Comparison of two classes of non-peptide drugs as antagonists of neutrophil receptors for f-Met-Leu-Phe. Pyrazolons and iodinated radiographic contrast agents.
The radiographic contrast agent sodium diatrizoate (DTR) reportedly inhibits f-Met-Leu-Phe-induced chemotaxis in human neutrophils. DTR is also an ingredient of Ficoll-Paque, a density centrifugation medium widely used to purify human polymorphonuclear leukocytes (PMNs). Exposure of PMNs to DTR during preparation had no detrimental effect on subsequent binding characteristics of tritiated f-Met-Leu-Phe, probably owing to a rapid dissociation of DTR from the PMN receptors. DTR competed directly with f-Met-Leu-Phe for receptor binding, but was 160- and 640-fold less potent than phenylbutazone and 1,2-diphenyl-4-[3-(1-naphthyl)-propyl]-3,5-pyrazolidinedione (DPN; an analog of phenylbutazone), respectively. Iohexol and the methylamide of DTR did not compete with [3H]f-Met-Leu-Phe in receptor binding, supporting the existence of a definite interaction between iodinated aromatic molecules and the f-Met-Leu-Phe receptor. DTR did not inhibit prostaglandin synthesis, as did DPN. Both drugs inhibited chemotactic peptide-induced release of superoxide anion in a concentration-dependent manner, and were relatively selective for f-Met-Leu-Phe, as opposed to C5a. Both drugs at 10 microM interfered non-selectively with chemotactic peptide-induced beta-glucuronidase release from PMNs. Available non-peptide antagonists of f-Met-Leu-Phe exhibited other pharmacodynamic properties that could make them unsuitable for future in vivo studies designed to probe the physiological role of the receptor.
Levesque
L
L
Department of Pharmacology, Faculty of Medicine, Université Laval, Québec, Canada.
Gaudreault
R C
RC
Marceau
F
F
D001667:Binding, Competitive; D003287:Contrast Media / Q000494:pharmacology*; D003973:Diatrizoate / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010653:Phenylbutazone / Q000031:analogs & derivatives* / Q000494:pharmacology; D011869:Radioligand Assay; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism
D003287:Contrast Media; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D013481:Superoxides; D003973:Diatrizoate; D009240:N-Formylmethionine Leucyl-Phenylalanine; D005966:Glucuronidase; D010653:Phenylbutazone; D015232:Dinoprostone