CXC chemokines CXCL8 and CXCL1 play essential roles in the activation and recruitment of neutrophils. CXCR1 and CXCR2 are two membrane receptors that bind to CXCL8 with high affinity. Reparixin is a small-molecule, allosteric CXCR1 inhibitor. Reparixin at 0.1 μM led to an 80% inhibition on CXCL8 (10 nM)-induced wild-type CXCR1/L1.2 transfectants migration. The efficacy of reparixin in cells expressing CXCR1 WT and Ile43Val CXCR1 mutant were significantly different (IC50 values of 5.6 and 80 nM, respectively)[3]. In C57BL/6 mice, subcutaneous administration with reparixin (30 mg/kg) reduced neutrophil activity in the brain after middle cerebral artery occlusion/reperfusion. Reparixin treatment also decreased the levels of interleukin-1β in the brain compared to the vehicle-treated group[4].
作用机制
Reparixin is a non-competitive allosteric CXCR1 inhibitor that binds to the transmembrane region of CXCR1, thereby effectively blocking agonist-induced receptor signaling in the intracellular compartment. However, reparixin does not directly affect the expressions of receptors or the CXCL8 binding affinity.
搜索
