Wright C D, Kuipers P J, Hoffman M D, Thueson D O, Conroy M C
Immunopathology Department, Parke-Davis Pharmaceutical Research Division Warner-Lambert Company, Ann Arbor, Michigan 48105.
Biochem Biophys Res Commun. 1990 Mar 16;167(2):828-34. doi: 10.1016/0006-291x(90)92100-e.
CI-949 [5-methyl-3-(1-methylethoxy)-1-phenyl-N-1H-tetrazol-5-yl-1H- indole-2- carboxamide, L-arginine salt] inhibits human neutrophil activation in response to stimuli which promote calcium mobilization or calcium influx. This report further examines the effect of CI-949 on phosphoinositide-dependent stimulus-response coupling. At 100 microM, CI-949 had no inhibitory effect on human neutrophil phospholipase C or protein kinase C. In contrast, CI-949 inhibited FMLP-stimulated intracellular calcium mobilization with an IC50 of 8.4 microM. The compound was also a potent calmodulin antagonist, inhibiting calmodulin-dependent phosphodiesterase activity with an IC50 of 31.0 microM. The calmodulin antagonist activity of CI-949 was confirmed by fluorescence spectroscopy. These results demonstrate that CI-949 may function through inhibition of calcium- and calmodulin-dependent signal transduction processes.
CI-949 [5-甲基-3-(1-甲乙氧基)-1-苯基-N-1H-四唑-5-基-1H-吲哚-2-甲酰胺，L-精氨酸盐] 可抑制人类中性粒细胞对促进钙动员或钙内流的刺激作出的激活反应。本报告进一步研究了CI-949对磷脂酰肌醇依赖性刺激-反应偶联的影响。在100微摩尔浓度下，CI-949对人类中性粒细胞磷脂酶C或蛋白激酶C无抑制作用。相比之下，CI-949抑制FMLP刺激的细胞内钙动员，IC50为8.4微摩尔。该化合物还是一种有效的钙调蛋白拮抗剂，抑制钙调蛋白依赖性磷酸二酯酶活性，IC50为31.0微摩尔。CI-949的钙调蛋白拮抗剂活性通过荧光光谱法得到证实。这些结果表明，CI-949可能通过抑制钙和钙调蛋白依赖性信号转导过程发挥作用。
