Inhibition of fatty acid amide hydrolase, a key endocannabinoid metabolizing enzyme, by analogues of ibuprofen and indomethacin.
There is evidence in the literature that the nonsteroidal anti-inflammatory drugs indomethacin and ibuprofen can interact with the cannabinoid system both in vitro and in vivo. In the present study, a series of analogues of ibuprofen and indomethacin have been investigated with respect to their ability to inhibit fatty acid amide hydrolase, the enzyme responsible for the hydrolysis of the endogenous cannabinoid anandamide. Of the fourteen compounds tested, the 6-methyl-pyridin-2-yl analogue of ibuprofen ("ibu-am5") was selected for further study. This compound inhibited rat brain anandamide hydrolysis in a non-competitive manner, with IC50 values of 4.7 and 2.5 microM being found at pH 6 and 8, respectively. By comparison, the IC50 values for ibuprofen were 130 and 750 microM at pH 6 and 8, respectively. There was no measurable N-acylethanolamine hydrolyzing acid amidase activity in rat brain membrane preparations. In intact C6 glioma cells, ibu-am5 inhibited the hydrolysis of anandamide with an IC50 value of 1.2 microM. There was little difference in the potencies of ibu-am5 and ibuprofen towards cyclooxygenase-1 and -2 enzymes, and neither compound inhibited the activity of monoacylglycerol lipase. Ibu-am5 inhibited the binding of [3H]-CP55,940 to rat brain CB1 and human CB2 cannabinoid receptors more potently than ibuprofen, but the increase in potency was less than the corresponding increase in potency seen for inhibition of FAAH activity. It is concluded that ibu-am5 is an analogue of ibuprofen with a greater potency towards fatty acid amide hydrolase but with a similar cyclooxygenase inhibitory profile, and may be useful for the study of the therapeutic potential of combined fatty acid amide hydrolase-cyclooxygenase inhibitors.
Holt
Sandra
S
Department of Pharmacology and Clinical Neuroscience, Umeå University, SE-901 87 Umeå, Sweden.
Paylor
Ben
B
Boldrup
Linda
L
Alajakku
Kirsi
K
Vandevoorde
Séverine
S
Sundström
Anna
A
Cocco
Maria Teresa
MT
Onnis
Valentina
V
Fowler
Christopher J
CJ
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007052:Ibuprofen / Q000031:analogs & derivatives*; D007213:Indomethacin / Q000031:analogs & derivatives*; D051379:Mice; D008807:Mice, Inbred BALB C; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D016861:Cyclooxygenase Inhibitors; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D007052:Ibuprofen; D007213:Indomethacin; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide