Specific inhibition of leukotriene B4-induced neutrophil activation by LY223982
Jackson, W.T.; Boyd, R.J.; Froelich, L.L.; Mallett, B.E.; Gapinski, D.M.
Journal of Pharmacology and Experimental Therapeutics 263(3): 1009-1014
1992
ISSN/ISBN: 0022-3565 PMID: 1335049 Document Number: 388769
LY223982, (E)-5-(3-carboxybenzoyl)-2-((6-(4-methoxyphenyl)-5-hexenyl)oxy)benzenepropranoic acid, is a newly discovered potent inhibitor of specific binding of leukotriene B-4 (LTB-4) to its receptor on human neutrophils. This study demonstrated that the compound is also a specific antagonist of LTB-4-induced neutrophil activation under both in vitro and in vivo conditions. LY223982 was found to be 189-fold more effective in displacing (3H)TB-4 than 35S-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) from their corresponding receptors on human neutrophils. The concentration inhibiting 50% of response (IC-50) for displacement of (3H)LTB-4 (13.2 nM) was only 6.8-fold higher than the value for nonradioactive LTB-4. The compound inhibited the aggregation of guinea pig neutrophils caused by LTB-4 more strongly than FMLP or platelet-activating factor. The IC-50 for inhibition of LTB-4-induced responses (74 nM) was 93- and gt 135-fold lower than the IC-50 for inhibition of the corresponding FMLP and platelet-activating factor-induced effects. LY223982 was also a potent antagonist of the aggregation of human neutrophils by LTB-4 (IC-50, 100 nM). Chemotaxis of human neutrophils induced by LTB-4 was only modestly inhibited by the compound (IC-50 = 6 mu-M) but it had even less effect on cell movement caused by FMLP. LY223982 inhibited transient leukopenia induced in rabbits with LTB-4 (ED-50, 3 mg/kg) but not with FMLP. It had no agonist activity in any of the test systems. In summary, the results indicate that LY223982 is a potent specific antagonist of LTB-4-induced neutrophil activation.