and 15, inhibited 2-AG formation via the diacylglycerol lipase α (DAGLα) with IC50 values lower than 50 nM (IC50 of THL = 1 μM) and were between 23- and 375-fold selective vs 2-AG hydrolysis by monoacylglycerol lipase (MAGL) as well as vs cannabinoid CB1 and CB2 receptors and anandamide hydrolysis by fatty acid amide hydrolase (FAAH). Three other THL analogues, i.e., 14, 16, and 18, were slightly more potent than THL against DAGLα and appreciably selective vs MAGL, CB receptors, and FAAH (15-26-fold). One compound, i.e., 8, was a potent inhibitor of MAGL-like activity (IC50 = 0.41 μM), and relatively (∼7-fold) selective vs the other targets tested. © 2008 American Chemical Society.

Tetrahydrolipstatin analogues as modulators of endocannabinoid 2-arachidonoylglycerol metabolism / Giorgio, Ortar; Tiziana, Bisogno; Alessia, Ligresti; Morera, Enrico; Nalli, Marianna; Vincenzo Di, Marzo. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 51:21(2008), pp. 6970-6979. [10.1021/jm800978m]

Tetrahydrolipstatin analogues as modulators of endocannabinoid 2-arachidonoylglycerol metabolism

MORERA, ENRICO;NALLI, Marianna;
2008

Abstract

A series of 21 analogues of tetrahydrolipstatin (THL, 1) were synthesized and tested as inhibitors of the formation or hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG). Three of the novel compounds, i.e., 11, 13, and 15, inhibited 2-AG formation via the diacylglycerol lipase α (DAGLα) with IC50 values lower than 50 nM (IC50 of THL = 1 μM) and were between 23- and 375-fold selective vs 2-AG hydrolysis by monoacylglycerol lipase (MAGL) as well as vs cannabinoid CB1 and CB2 receptors and anandamide hydrolysis by fatty acid amide hydrolase (FAAH). Three other THL analogues, i.e., 14, 16, and 18, were slightly more potent than THL against DAGLα and appreciably selective vs MAGL, CB receptors, and FAAH (15-26-fold). One compound, i.e., 8, was a potent inhibitor of MAGL-like activity (IC50 = 0.41 μM), and relatively (∼7-fold) selective vs the other targets tested. © 2008 American Chemical Society.
2008
tetrahydrolpstatin analogues diacylglycerol lipase (dagl) monoacylglycerol lipase (magl)
01 Pubblicazione su rivista::01a Articolo in rivista
Tetrahydrolipstatin analogues as modulators of endocannabinoid 2-arachidonoylglycerol metabolism / Giorgio, Ortar; Tiziana, Bisogno; Alessia, Ligresti; Morera, Enrico; Nalli, Marianna; Vincenzo Di, Marzo. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 51:21(2008), pp. 6970-6979. [10.1021/jm800978m]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/225827
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