MULTIPLE ACTIONS OF THE LEUKOTRIENE-B4 RECEPTOR ANTAGONIST SC-41930

7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid (SC-41930), a leukotriene B4 (LTB4) receptor antagonist with anti-inflammatory activity in animal models of colitis, was evaluated for effects on superoxide, LTB4 and prostaglandin E2 production. SC-41930 inhibited human neutrophil (PMN) superoxide generation maximally stimulated by f-Met-Leu-Phe (IC50 4-mu-M) and C5a (IC50 approximately 12mu-M). Moreover, postreceptor stimulation of superoxide production by NaF (a G protein activator), but not by phorbol myristate acetate, was significantly inhibited by SC-41930, indicating that SC-41930 may act via attenuation of a G protein-mediated signal transduction. SC-41930 also inhibited A23187-stimulated LTB4 production (IC50 5.3-mu-M) in human PMN as well as LTB4 (IC50 2.1-mu-M) and prostaglandin E2 (IC50 2.9-mu-M) production in HL-60 cells. When coinjected intradermally (400-mu-g/site), SC-41930 inhibited A23187-stimulated increases in LTB4 levels in guinea pig skin. SC-41930 inhibited human synovial phospholipase A2 (IC50 72-mu-M), A23187-stimulated 5-hydroxy-eicosatetranoic acid production in human PMN (IC50 8.5-mu-M), and rat peritoneal leukotriene A4 hydrolase (IC50 20-mu-M), but not ram seminal vesical cyclooxygenase. The results suggest that the anti-inflammatory activity of SC-41930 could be attributed to postreceptor inhibition of inflammatory mediator production by PMN and other cells in addition to antagonism of PMN LTB4 receptors.