title: Differential effects of 20-trifluoromethyl leukotriene B4 on human neutrophil functions.
abstract: A leukotriene B4 (LTB4) analog, 20-trifluoromethyl LTB4 (20CF3-LTB4), has been synthesized and evaluated with human neutrophils for effects on chemotaxis and degranulation. 20CF3-LTB4 was equipotent to LTB4 as a chemoattractant (EC50, 3 nM), produced 50% of maximal activity of LTB4, and competed with [H] LTB4 for binding to intact human neutrophil LTB4 receptors. In contrast to chemotactic activity, 20CF3-LTB4 in nanomolar concentrations exhibited antagonist activity without agonist activity up to 10 microM on LTB4-induced degranulation. The analog had no significant effect on degranulation induced by the chemoattractant peptide, N-formyl-methionyl-leucyl-phenylalanine (fMLP). Like LTB4, 20CF3-LTB4 induced neutrophil desensitization to degranulation by LTB4. The results indicate that hydrogen atoms at C-20 of LTB4 are critical for its intrinsic chemotactic and degranulation activities. The fact that 20CF3-LTB4 is a partial agonist for chemotaxis and an antagonist for degranulation suggests that different LTB4 receptor subtypes are coupled to these neutrophil functions. Desensitization of the neutrophil degranulation response to LTB4 can result from receptor occupancy by an antagonist, and therefore, the desensitization is not specific for an agonist.
authors.affiliation: Gastrointestinal Diseases Research, G. D. Searle, Skokie, IL 60077.
authors.forename: B S
authors.initials: BS
authors.lastname: Tsai
authors.forename: R H
authors.initials: RH
authors.lastname: Keith
authors.forename: D
authors.initials: D
authors.lastname: Villani-Price
authors.forename: R A
authors.initials: RA
authors.lastname: Haack
authors.forename: R F
authors.initials: RF
authors.lastname: Bauer
authors.forename: R
authors.initials: R
authors.lastname: Leonard
authors.forename: Y
authors.initials: Y
authors.lastname: Abe
authors.forename: K C
authors.initials: KC
authors.lastname: Nicolaou
mesh_terms: D001667:Binding, Competitive; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003594:Cytoplasmic Granules / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000138:chemical synthesis / Q000494:pharmacology* / Q000031:analogs & derivatives; D009504:Neutrophils / Q000187:drug effects*; D009195:Peroxidase / Q000097:blood; D011971:Receptors, Immunologic / Q000378:metabolism; D018102:Receptors, Leukotriene B4
chemical_list: D011971:Receptors, Immunologic; D018102:Receptors, Leukotriene B4; C059892:20-trifluoromethylleukotriene B4; D007975:Leukotriene B4; D009195:Peroxidase