Pharmacologic actions of the second-generation leukotriene B-4 receptor antagonist LY293111: In vitro studies

The in vitro actions were investigated of LY293111, a potent and selective leukotriene B-4 (LTB4) receptor antagonist, on human neutrophils, human blo od fractions, guinea pig lung membranes, and guinea pig parenchymal and tra cheal strips. The IC50 for inhibiting [H-3]LTB4 binding to human neutrophil s was 17.6 +/- 4.8 nM. LY293111 inhibited LTB4-induced human neutrophil agg regation (IC50 = 32 +/- 5 nM), luminol-dependent chemiluminescence (IC50 = 20 +/- 2 nM), chemotaxis (IC50 = 6.3 +/- 1.7 nM), and superoxide production by adherent cells (IC50 = 0.5 nM). Corresponding responses induced by N-fo rmyl-L-methionyl-L-leucyl-L-phenylalanine were inhibited by 100-fold higher concentrations of LY293111. LTB4 binding to guinea pig tissues and subsequ ent activation were also inhibited. The K-I for inhibition of [H-3]LTB4 bin ding to lung membranes was 7.1 +/- 0.8 nM; IC50 for preventing binding of [ H-3]LTB4 to spleen membranes was 65 nM. The compound inhibited LTB4-induced contraction of guinea pig lung parenchyma. At 10 nM, LY293111 caused a par allel rightward shift of the LTB4 concentration-response curve. At higher c oncentrations, plots were shifted in a nonparallel manner, and maximum resp onses were depressed. LY293111 did not prevent antigen-stimulated contracti on of sensitized trachea strips. At micromolar concentrations, LY293111 inh ibited production of LTB4 and thromboxane B-2 by plasma-depleted human bloo d stimulated with N-formyl-L-methionyl-L-leucyl-L-phenylalanine and thrombi n. In addition, at these higher concentrations, formation of LTB4 by A23187 -activated whole blood and conversion of arachidonic acid to LTB4 by a huma n neutrophil cytosolic fraction were inhibited. In summary, LY293111 is a s econd-generation LTB4 receptor antagonist with much improved potency in a v ariety of functional assay systems.