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 LTC 4-, LTD 4- and LTE 4-induced increases in cutaneous vascular permeability in the guinea pig, with i.v. ED 50 values of 0.083, 0.11 and 0.067 μmol/kg, respectively. Against LTD 4, 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 LTC 4 to LTD 4, did not influence the antagonism by ICI 198,615 of LTC 4-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 B 2 or 6-keto-prostaglandin F 1α from chopped guinea pig lung. At 10 μM, the compound did not inhibit 5-, 12- or 15-lipoxygenase. Finally, ICI 198,615 antagonized LTD 4-induced increases in TxB 2 release from chopped guinea-pig lung.