Tsai B S, Keith R H, Villani-Price D, Kachur J F, Yang D C, Djuric S W, Yu S
Department of Immunoinflammatory Diseases Research, Searle Research and Development, Skokie, Illinois.
J Pharmacol Exp Ther. 1994 Mar;268(3):1499-505.
Previously, we reported that SC-41930 is a potent leukotriene B4 (LTB4) receptor antagonist. An analog of SC-41930, SC-51146, was evaluated as an antagonist of LTB4 receptors. SC-51146 was shown to bind to LTB4 high affinity binding sites on human neutrophils (PMN) with a dissociation constant (KD) value of 1.5 +/- 0.1 nM, compared to 19 +/- 1.3 nM for SC-41930. PMN chemotaxis studies and Scatchard analyses of [3H]LTB4 binding in PMN membranes indicated that SC-51146 acted as a competitive antagonist. The IC50 value of SC-51146 for the inhibition of PMN chemotaxis induced by 30 nM LTB4 was 38 +/- 12 nM. SC-51146 inhibited PMN degranulation induced by 50 nM LTB4 with an IC50 value of 29 +/- 7 nM. The antagonism by SC-51146 of LTB4-induced PMN degranulation appeared to be noncompetitive. The specificity of SC-51146 for LTB4 receptors vs. fMLP receptors was improved approximately 29 and 44 times over SC-41930. SC-51146 showed relatively weak inhibitory activity on the production of superoxide, LTB4 and/or prostaglandin E2 by human PMN or HL-60 cells. SC-51146 had little activity on ram seminal vesicle cyclooxygenase, and no activity on porcine pancreatic phospholipase A2. SC-51146 is a racemate comprised of the (+) enantiomer, SC-53228, and the (-) enantiomer, SC-53229. Both stereoisomers exhibited pharmacological profiles similar to SC-51146 in these aforementioned in vitro systems. The highly potent and specific antagonistic action of SC-51146 on LTB4 receptors should be particularly useful in elucidating the role of LTB4 in the pathogenesis of inflammatory diseases where excessive levels of LTB4 have been reported.
此前，我们报道过SC - 41930是一种有效的白三烯B4（LTB4）受体拮抗剂。对SC - 41930的类似物SC - 51146进行了评估，以确定其作为LTB4受体拮抗剂的活性。结果显示，SC - 51146与人中性粒细胞（PMN）上的LTB4高亲和力结合位点结合，解离常数（KD）值为1.5±0.1 nM，而SC - 41930的该值为19±1.3 nM。PMN趋化性研究以及对PMN膜中[3H]LTB4结合的Scatchard分析表明，SC - 51146起竞争性拮抗剂的作用。SC - 51146抑制30 nM LTB4诱导的PMN趋化性的IC50值为38±12 nM。SC - 51146抑制50 nM LTB4诱导的PMN脱颗粒，IC50值为29±7 nM。SC - 51146对LTB4诱导的PMN脱颗粒的拮抗作用似乎是非竞争性的。与SC - 41930相比，SC - 51146对LTB4受体相对于fMLP受体的特异性提高了约29倍和44倍。SC - 51146对人PMN或HL - 60细胞产生超氧化物、LTB4和/或前列腺素E2的抑制活性相对较弱。SC - 51146对公羊精囊环氧化酶几乎没有活性，对猪胰磷脂酶A2也没有活性。SC - 51146是一种外消旋体，由（+）对映体SC - 53228和（ - ）对映体SC - 53229组成。在上述体外系统中，两种立体异构体均表现出与SC - 51146相似的药理学特征。SC - 51146对LTB4受体具有高效且特异性的拮抗作用，这在阐明LTB4在已报道LTB4水平过高的炎症性疾病发病机制中的作用方面应特别有用。
