Abstract

SC-45694 (7-[4-(1-hydroxy-3Z-nonenyl)phenyl]-5S-hydroxy-6Z-hept enoic acid lithium salt), a representative of a new class of leukotriene B4 (LTB4) analogs that are conformationally restricted, was evaluated for effects on human neutrophil functions. SC-45694 inhibited [3H] LTB4 binding to the high-affinity receptors on human neutrophils with a KD value of 0.76 microM, but it was a very weak inhibitor of [3H]N-formyl-methionyl-leucyl-phenylalanine binding (KD > 83 microM). SC-45694 stimulated neutrophil chemotaxis with half-maximal and maximal effects at 1 and 10 microM, respectively, and produced a maximal chemotactic response similar to that produced by LTB4. The chemotactic activity of SC-45694 was blocked by the LTB4 receptor antagonists SC-41930 and LY-255283. At concentrations that showed agonist activity for neutrophil chemotactic response, SC-45694 showed no agonist activity for degranulation, antagonized LTB4-induced degranulation and inhibited [3H] LTB4 binding to low-affinity receptors. SC-45694 inhibited LTB4-induced maximal degranulation with an IC50 value of 0.3 microM, but it did not inhibit N-formyl-methionyl-leucyl-phenylalanine-induced degranulation. The inhibition by SC-45694 of LTB4-induced degranulation was time-dependent, noncompetitive and reversible. Thus SC-45694 exhibited a specific, full LTB4 agonist activity for chemotaxis and an antagonist activity against LTB4-induced degranulation. These properties suggest that members of the new class of LTB4 analogs, such as SC-45694, may be useful in further characterizing distinct LTB4 receptor subtypes that mediate these two neutrophil functions.