ANTI-INFLAMMATORY PROPERTIES OF N-PHENYLANTHRANILIC ACID DERIVATIVES IN RELATION TO UNCOUPLING OF OXIDATIVE PHOSPHORYLATION

摘要

References(37) Cited-By(8) It has been known that a variety of non-steroidal anti-inflammatory drugs uncouple oxidative phosphorylation in mitochondria (1-5). Adams and Cobb (2) have studied whether or not the inhibition of inflammation by non-steroidal drugs was related to their in vitro capacity to uncouple oxidative phosphorylation. Whitehouse (6) has made an extensive survey on this problem. We have reported that a variety of non-steroidal anti-inflammatory drugs inhibit the degranulation of isolated mast cells of the rat, which is blocked by uncouplers of oxidative phosphorylation as well as by inhibitors of the respiratory chain (7). It was then found that anti-inflammatory activity of these drugs bore quantitative relation to their in vitro capacity to inhibit the degranulation. In addition, anti-inflammatory effect of 2, 4-dinitrophenol, dicoumarol and warfarin was also demonstrated. These results appear to favor the hypothesis proposed by Whitehouse (6) that the uncoupling activity of non-steroidal anti-inflammatory drugs may be causally related to their inhibitory effect on inflammation. Flufenamic acid [N-(3-trifluoromethylphenyl) anthranilic acid; Fig. 1, R1=H, R2=CF3] and mefenamic acid [N-(2, 3-dimethylphenyl) anthranilic acid; Fig. 1, R1=CH3, R2=CH3] have proven to have potent anti-inflammatory activities and are being applied to clinical uses (8-10). If the above hypothesis is acceptable, antiinflammatory activities of a series of N-phenylanthranilic acid (PAA) derivatives, including these two drugs, may be reflected by their relative activities in uncoupling oxidative phosphorylation. The present experiment was undertaken to determine whether or not a correlation exists between the uncoupling potencies of PAA derivatives on oxidative phosphorylation in rat liver mitochondria and their anti-inflammatory activities on the carrageenin edema in rat paws. Some physicochemical properties of the compounds were also examined.