Stereoisomeric relationships among anti-inflammatory activity, inhibition of platelet aggregation, and inhibition of prostaglandin synthetase.
This study compares the affects of a new non-steroidal anti-inflammatory drug, d,l-6-chloro-alpha-methyl-carbazole-2-acetic acid, its enantiomers, and indomethacin on platelet aggregation, prostaglandin synthetase, adjuvant arthritis, gastric ulceration and arachidonic acid induced diarrhea. In the adjuvant arthritic rat, doses producing anti-inflammatory activity were similar for all compounds with the exception of the l-isomer which was much less active. On the other hand, indomethacin was 10 to 25 times more potent with regard to inhibition of platelet aggregation, inhibition on prostaglandin synthetase, inhibition of arachidonic acid induced diarrhea, and induction of gastric ulceration than the racemate and its isomers. Such divergence of potencies suggests that the racemate, unlike indomethacin, would have no affect on platelet aggregation and, hence, produce no prolongation of bleeding time at doses possessing anti-inflammatory activity. The data also suggest that the racemate and d-isomer have greater specificity toward anti-arthritic acitvity and are less ulcerogenic than indomethacin. The d-isomer apparently is the more active component of the racemate in all the systems tested since: (a) the d-isomer has 2 to 3 times the inhibitory potency of the racemate and (b) the l-isomer, at high dosages or high concentrations had considerable less affect. Comparison of potencies relative to inhibition of platelet aggregation and of prostaglandin synthetase, are quite close; therefore, mechanistically, the anti-aggregatory affects of these drugs, or lack thereof, may be related to inhibition of prostaglandin synthetase.
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010973:Platelet Adhesiveness / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D013237:Stereoisomerism; D013268:Stimulation, Chemical
D000085:Acetates; D000893:Anti-Inflammatory Agents; D006899:Mixed Function Oxygenases; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin