Formyl Peptide Receptor 1 and 2 Dual Agonist Inhibits Human Neutrophil Chemotaxis by the Induction of Chemoattractant Receptor Cross-desensitization

Journal of Pharmacological Sciences

Kazuki Hirahara³  Takao Ohyama²  Yoshitaka Sogawa¹  Hiroaki Maeda³ 

[1] Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd., Japan;Biologics Research Laboratories, Daiichi Sankyo Co., Ltd., Japan;Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Japan

关键词: formyl peptide receptor;    neutrophil;    chemotaxis;    cross-desensitization;   

DOI  :  10.1254/jphs.10194FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(22)Cited-By(5)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 B4 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.

【 授权许可】

Unknown