Inhibitory properties of ibuprofen and its amide analogues towards the hydrolysis and cyclooxygenation of the endocannabinoid anandamide.
A dual-action cyclooxygenase (COX)-fatty acid amide hydrolase (FAAH) inhibitor may have therapeutic usefulness as an analgesic, but a key issue is finding the right balance of inhibitory effects. This can be done by the design of compounds exhibiting different FAAH/COX-inhibitory potencies. In the present study, eight ibuprofen analogues were investigated. Ibuprofen (1), 2-(4-Isobutylphenyl)-N-(2-(3-methylpyridin-2-ylamino)-2-oxoethyl)propanamide (9) and N-(3-methylpyridin-2-yl)-2-(4'-isobutylphenyl)propionamide (2) inhibited FAAH with IC(50) values of 134, 3.6 and 0.52 µM respectively. The corresponding values for COX-1 were ~29, ~50 and ~60 µM, respectively. Using arachidonic acid as substrate, the compounds were weak inhibitors of COX-2. However, when anandamide was used as COX-2 substrate, potency increased, with approximate IC(50) values of ~6, ~10 and ~19 µM, respectively. Compound 2 was confirmed to be active in vivo in a murine model of visceral nociception, but the effects of the compound were not blocked by CB receptor antagonists.
Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden. cf@pharm.umu.se
Christopher J
CJ
Fowler
Emmelie
E
Björklund
Aron H
AH
Lichtman
Pattipati S
PS
Naidu
Cenzo
C
Congiu
Valentina
V
Onnis
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D060326:Chemistry Techniques, Synthetic; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D015195:Drug Design; D063388:Endocannabinoids / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006868:Hydrolysis; D007052:Ibuprofen / Q000031:analogs & derivatives* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D059265:Visceral Pain / Q000188:drug therapy; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D007052:Ibuprofen; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; C078814:anandamide