title: Biochemical and pharmacological characterization of ICI 198,615: a peptide leukotriene receptor antagonist.
abstract: ICI 198,615 is one representative of a new chemical class of peptide leukotriene receptor antagonists that are the most potent and selective described to date. ICI 198,615 antagonized LTC4-, LTD4- and LTE4-induced increases in cutaneous vascular permeability in the guinea pig, with i.v. ED50 values of 0.083, 0.11 and 0.067 mumol/kg, respectively. Against LTD4, ICI 198,615 was 615 and 415 times more potent than LY 171883 and FPL 55712, respectively. L-Serine borate, an inhibitor of the metabolism of LTC4 to LTD4, did not influence the antagonism by ICI 198,615 of LTC4-induced increases in cutaneous vascular permeability. The compound both inhibited and reversed aerosol ovalbumin antigen-induced increases in pulmonary resistance in passively sensitized guinea pigs, but demonstrated little ability to inhibit or reverse ovalbumin antigen-induced decreases in dynamic lung compliance. At concentrations ranging from 10(-8) to 10(-5) M, ICI 198,615 had no significant effect on either the spontaneous or ovalbumin antigen-induced release of histamine, peptide leukotrienes, thromboxane B2 or 6-keto-prostaglandin F1 alpha from chopped guinea pig lung. At 10 microM, the compound did not inhibit 5-, 12- or 15-lipoxygenase. Finally, ICI 198,615 antagonized LTD4-induced increases in TxB2 release from chopped guinea-pig lung.
authors.affiliation: ICI Americas Inc., Department of Pharmacology, Wilmington, DE 19897.
authors.forename: R D
authors.initials: RD
authors.lastname: Krell
authors.forename: E J
authors.initials: EJ
authors.lastname: Kusner
authors.forename: D
authors.initials: D
authors.lastname: Aharony
authors.forename: R E
authors.initials: RE
authors.lastname: Giles
mesh_terms: D000818:Animals; D001980:Bronchi / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology*; D017999:Leukotriene E4; D016859:Lipoxygenase Inhibitors; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010047:Ovalbumin / Q000276:immunology; D011720:Pyrazoles / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000187:drug effects*; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors*; D013929:Thromboxane B2 / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors
chemical_list: D007191:Indazoles; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; C054217:ICI 198615; D013929:Thromboxane B2; D017999:Leukotriene E4; D010047:Ovalbumin; D005723:gamma-Glutamyltransferase