title: Characterization of the antagonist activity of the PAF antagonists RP 59227 and WEB 2086 on elicited guinea pig peritoneal macrophages. Evidence for variable affinities and kinetics.
abstract: The pharmacological selectivity and affinity of the two PAF antagonists RP 59227 and WEB 2086 for macrophage platelet activating factor (PAF) receptors have been investigated. PAF produced a dose-related increase in superoxide generation from elicited guinea pig peritoneal macrophages (IC50 41 +/- 16 nM, n = 9). After a 5 min preincubation time RP 59227 (0.1, 1.0 and 10 microM) produced a dose-related rightward displacement of the PAF dose-response curve, the Schild plot gave a pA2 of 7.39 +/- 0.07 (n = 5) with a slope of 1.17 +/- 0.11, indicating competitive antagonism. WEB 2086 over the same concentration range was without effect at the lower two concentrations, but at 10 microM, the displacement of the PAF dose-response curve was similar to that obtained with 10 microM RP 59227. Increasing the preincubation time to 30 min increased the affinity of RP 59227 (apparent pA2 8.76 +/- 0.28, n = 5). This was associated with a reduction in the slope of the Schild plot to 0.67 +/- 0.11, suggesting noncompetitive kinetics. The affinity of WEB 2086 could not be determined, but the antagonism appeared noncompetitive in nature. The results indicate that PAF antagonists can show variable affinities for macrophage PAF receptors depending on the experimental conditions, as well as competitive or noncompetitive kinetics depending on the contact time.
authors.affiliation: Rhone-Poulenc Rorer Ltd., Dagenham Research Centre, Essex, England.
authors.forename: N C
authors.initials: NC
authors.lastname: Turner
authors.forename: L J
authors.initials: LJ
authors.lastname: Wood
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D007700:Kinetics; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010537:Peritoneum; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D001381:Azepines; D010972:Platelet Activating Factor; D011725:Pyridines; D013844:Thiazoles; D014230:Triazoles; C052518:WEB 2086; D013481:Superoxides; C065022:RP 59227