Development of a potent inhibitor of 2-arachidonoylglycerol hydrolysis with antinociceptive activity in vivo

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• 作者：Tiziana Bisogno ; Giorgio Ortar ; Stefania Petrosino ; Enrico Morera ; Enza Palazzo ; Marianna Nalli ; Sabatino Maione ; Vincenzo Di Marzo ; Endocannabinoid Research Group
• 关键词：Endocannabinoid ; Cannabinoid receptor ; 2-arachidonoylglycerol ; Anandamide ; Monoacylglycerol lipase ; Diacylglycerol lipase ; Fatty acid amide hydrolase ; Pain ; Inhibitor
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids
• 出版年：2009
• 出版时间：January 2009
• 年：2009
• 卷：1791
• 期：1
• 页码：53-60
• 全文大小：685 K

文摘

Although inhibitors of the enzymatic hydrolysis of the endocannabinoid 2-arachidonoylglycerol are available, they are either rather weak in vitro (IC₅₀ > 30 μM) or their selectivity towards other proteins of the endocannabinoid system has not been tested. Here we describe the synthesis and activity in vitro and in vivo of a tetrahydrolipstatin analogue, OMDM169, as a potent inhibitor of 2-AG hydrolysis, capable of enhancing 2-AG levels and of exerting analgesic activity via indirect activation of cannabinoid receptors. OMDM169 exhibited 0.13 μM < IC₅₀ < 0.41 μM towards 2-AG hydrolysing activities in COS-7 cells and rat cerebellum, and inhibited (IC₅₀ = 0.89 μM) the human recombinant MAGL, whilst being inactive (K_i > 10 μM) at human CB₁ and CB₂ receptors. However, OMDM169 shared with tetrahydrolipstatin the capability of inhibiting the human pancreatic lipase (IC₅₀ = 0.6 μM). OMDM169 inhibited fatty acid amide hydrolase and diacylglycerol lipase only at higher concentrations (IC₅₀ = 3.0 and 2.8 μM, respectively), and, accordingly, it increased by  1.6-fold the levels of 2-AG, but not anandamide, in intact ionomycin-stimulated N18TG2 neuroblastoma cells. Acute intraperitoneal (i.p.) administration of OMDM169 to mice inhibited the second phase of the formalin-induced nocifensive response with an IC₅₀ of  2.5 mg/kg, and concomitantly elevated 2-AG, but not anandamide, levels in the ipsilateral paw of formalin-treated mice. The antinociceptive effect of OMDM169 was antagonized by antagonists of CB₁ and CB₂ receptors, AM251 and AM630, respectively (1 mg/kg, i.p.). OMDM69 might represent a template for the development of selective and even more potent inhibitors of 2-AG hydrolysis.