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.

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Summary:Purpose: The purpose of this study was to evaluate in mice the anticonvulsant potential of N-palmitoylethanolamide, a putative endocannabinoid that accumulates in the body during inflammatory processes.Methods: N-palmitoylethanolamide was injected intraperitoneally (i.p.) in mice and evaluated for anticonvulsant activity [in maximal electroshock seizure (MES) and chemical-induced convulsions] and for neurologic impairment (rotorod). It was compared with anandamide and with different palmitic acid analogues as well as with reference anticonvulsants (AEDs) injected under the same conditions.Results: The MES test showed, after i.p. administration to mice, that N-palmitoylethanolamide had an median effective dose (ED 50 ) value comparable to that of phenytoin (PHT; 8.9 and 9.2 mg/kg, respectively). In the subcutaneous pentylenetetrazol test and in the 3-mercaptropropionic acid test, it was effective only against tonic convulsions. N-palmitoylethanolamide was devoid of neurologic impairment Յ250 mg/kg, yielding a high protective index.Conclusions: N-palmitoylethanolamide, an endogenous compound with antiinflammatory and analgesic activities, is a potent AED in mice. Its precise mechanism of action remains to be elucidated.

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.