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
British Journal of Pharmacology – Wiley
Published: Nov 1, 2004
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