title: Pharmacologic actions of the second-generation leukotriene B4 receptor antagonist LY293111: in vitro studies.
abstract: 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]LTB4 binding 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 by N-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 with N-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.
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana, USA.
authors.forename: W T
authors.initials: WT
authors.lastname: Jackson
authors.forename: L L
authors.initials: LL
authors.lastname: Froelich
authors.forename: R J
authors.initials: RJ
authors.lastname: Boyd
authors.forename: J P
authors.initials: JP
authors.lastname: Schrementi
authors.forename: D L
authors.initials: DL
authors.lastname: Saussy
authors.forename: R M
authors.initials: RM
authors.lastname: Schultz
authors.forename: J S
authors.initials: JS
authors.lastname: Sawyer
authors.forename: M J
authors.initials: MJ
authors.lastname: Sofia
authors.forename: D K
authors.initials: DK
authors.lastname: Herron
authors.forename: T
authors.initials: T
authors.lastname: Goodson
authors.forename: D W
authors.initials: DW
authors.lastname: Snyder
authors.forename: P A
authors.initials: PA
authors.lastname: Pechous
authors.forename: S M
authors.initials: SM
authors.lastname: Spaethe
authors.forename: C R
authors.initials: CR
authors.lastname: Roman
authors.forename: J H
authors.initials: JH
authors.lastname: Fleisch
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D002449:Cell Aggregation / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D015777:Eicosanoids / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006168:Guinea Pigs; D006801:Humans; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D016877:Oxidants / Q000096:biosynthesis; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D014132:Trachea / Q000187:drug effects / Q000378:metabolism
chemical_list: D001565:Benzoates; D015777:Eicosanoids; C094099:LY 293111; D020024:Leukotriene Antagonists; D016877:Oxidants; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4