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A chemically synthesized form of leukotriene E4 (LTE4) has been studied for its ability to induce contractions in isolated guinea pig ilea, to induce vascular permeability changes in rat skin when injected intradermally, and to induce bronchoconstriction in guinea pigs after intravenous injection. The synthetic compound induced a contraction in the guinea pig ileum which was slower in developing than that induced by histamine but faster in developing than that induced by a crude preparation of SRS-A isolated from guinea pig lung. The compound was 70-fold more active than histamine on the guinea pig ileum (EC50 of 5 x 10(-9) and 3.5 x 10(-7) M, respectively). FPL 55712, a known SRS-A antagonist, exhibited the same potency in blocking the contractions elicited by the synthetic material as it did in blocking contractions produced by guinea pig SRS-A generated biologically (IC50 of 3.5 x 10(-8) M). The synthetic LTE4 induced a dose dependent increase in vascular permeability in the rat skin which was antagonized by the intravenous injection of FPL 55712 (ID50 of 1.2 mg/kg). The synthetic material was also a potent bronchoconstrictor in the guinea pig when injected intravenously. The bronchoconstriction, too, was antagonized by FPL 55712 when injected intravenously (ID50 of 0.2 mg/kg). In both the rat and guinea pig, FPL 55712 exhibited a short duration of action in vivo. The in vivo model systems discussed in this study, utilizing the synthetic form of LTE4 should be useful in the future evaluation of other SRS-A antagonists.

The ability of (all Z)-7,7-dimethyl-5,8,11,14-eico-satetraenoic acid, (all Z)-7,7-dimethyl-5,8,11-eicosatrienoic acid, (Z,Z)-7,7-dimethyl-5,8-eicosadienoic acid, (all Z)-10,10-dimethyl-5,8,11,14-eicosatetraenoic acid, (all Z)-10,10-dimethyl-5,8,11-eicosatrienoic acid, and rac-(Z,Z)-15-hydroxy-7,7-dimethyl-5,8-eicosadienoic acid to inhibit ionophore-induced slow-reacting substance of anaphylaxis (SRS-A) biosynthesis in rat peritoneal cells was studied. It was thought that compounds such as these might inhibit proton abstractions at the 7 or 10 carbon positions on arachidonic acid which are thought to be important in the mechanism of catalysis of Δ 5 -lipoxygenase( Δ 5 -LO). All compounds were found to be potent inhibitors of SRS-A biosynthesis in the in vitro rat peritoneal cell system (IC 50 μ M). In fact they were more potent inhibitors in the test system than standard Δ 5 -LO inhibitors such as NDGA and quercetin. To determine if the mechanism of inhibition of the dimethyl arachidonic acid analogs did involve gD 5 -LO inhibition these compounds were evaluated in an assay system utilizing the Δ 5 -LO from rat basophilic leukemia (RBL −1 _cells. It was found, however, that these compounds were much less potent inhibitors of this enzyme (IC 50 ∼ 100 μ M) than standard compounds such as NDGA (IC 50 0.14 μM) and quercetin (IC 50 , 0.2 μM). The arachidonic acid analogs were subsequently found to be potent inhibitors of phospholipase A 2 (PLA 2 ) enzymes with IC 50 's between 10–20 μM as inhibitors of a snake venom enzyme. In fact these compounds are among the most potent inhibitors of PLA 2 yet studied, having potencies better than standards such as p-bromophenacyl bromide (IC 50 , 87 μM) and U-10029A (IC 50 , 36 μM). These results suggest that the methylated arachidonic acid analogs may inhibit SRS-A biosynthesis through inhibiting PLA 2 .