Effects of homologues and analogues of palmitoylethanolamide upon the inactivation of the endocannabinoid anandamide.
1. The ability of a series of homologues and analogues of palmitoylethanolamide to inhibit the uptake and fatty acid amidohydrolase (FAAH)-catalysed hydrolysis of [(3)H]-anandamide ([(3)H]-AEA) has been investigated. 2. Palmitoylethanolamide and homologues with chain lengths from 12 - 18 carbon atoms inhibited rat brain [(3)H]-AEA metabolism with pI(50) values of approximately 5. Homologues with chain lengths < or = eight carbon atoms gave < 20% inhibition at 100 microM. 3. R-palmitoyl-(2-methyl)ethanolamide, palmitoylisopropylamide and oleoylethanolamide inhibited [(3)H]-AEA metabolism with pI(50) values of 5.39 (competitive inhibition), 4.89 (mixed type inhibition) and 5.33 (mixed type inhibition), respectively. 4. With the exception of oleoylethanolamide, the compounds did not produce dramatic inhibition of [(3)H]-WIN 55,212-2 binding to human CB(2) receptors expressed on CHO cells. Palmitoylethanolamide, palmitoylisopropylamide and R-palmitoyl-(2-methyl)ethanolamide had modest effects upon [(3)H]-CP 55,940 binding to human CB(1) receptors expressed on CHO cells. 5. Most of the compounds had little effect upon the uptake of [(3)H]-AEA into C6 and/or RBL-2H3 cells. However, palmitoylcyclohexamide (100 microM) and palmitoylisopropylamide (30 and 100 microM) produced more inhibition of [(3)H]-AEA uptake than expected to result from inhibition of [(3)H]-AEA metabolism alone. 6. In intact C6 cells, palmitoylisopropylamide and oleoylethanolamide inhibited formation of [(3)H]-ethanolamine from [(3)H]-AEA to a similar extent as AM404, whereas palmitoylethanolamide, palmitoylcyclohexamide and R-palmitoyl-(2-methyl)ethanolamide were less effective. 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 affecting either CB(1) or CB(2) receptors.
Jonsson
K O
KO
Department of Pharmacology and Clinical Neuroscience, Umeå University, SE-901 87 Umeå, Sweden. Kentolov.Jonsson@pharm.umu.se
Vandevoorde
S
S
Lambert
D M
DM
Tiger
G
G
Fowler
C J
CJ
D000577:Amides; D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry / Q000378:metabolism*; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D016466:CHO Cells; D063385:Cannabinoid Receptor Modulators; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006224:Cricetinae; D063388:Endocannabinoids; D019856:Ethanolamine / Q000378:metabolism; D004983:Ethanolamines; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D010169:Palmitic Acids / Q000737:chemistry / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides; D051381:Rats; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D014407:Tumor Cells, Cultured; D000099252:Fatty Acid Amide Hydrolases
D000577:Amides; D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D019856:Ethanolamine; D004983:Ethanolamines; D010169:Palmitic Acids; D053284:Polyunsaturated Alkamides; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D000099252:Fatty Acid Amide Hydrolases; C469526:Cnr2 protein, rat; C005958:palmidrol; C078814:anandamide