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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 either [3H]‐2‐oleoylglycerol or [3H]‐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 IC50 values of 25 and 48 μM, respectively. Anandamide hydrolysis by brain membranes was not sensitive to URB754, but was inhibited by URB602 (IC50 value 17 μM). 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. British Journal of Pharmacology (2007) 150, 186–191. doi:10.1038/sj.bjp.0706971

The ability of a series of homologues and analogues of palmitoylethanolamide to inhibit the uptake and fatty acid amidohydrolase (FAAH)‐catalysed hydrolysis of [3H]‐anandamide ([3H]‐AEA) has been investigated. Palmitoylethanolamide and homologues with chain lengths from 12–18 carbon atoms inhibited rat brain [3H]‐AEA metabolism with pI50 values of ∼5. Homologues with chain lengths eight carbon atoms gave <20% inhibition at 100 μM. R‐palmitoyl‐(2‐methyl)ethanolamide, palmitoylisopropylamide and oleoylethanolamide inhibited [3H]‐AEA metabolism with pI50 values of 5.39 (competitive inhibition), 4.89 (mixed type inhibition) and 5.33 (mixed type inhibition), respectively. With the exception of oleoylethanolamide, the compounds did not produce dramatic inhibition of [3H]‐WIN 55,212‐2 binding to human CB2 receptors expressed on CHO cells. Palmitoylethanolamide, palmitoylisopropylamide and R‐palmitoyl‐(2‐methyl)ethanolamide had modest effects upon [3H]‐CP 55,940 binding to human CB1 receptors expressed on CHO cells. Most of the compounds had little effect upon the uptake of [3H]‐AEA into C6 and/or RBL‐2H3 cells. However, palmitoylcyclohexamide (100 μM) and palmitoylisopropylamide (30 and 100 μM) produced more inhibition of [3H]‐AEA uptake than expected to result from inhibition of [3H]‐AEA metabolism alone. In intact C6 cells, palmitoylisopropylamide and oleoylethanolamide inhibited formation of [3H]‐ethanolamine from [3H]‐AEA to a similar extent as AM404, whereas palmitoylethanolamide, palmitoylcyclohexamide and R‐palmitoyl‐(2‐methyl)ethanolamide were less effective. 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 affecting either CB1 or CB2 receptors. British Journal of Pharmacology (2001) 133, 1263–1275; doi:10.1038/sj.bjp.0704199

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 inflam-mation 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.

The abilities of a series of saturated N‐acyl ethanolamines and related compounds to affect the ability of anandamide (AEA) to produce a Ca2+ influx into human embryonic kidney cells expressing the human vanilloid receptor (hVR1‐HEK293 cells) has been investigated. The C3:0, C4:0, C6:0 and C10:0 ethanolamides neither affected basal Ca2+‐influx, nor the influx in response to a submaximal concentration of AEA (1 μM). 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. Lauroylethanolamide (C12:0) produced a leftward shift in the dose‐response curve for AEA. EC50 values for AEA to produce Ca2+ influx into hVR1‐HEK293 cells were 1.8, 1.5, 1.1 and 0.22 μM in the presence of 0, 1, 3 and 10 μM lauroylethanolamide, respectively. Lauroylethanolamide did not affect the dose – response curves to capsaicin. Palmitoylethylamide was synthesized and found to be a mixed‐type inhibitor (Ki(slope) 4.1 μM, Ki(intercept) 66 μM) of [3H]‐AEA metabolism by rat brain membranes. The ‐amide, ‐ethylamide, ‐isopropylamide, ‐butylamide, ‐cyclohexamide and ‐trifluoromethyl ketone analogues of palmitoylethanolamide had little or no effect on the Ca2+ influx response to 1 μM AEA. There was no obvious relation between the abilities of the compounds to enhance the Ca2+ influx response to 1 μM AEA into hVR1‐HEK293 cells and to prevent the hydrolysis of AEA by rat brain membranes. It is concluded that although palmitoylethanolamide has entourage‐like effects at VR1 receptors expressed on hVR1‐HEK293 cells, other N‐acyl ethanolamines have even more dramatic potentiating effects. It is possible that they may play an important role under conditions where their synthesis is increased, such as in severe inflammation. British Journal of Pharmacology (2002) 136, 452–458; doi:10.1038/sj.bjp.0704732

AM404 [ N-(4-hydroxyphenyl)arachidonylamide] and VDM 11 [(5 Z,8 Z,11 Z,14 Z)- N-(4-hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide] are commonly used to prevent the cellular accumulation of the endocannabinoid anandamide, and thereby to potentiate its actions. However, it has been reported that AM404 can produce an influx of calcium into cells, which might be expected to have deleterious effects on cell proliferation. In the present study, AM404 and VDM 11 were found to reduce C6 glioma cell proliferation with IC(50) values of 4.9 and 2.7 microM, respectively. The inhibition of cell proliferation following a 96-h exposure was not accompanied by dramatic caspase activation, and was not prevented by either a combination of cannabinoid and vanilloid receptor antagonists, or by the antioxidant alpha-tocopherol, suggestive of a non-specific mode of action. Similar results were seen with palmitoylisopropylamide, although this compound only produced significant inhibition of cell proliferation at 30 microM concentrations. AM404 (1 microM), VDM 11 (1 microM) and palmitoylisopropylamide (3-30 microM), i.e. concentrations producing relatively modest effects on cell proliferation per se, reduced the vanilloid receptor-mediated antiproliferative effects of anandamide, as would be expected for compounds preventing the cellular accumulation of anandamide (and thereby access to its binding site on the vanilloid receptor). It is concluded that concentrations of AM404 and VDM 11 that are generally used to reduce the cellular accumulation of anandamide have deleterious effects upon cell proliferation, and that lower concentrations of these compounds may be more appropriate to use in vitro.

In situ measurements of stratospheric sulphate aerosol, reactive nitrogen and chlorine concentrations at middle latitudes confirm the importance of aerosol surface reactions that convert active nitrogen to a less active, reservoir form. This makes mid-latitude stratospheric ozone less vulnerable to active nitrogen and more vulnerable to chlorine species. The effect of aerosol reactions on active nitrogen depends on gas phase reaction rates, so that increases in aerosol concentration following volcanic eruptions will have only a limited effect on ozone depletion at these latitudes.

The main objective of this study was to improve the precision of stock assessments of demersal fish in Icelandic waters, with particular emphasis on cod. Sampling was carried out on approximately 600 stations in the Iceland shelf area in March 1985 and again in March 1986. Stations were distributed in the survey area through a semi-randomly stratified process. A standardized bottom trawl was designed for the sampling and the data collected included length measurements, otolith samples and sex determination, as well as information on the environment and fishing gear. Results are presented for cod, haddock, saithe, redfish, catfish and long rough dab. The distributions of the different species indicate common nursery grounds in the northern part of the survey area. The youngest age-groups were generally not fully represented in the survey. Pronounced diurnal catch variations were observed for catfish and redfish. Age disaggregated stock indices of the gadoid species are well correlated with virtual population analysis (VPA) values. However, the total stock indices differ in their proportion of the VPA stock size. In comparison with previous surveys, the precision of stock indices has been increased markedly through this survey for all species except saithe. This is basically the result of an increased number of stations. Skipper-selected stations (non-random) generally gave higher aggregated indices than random ones, although statistically significant differences are exceptional. On a length disaggregated basis, however, a highly significant difference was observed for all species.