Selective inhibitors of platelet arachidonic acid metabolism: aggregation independent of lipoxygenase.

The use of acetylenic acid analogs differing in chain length or position of the triple bonds permitted the systemic study of structure activity relationships for the arachidonate metabolizing enzymes (i.e, cyclo-oxygenase and lipoxygenase) in platelets and the relationship of these enzymes to aggregation. We were able to demonstrate analogs that were differentially selective in altering platelet arachidonic acid metabolism. We found analogs that preferentially: (a) inhibited cyclo-oxygenase only, (b) inhibited the 12-lipoxygenase only, (c) inhibited the cyclo-oxygenase and lipoxygenase, and (d) inhibited neither enzyme in platelets. There was a direct correlation between the rank order of potency of the acetylenic analogs to inhibit platelet cyclo-oxygenase and to suppress aggregation. Certain structural features of the triynoic acetylenic analogs were critical in influencing platelet function; thus the presence of a triple bond at position 14 as well as the lack of triple bond at position 5 resulted in analogs which inhibited both cyclo-oxygenase and platelet aggregation. On the other hand, analogs that inhibited only platelet 12-lipoxygenase were very weak inhibitors of platelet aggregation. These inhibitors provide potentially powerful tools for dissociating the two arachidonate metabolic pathways. If other tissues are are readily manipulated as platelets, the analogs may be especially useful for gaining insight into the contribution of lipoxygenase products to biological function.