Inhibition of monoacylglycerol lipase and fatty acid amide hydrolase by analogues of 2-arachidonoylglycerol


Department of Pharmacology and Clinical Neuroscience, Umeå University, SE-901 87 Umeå, Sweden. E-mail:


  • The pharmacology of monoacylglycerol lipase (MAGL) is not well understood. In consequence, the abilities of a series of analogues of 2-arachidonoylglycerol (2-AG) to inhibit cytosolic 2-oleoylglycerol and membrane-bound anandamide hydolysis by MAGL and fatty acid amide hydrolase (FAAH), respectively, have been investigated.

  • 2-AG and its 1-regioisomer (1-AG) interacted with MAGL with similar affinities (IC50 values 13 and 17 μM, respectively). Shorter homologues of 2-AG (2-linoleoylglycerol and 2-oleoylglycerol) had affinities for MAGL similar to 2-AG. This pattern was also seen when the arachidonoyl side chain of arachidonoyl trifluoromethylketone was replaced by an oleoyl side chain.

  • Arachidonoyl serinol (IC50 value 73 μM) was a weaker inhibitor of MAGL than 2-AG. The IC50 values of noladin ether towards MAGL and FAAH were 36 and 3 μM, respectively. Arachidonoyl glycine interacted with FAAH (IC50 value 4.9 μM) but only weakly interacted with MAGL (IC50 value >100 μM).

  • α-Methyl-1-AG had similar potencies towards MAGL and FAAH (IC50 values of 11 and 33 μM, respectively). O-2203 (1-(20-cyano-16,16-dimethyl-eicosa-5,8,11,14-tetraenoyl) glycerol) and O-2204 (2-(20-hydroxy-16,16-dimethyl-eicosa-5,8,11,14-tetraenoyl) glycerol) were slightly less potent, but again affected both enzymes equally. α-Methyl-1-AG, O-2203 and O-2204 interacted only weakly with cannabinoid CB1 receptors expressed in CHO cells (Ki values 1.8, 3.7 and 3.2 μM, respectively, compared with 0.24 μM for 1-AG) and showed no evidence of central cannabinoid receptor activation in vivo at doses up to 30 mg kg−1 i.v.

  • It is concluded that compounds like α-Methyl-1-AG, O-2203 and O-2204 may be useful as leads for the discovery of selective MAGL inhibitors that lack direct effects upon cannabinoid receptors.

British Journal of Pharmacology (2004) 143, 774–784. doi:10.1038/sj.bjp.0705948