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.
Herbert
J M
JM
Haemobiology Research Department, Sanofi-Recherche, Toulouse, France.
Laplace
M C
MC
Cailleau
C
C
Maffrand
J P
JP
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