Inhibition of human neutrophil activation by the allergic mediator release inhibitor, CI-949: mechanism of inhibitory activity.
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.
Wright
C D
CD
Immunopathology Department, Parke-Davis Pharmaceutical Research Division Warner-Lambert Company, Ann Arbor, Michigan 48105.
Kuipers
P J
PJ
Hoffman
M D
MD
Thueson
D O
DO
Conroy
M C
MC
D001393:Azoles / Q000494:pharmacology*; D002118:Calcium / Q000097:blood; D002147:Calmodulin / Q000097:blood; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000097:blood; D007700:Kinetics; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D013050:Spectrometry, Fluorescence; D013777:Tetrazoles / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000097:blood
D001393:Azoles; D002147:Calmodulin; D007211:Indoles; D007295:Inositol Phosphates; D013777:Tetrazoles; C061320:CI 949; D009240:N-Formylmethionine Leucyl-Phenylalanine; D010738:Type C Phospholipases; D002118:Calcium