摘要：The inhibitory activity of 2-(8-methyl-10, 11-dihydro-11-oxodibenz [b, f] oxepin-2-yl) propionic acid (AD-1590) against prostaglandin (PG) generation in the rabbit brain was compared with that of indomethacin in vitro. AD-1590 inhibited PGE2 generation by hypothalamus microsomes at concentrations of 0.1μg/ml or more, its IC50 value being 0.258μg/ml. On the other hand, PGE2 generation by cerebral cortex slices was suppressed by about 10 times lower concentrations of AD-1590 in comparison with that by hypothalamus microsomes ; its IC50 value was 0.0292 μg/ml. The potency of AD-1590 was 3.4 and 2.6 times that of indomethacin in the hypothalamus microsomes and cerebral cortex slices, respectively. The inhibitory activity of AD-1590 against PGE2 generation by hypothalamus microsomes was similar to the result with renal medulla microsomes ; the ratio of renal medulla to hypothalamus IC50 values of AD-1590 (0.496) was nearly equal to that of indomethacin (0.384) and aspirin (0.452). The present studies confirmed that AD-1590 inhibited PGE2 generation within the hypothalamic region. However, these results suggest that the inhibitory potency of AD-1590 against brain PG synthetase cannot explain the 20-50 times more potent antipyretic activity than that of indomethacin, previously reported. The mode of potent antipyretic action of AD-1590 is discussed.
