Inhibitors of the metabolism of the endogenous cannabinoid ligand anandamide by fatty acid amide hydrolase (FAAH) reduce the gastric damage produced by non-steroidal anti-inflammatory agents and synergise with them in experimental pain models. This motivates the design of compounds with joint FAAH/cyclooxygenase (COX) inhibitory activity. Here we present data on the N-(3-methylpyridin-2-yl)amide derivatives of flurbiprofen and naproxen (Flu-AM1 and Nap-AM1, respectively) with respect to their properties towards these two enzymes. Flu-AM1 and Nap-AM1 inhibited FAAH-catalysed hydrolysis of [(3)H]anandamide by rat brain homogenates with IC50 values of 0.44 and 0.74 µM. The corresponding values for flurbiprofen and naproxen were 29 and >100 µM, respectively. The inhibition by Flu-AM1 was reversible, mixed-type, with K(i)slope and K(i)intercept values of 0.21 and 1.4 µM, respectively. Flurbiprofen and Flu-AM1 both inhibited COX in the same manner with the order of potencies COX-2 vs. 2-arachidonoylglycerol>COX-1 vs. arachidonic acid>COX-2 vs. arachidonic acid with flurbiprofen being approximately 2-3 fold more potent than Flu-AM1 in the assays. Nap-AM1 was a less potent inhibitor of COX. Flu-AM1 at low micromolar concentrations inhibited the FAAH-driven uptake of [(3)H]anandamide into RBL2H3 basophilic leukaemia cells in vitro, but did not penetrate the brain in vivo sufficiently to block the binding of [(18)F]DOPP to brain FAAH. It is concluded that Flu-AM1 is a dual-action inhibitor of FAAH and COX that may be useful in exploring the optimal balance of effects on these two enzyme systems in producing peripheral alleviation of pain and inflammation in experimental models.
Keywords: 2-arachidonoylglycerol; Anandamide; Cyclooxygenase; Fatty acid amide hydrolase; Non-steroidal anti-inflammatory drug.
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