The discovery of anandamide as an endogenous ligand for the cannabinoid receptors has led to a resurgence of interest in the fatty acid amides. However, N-palmitoylethanolamine (PEA), a shorter and fully saturated analogue of anandamide, has been known since the fifties. This endogenous compound is a member of the N-acylethanolamines, found in most mammalian tissues. PEA is accumulated during inflammation and has been demonstrated to have a number of anti-inflammatory effects, including beneficial effects in clinically relevant animal models of inflammatory pain. It is now engaged in phase II clinical development, and two studies regarding the treatment of chronic lumbosciatalgia and multiple sclerosis are in progress. However, its precise mechanism of action remains debated. In the present review, the biochemical and pharmacological properties of PEA are discussed, in particular with respect to its analgesic and anti-inflammatory properties.

1 The ability of a series of homologues and analogues of palmitoylethanolamide to inhibit the uptake and fatty acid amidohydrolase (FAAH) H]-AEA to a similar extent as AM404, whereas palmitoylethanolamide, palmitoylcyclohexamide and R-palmitoyl-(2-methyl)ethanolamide were less e ective. 7 These data provide useful information upon the ability of palmitoylethanolamide analogues to act as`entourage' compounds. Palmitoylisopropylamide may prove useful as a template for design of compounds that reduce the cellular accumulation and metabolism of AEA without a ecting either CB 1 or CB 2 receptors.

1 The abilities of a series of saturated N-acyl ethanolamines and related compounds to aect the ability of anandamide (AEA) to produce a Ca 2+ in¯ux into human embryonic kidney cells expressing the human vanilloid receptor (hVR1-HEK293 cells) has been investigated. 2 The C3:0, C4:0, C6:0 and C10:0 ethanolamides neither aected basal Ca 2+ -in¯ux, nor the in¯ux in response to a submaximal concentration of AEA (1 mM). In contrast, the C12:0, C17:0, C18:0 ethanolamides and the monounsaturated compound oleoylethanolamide (C18:1) greatly potentiated the response to AEA. Palmitoylethanolamide (C16:0) produced both a response per se and an augmentation of the response to AEA. 3 Lauroylethanolamide (C12:0) produced a leftward shift in the dose-response curve for AEA. EC 50 values for AEA to produce Ca 2+ in¯ux into hVR1-HEK293 cells were 1.8, 1.5, 1.1 and 0.22 mM in the presence of 0, 1, 3 and 10 mM lauroylethanolamide, respectively. Lauroylethanolamide did not aect the dose ± response curves to capsaicin. 4 Palmitoylethylamide was synthesized and found to be a mixed-type inhibitor (K i(slope) 4.1 mM,H]-AEA metabolism by rat brain membranes. 5 The -amide, -ethylamide, -isopropylamide, -butylamide, -cyclohexamide and -tri¯uoromethyl ketone analogues of palmitoylethanolamide had little or no eect on the Ca 2+ in¯ux response to 1 mM AEA. 6 There was no obvious relation between the abilities of the compounds to enhance the Ca 2+ in¯ux response to 1 mM AEA into hVR1-HEK293 cells and to prevent the hydrolysis of AEA by rat brain membranes. 7 It is concluded that although palmitoylethanolamide has entourage-like eects at VR1 receptors expressed on hVR1-HEK293 cells, other N-acyl ethanolamines have even more dramatic potentiating eects. It is possible that they may play an important role under conditions where their synthesis is increased, such as in severe in¯ammation.

Background and purpose: Two compounds, URB602 and URB754, have been reported in the literature to be selective inhibitors of monoacylglycerol lipase, although a recent study has questioned their ability to prevent 2-arachidonoyl hydrolysis by brain homogenates and cerebellar membranes. In the present study, the ability of these compounds to inhibit monoacylglycerol lipase and fatty acid amide hydrolase has been reinvestigated. Experimental approach: Homogenates and cell lines were incubated with test compounds and, thereafter, with either3 H]-anandamide. Labelled reaction products were separated from substrate using chloroform: methanol extraction. Key results: In cytosolic fractions from rat brain, URB602 and URB754 inhibited the hydrolysis of 2-oleoylglycerol with IC 50 values of 25 and 48 mM, respectively. Anandamide hydrolysis by brain membranes was not sensitive to URB754, but was inhibited by URB602 (IC 50 value 17 mM). Hydrolysis of 2-oleoylglycerol by human recombinant monoacylglycerol lipase was sensitive to URB602, but not URB754. The lack of selectivity of URB602 for 2-oleoylglycerol compared to anandamide hydrolysis was also observed for intact RBL2H3 basophilic leukaemia cells. C6 glioma expressed mRNA for monoacylglycerol lipase, and hydrolyzed 2-oleoylglycerol in a manner sensitive to inhibition by methyl arachidonoyl fluorophosphonate but not URB754 or URB597. MC3T3-E1 mouse osteoblastic cells, which did not express mRNA for monoacylglycerol lipase, hydrolyzed 2-oleoylglycerol in the presence of URB597, but the hydrolysis was less sensitive to methyl arachidonoyl fluorophosphonate than for C6 cells. Conclusions and implications:The data demonstrate that the compounds URB602 and URB754 do not behave as selective and/or potent inhibitors of monoacylglycerol lipase.

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