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

Abstract

Although inhibitors of the enzymatic hydrolysis of the endocannabinoid 2-arachidonoylglycerol are available, they are either rather weak in vitro (IC(50)>30 microM) 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 microM<IC(50)<0.41 microM towards 2-AG hydrolysing activities in COS-7 cells and rat cerebellum, and inhibited (IC(50)=0.89 microM) the human recombinant MAGL, whilst being inactive (K(i)>10 microM) at human CB(1) and CB(2) receptors. However, OMDM169 shared with tetrahydrolipstatin the capability of inhibiting the human pancreatic lipase (IC(50)=0.6 microM). OMDM169 inhibited fatty acid amide hydrolase and diacylglycerol lipase only at higher concentrations (IC(50)=3.0 and 2.8 microM, respectively), and, accordingly, it increased by approximately 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 IC(50) of approximately 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 CB(1) and CB(2) 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.

• Authors: Tiziana Bisogno, Giorgio Ortar, Stefania Petrosino, Enrico Morera, Enza Palazzo, Marianna Nalli, Sabatino Maione, Vincenzo Di Marzo, Endocannabinoid Research Group
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1791 Issue 1 Pg. 53-60 (Jan 2009) ISSN: 0006-3002 [Print] Netherlands
• PMID: 19027877 (Publication Type: Journal Article)

Chemical References

• Analgesics
• Arachidonic Acids
• Endocannabinoids
• Enzyme Inhibitors
• Formamides
• Glycerides
• OMDM 169
• Propiolactone
• glyceryl 2-arachidonate
• Monoacylglycerol Lipases
• Lipoprotein Lipase

Topics

• Analgesics (chemical synthesis, pharmacology)
• Animals
• Arachidonic Acids (antagonists & inhibitors, metabolism)
• COS Cells
• Chlorocebus aethiops
• Endocannabinoids
• Enzyme Inhibitors (chemical synthesis, pharmacology)
• Formamides (chemical synthesis, pharmacology)
• Glycerides (antagonists & inhibitors, metabolism)
• Humans
• Hydrolysis (drug effects)
• Inhibitory Concentration 50
• Lipoprotein Lipase (metabolism)
• Mice
• Monoacylglycerol Lipases (metabolism)
• Propiolactone (analogs & derivatives, chemical synthesis, pharmacology)
• Rats