Pharmacologic analysis of two novel inhibitors of leukotriene (slow reacting substance) release.

LY83583 , a quinolinedione , and LY151364 , a quinoxalinedione , were developed as inhibitors of leukotriene (slow reacting substance of anaphylaxis) release. They preferentially inhibited the release of leukotrienes over histamine from fragmented guinea-pig lung and rat peritoneal cells in vitro, regardless of whether the mediators were released immunologically by antigen or chemically by the divalent cationic ionophore, A23187. Similar results were obtained with rat peritoneal cells in vivo. In that system, comparison of LY83583 with disodium cromoglycate showed the former to preferentially inhibit release of leukotrienes, whereas the latter favored inhibition of histamine release. LY83583 did not significantly decrease antigen-induced bronchospasm in guinea pigs after i.v. administration of doses that approached toxic levels. In addition, LY83583 did not antagonize contractions to carbachol or histamine on guinea-pig trachea, prostaglandin F2 alpha-elicited contraction on guinea-pig ileum or contractions produced by serotonin on guinea-pig aorta. This agent, at 1 X 10(-5) M, reduced the maximal responses to bradykinin on ileum and caused a rightward displacement with a reduction in the maximal response to norepinephrine on guinea-pig aorta. In summary, LY83583 and LY151364 have interesting pharmacologic profiles which make them useful as tools in understanding the role of the leukotrienes in isolated tissue systems.