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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 syntheses and biological activity of (all Z)-7,7-dimethyl-5,8,11,14- eicosatetraenoic 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 are described. These arachidonic acid analogs are all inhibitors of ionophore-induced SRS-A biosynthesis in rat peritoneal cells. Their mode of action may involve inhibition of phospholipase A2 rather than delta 5-lipoxygenase. These compounds failed to exhibit significant activity in an in vivo model designed to detect inhibitors of antigen-induced, leukotriene-mediated bronchoconstriction in sensitized guinea pigs.

Leutriene (LTC4) is one of the components of Slow Reacting Substance of Anaphylaxis (SRS-A) and is a potent constrictor of guinea pig ilea. The contraction is likely to be a receptor-mediated process. Here we report the existence of specific binding sites for 3H-LTC4 in a crude membrane preparation from guinea pig ileal longitudinal muscle. At 4 degrees C in the presence of 20 mM Serine-borate, binding increases linearly with protein concentration, reaches equilibrium in 10 minutes, and is reversible upon addition of 3 x 10(-5) M unlabelled LTC4. The dissociation curve is consistent with the existence of more than one class of binding site. Ca++ and Mg++ greatly enhance the binding of 3H-LTC4 at equilibrium. In the presence of 5 mM CaCl2 and MgCl2 not only LTC4 (IC50 10(-7)M), but also LTD4 (albeit with much lower affinity, IC50 = 6 x 10(-5) M) and the SRS-A antagonist FPL 55712 (IC50 = 10(-5) M) can compete with 3H-LTC4 for its binding sites. FPL 55712 only displaces 60-70% of the total amount bound, while LTC4 displaces 90-95%. These studies indicate that multiple classes of binding sites exist for 3H-LTC4 in guinea pig ileal longitudinal muscle, and that at least part of these binding sites might be related to the ability of LTC4 to contract guinea pig ilea.