RT Journal Article
SR Electronic
T1 Pharmacologic Actions of the Second-Generation Leukotriene B<sub>4</sub> Receptor Antagonist LY293111: In Vitro Studies
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 286
OP 294
VO 288
IS 1
A1 Jackson, William T.
A1 Froelich, Larry L.
A1 Boyd, Robert J.
A1 Schrementi, James P.
A1 Saussy, David L.
A1 Schultz, Richard M.
A1 Sawyer, J. Scott
A1 Sofia, Michael J.
A1 Herron, David K.
A1 Goodson, Theodore
A1 Snyder, David W.
A1 Pechous, Penni A.
A1 Spaethe, Stephen M.
A1 Roman, Carlos R.
A1 Fleisch, Jerome H.
YR 1999
UL http://jpet.aspetjournals.org/content/288/1/286.abstract
AB 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