Tsai B S, Keith R H, Villani-Price D, Haack R A, Djuric S W
G.D. Searle & Co., Skokie, Illinois.
J Pharmacol Exp Ther. 1994 Mar;268(3):1493-8.
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.
SC - 45694（7 - [4 - (1 - 羟基 - 3Z - 壬烯基)苯基] - 5S - 羟基 - 6Z - 庚烯酸锂盐）是一类新型的构象受限的白三烯B4（LTB4）类似物的代表，对其影响人类中性粒细胞功能进行了评估。SC - 45694抑制[3H]LTB4与人中性粒细胞上高亲和力受体的结合，KD值为0.76微摩尔，但它是[3H]N - 甲酰 - 甲硫氨酰 - 亮氨酰 - 苯丙氨酸结合的非常弱的抑制剂（KD > 83微摩尔）。SC - 45694刺激中性粒细胞趋化作用，半最大效应和最大效应分别在1微摩尔和10微摩尔时出现，并产生与LTB4产生的最大趋化反应相似的反应。SC - 45694的趋化活性被LTB4受体拮抗剂SC - 41930和LY - 255283阻断。在对中性粒细胞趋化反应显示激动剂活性的浓度下，SC - 45694对脱颗粒无激动剂活性，拮抗LTB4诱导的脱颗粒并抑制[3H]LTB4与低亲和力受体的结合。SC - 45694抑制LTB4诱导的最大脱颗粒，IC50值为0.3微摩尔，但它不抑制N - 甲酰 - 甲硫氨酰 - 亮氨酰 - 苯丙氨酸诱导的脱颗粒。SC - 45694对LTB4诱导的脱颗粒的抑制是时间依赖性、非竞争性和可逆的。因此，SC - 45694对趋化作用表现出特异性的、完全的LTB4激动剂活性，对LTB4诱导的脱颗粒表现出拮抗剂活性。这些特性表明，新型LTB4类似物成员，如SC - 45694，可能有助于进一步表征介导这两种中性粒细胞功能的不同LTB4受体亚型。
