title: 'Entourage' effects of N-acyl ethanolamines at human vanilloid receptors. Comparison of effects upon anandamide-induced vanilloid receptor activation and upon anandamide metabolism.
abstract: 1. 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. 2. 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 microM). 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. EC50 values for AEA to produce Ca2+ influx into hVR1-HEK293 cells were 1.8, 1.5, 1.1 and 0.22 microM in the presence of 0, 1, 3 and 10 microM lauroylethanolamide, respectively. Lauroylethanolamide did not affect the dose - response curves to capsaicin. 4. Palmitoylethylamide was synthesized and found to be a mixed-type inhibitor (K(i(slope)) 4.1 microM, K(i(intercept)) 66 microM) of [3H]-AEA metabolism by rat brain membranes. 5. The -amide, -ethylamide, -isopropylamide, -butylamide, -cyclohexamide and -trifluoromethyl ketone analogues of palmitoylethanolamide had little or no effect on the Ca2+ influx response to 1 microM AEA. 6. There was no obvious relation between the abilities of the compounds to enhance the Ca2+ influx response to 1 microM 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 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.
authors.affiliation: Neuroscience Research, Glaxo SmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.
authors.forename: Darren
authors.initials: D
authors.lastname: Smart
authors.forename: Kent-Olov
authors.initials: KO
authors.lastname: Jonsson
authors.forename: Séverine
authors.initials: S
authors.lastname: Vandevoorde
authors.forename: Didier M
authors.initials: DM
authors.lastname: Lambert
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Fowler
mesh_terms: D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002460:Cell Line; D063388:Endocannabinoids; D004983:Ethanolamines / Q000494:pharmacology*; D006801:Humans; D053284:Polyunsaturated Alkamides; D011955:Receptors, Drug / Q000819:agonists / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D004983:Ethanolamines; C022203:N-acylethanolamines; D053284:Polyunsaturated Alkamides; D011955:Receptors, Drug; D002211:Capsaicin; D002118:Calcium; C078814:anandamide