Formyl peptide receptor 1 and 2 dual agonist inhibits human neutrophil chemotaxis by the induction of chemoattractant receptor cross-desensitization

Formyl peptide receptor 1 (fpr1) and fpr2/alx are known to control neutrophil chemotaxis in response to various ligands. in this study,we investigated the inhibitory mechanism of compound 43 (cpd43),an fpr1 and fpr2/alx dual agonist,on human neutrophil chemotaxis. precedent stimulation of human peripheral blood neutrophils with cpd43 rendered the cells unresponsive in calcium mobilization induced by interleukin-8,c5a,or leukotriene b4. in addition,neutrophils pretreated with cpd43 lost their chemotactic responses against these chemoattractants,wherein the expressions of chemoattractant receptors cxcr1,cxcr2,c5a receptor,and leukotriene b 4 receptor 1 on the surface of neutrophils were all diminished significantly by treatment with cpd43. by evaluating its pharmacological effect on 341 molecules,including receptors and enzymes,we also confirmed that cpd43 has a highly specific affinity to fpr1 and fpr2/alx and does not show binding affinity to the other chemoattractant receptors. these results indicate a previously unrecognized inhibitory mechanism of cpd43 on neutrophil chemotaxis: the induction of cross-desensitization of multiple chemoattractant receptors in human neutrophils through its fpr1 and fpr2/alx dual agonism. © the japanese pharmacological society.