%0 Journal Article %A William T. Jackson %A Larry L. Froelich %A Robert J. Boyd %A James P. Schrementi %A David L. Saussy, Jr. %A Richard M. Schultz %A J. Scott Sawyer %A Michael J. Sofia %A David K. Herron %A Theodore Goodson, Jr. %A David W. Snyder %A Penni A. Pechous %A Stephen M. Spaethe %A Carlos R. Roman %A Jerome H. Fleisch %T Pharmacologic Actions of the Second-Generation Leukotriene B4 Receptor Antagonist LY293111: In Vitro Studies %D 1999 %J Journal of Pharmacology and Experimental Therapeutics %P 286-294 %V 288 %N 1 %X The in vitro actions were investigated of LY293111, a potent and selective leukotriene B4 (LTB4) receptor antagonist, on human neutrophils, human blood fractions, guinea pig lung membranes, and guinea pig parenchymal and tracheal strips. The IC50 for inhibiting [3H]LTB4binding to human neutrophils was 17.6 ± 4.8 nM. LY293111 inhibited LTB4-induced human neutrophil aggregation (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 byN-formyl-l-methionyl-l-leucyl-l-phenylalanine were inhibited by 100-fold higher concentrations of LY293111. LTB4 binding to guinea pig tissues and subsequent activation were also inhibited. The Ki for inhibition of [3H]LTB4 binding to lung membranes was 7.1 ± 0.8 nM; IC50 for preventing binding of [3H]LTB4 to spleen membranes was 65 nM. The compound inhibited LTB4-induced contraction of guinea pig lung parenchyma. At 10 nM, LY293111 caused a parallel rightward shift of the LTB4 concentration-response curve. At higher concentrations, plots were shifted in a nonparallel manner, and maximum responses were depressed. LY293111 did not prevent antigen-stimulated contraction of sensitized trachea strips. At micromolar concentrations, LY293111 inhibited production of LTB4 and thromboxane B2 by plasma-depleted human blood stimulated withN-formyl-l-methionyl-l-leucyl-l-phenylalanine and thrombin. In addition, at these higher concentrations, formation of LTB4 by A23187-activated whole blood and conversion of arachidonic acid to LTB4 by a human neutrophil cytosolic fraction were inhibited. In summary, LY293111 is a second-generation LTB4 receptor antagonist with much improved potency in a variety of functional assay systems. The American Society for Pharmacology and Experimental Therapeutics %U https://jpet.aspetjournals.org/content/jpet/288/1/286.full.pdf