SC-41930: an inhibitor of leukotriene B4-stimulated human neutrophil functions.
SC-41930 was evaluated for effects on human neutrophil chemotaxis and degranulation. At concentrations up to 100 microM, SC-41930 alone exhibited no effect on neutrophil migration, but dose-dependently inhibited neutrophil chemotaxis induced by leukotriene B4 (LTB4) in a modified Boyden chamber. Concentrations of SC-41930 from 0.3 microM to 3 microM competitively inhibited LTB4-induced chemotaxis with a pA2 value of 6.35. While inactive at 10 microM against C5a-induced chemotaxis, SC-41930 inhibited N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced chemotaxis, with 10 times less potency than against LTB4-induced chemotaxis. SC-41930 inhibited [3H]LTB4 and [3H]fMLP binding to their receptor sites on human neutrophils with KD values of 0.2 microM and 2 microM, respectively. SC-41930 also inhibited neutrophil chemotaxis induced by 20-OH LTB or 12(R)-HETE. At concentrations up to 10 microM, SC-41930 alone did not cause neutrophil degranulation, but inhibited LTB4-induced degranulation in a noncompetitive manner. SC-41930 also inhibited fMLP- or C5a-induced degranulation, but was about 8 and 10 times less effective for fMLP and C5a, respectively. The results indicate that SC-41930 is a human neutrophil LTB4 receptor antagonist with greater specificity for LTB4 than for fMLP or C5a receptors.
Tsai
B S
BS
Gastrointestinal Diseases Research, G.D. Searle & Co., Skokie, IL 60077.
Villani-Price
D
D
Keith
R H
RH
Zemaitis
J M
JM
Bauer
R F
RF
Leonard
R
R
Djuric
S W
SW
Shone
R L
RL
D001578:Benzopyrans / Q000494:pharmacology*; D001667:Binding, Competitive; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000037:antagonists & inhibitors; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology*; D014316:Tritium
D001578:Benzopyrans; D014316:Tritium; C059950:SC 41930; D007975:Leukotriene B4; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015936:Complement C5a