Effect of SR 27417 on the binding of [3H]PAF to rabbit and human platelets and human polymorphonuclear leukocytes.
SR 27417, the first member of a newly developed PAF antagonist series, fully and competitively displaced [3H]PAF from its high-affinity binding sites on washed rabbit and human platelets with Ki values of 57 +/- 0.02 and 50 +/- 0.8 pM (n = 3), respectively. Studies carried out in parallel demonstrated that SR 27417 was 5-7-times more potent than C16-PAF itself and more than 50-60-fold as active as the best synthetic PAF antagonist yet described. Additionally, SR 27417 selectively and competitively inhibited the specific binding of [3H]WEB-2086, a selective PAF receptor antagonist to its high-affinity receptors on washed rabbit platelets (IC50 = 0.18 +/- 0.01 nM). On human polymorphonuclear leukocytes, [3H]PAF bound to two classes of specific binding sites with high (KD = 0.31 +/- 0.05 nM; Bmax = 1.2 +/- 0.07 fmol/10(6) cells) and low affinity (KD = 11.1 +/- 1.5 nM; Bmax = 13.7 +/- 0.8 fmol/10(6) cells). On these cells, SR 27417 selectively inhibited the specific binding of [3H]PAF to its high- and low-affinity receptors (IC50 values of 0.17 +/- 0.02 and 6.9 +/- 0.7 nM, respectively) and displayed the same inhibitory pattern as that already reported on platelets. In conclusion, SR 27417 can be considered as the most potent PAF receptor antagonist described to date.
Haemobiology Research Department, Sanofi-Recherche, Toulouse, France.
J M
JM
Herbert
M C
MC
Laplace
C
C
Cailleau
J P
JP
Maffrand
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins; D011817:Rabbits; D011869:Radioligand Assay; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D013844:Thiazoles / Q000494:pharmacology*; D014316:Tritium
D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013844:Thiazoles; C039351:platelet activating factor receptor; D014316:Tritium; C071317:Foropafant