Effect of AD-1590, a non-steroidal anti-inflammatory agent with a potent antipyretic activity, on in vitro prostaglandin generation in rabbit brain.
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 0.1 micrograms/ml or more, its IC50 value being 0.258 micrograms/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 micrograms/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.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D002540:Cerebral Cortex / Q000201:enzymology; D016861:Cyclooxygenase Inhibitors; D003990:Dibenzoxepins / Q000494:pharmacology*; D015232:Dinoprostone; D007031:Hypothalamus / Q000201:enzymology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008861:Microsomes / Q000201:enzymology; D011453:Prostaglandins / Q000096:biosynthesis*; D011458:Prostaglandins E / Q000096:biosynthesis; D011817:Rabbits
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D003990:Dibenzoxepins; D011453:Prostaglandins; D011458:Prostaglandins E; C040006:bermoprofen; D015232:Dinoprostone; D007213:Indomethacin