Inhibition of human neutrophil activation by the allergic mediator release inhibitor, CI-922: mechanism of inhibitory activity.
3,7-Dimethoxy-4-phenyl-N-1H tetrazol-5-yl-4H-furo[3,2-b]-indole-2- carboxamide, L-arginate (CI-922) is a potent inhibitory of human neutrophil functions in response to a variety of stimuli. In this report, the effects of CI-922 on specific processes involved in stimulus-response coupling are evaluated. CI-922 does not inhibit human neutrophil phospholipase C or protein kinase C activities. CI-922 is shown to inhibit calmodulin-dependent enzyme activation. The calmodulin antagonist activity is confirmed by calmodulin-Sepharose affinity chromatography. These results suggest that CI-922 inhibits neutrophil activation by preventing the activation of calmodulin-dependent enzymes, implying a critical role for such enzymes in stimulus-response coupling.
Wright
C D
CD
Pharmacology Department, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Hoffman
M D
MD
Thueson
D O
DO
Conroy
M C
MC
D001393:Azoles / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002846:Chromatography, Affinity; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D010587:Phagocytosis; D010716:Phosphatidylinositols / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013777:Tetrazoles / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000378:metabolism
D001393:Azoles; D002147:Calmodulin; D007211:Indoles; D010716:Phosphatidylinositols; D013777:Tetrazoles; C045584:CI 922; D010738:Type C Phospholipases