The bradykinin B1 receptor in tissues is significantly upregulated in response to inflammation and tissue injury. ELN-441958 is a bradykinin B1 receptor antagonist that potently and competitively inhibits the binding of the B1 agonist ligand [3H] DAKD to IMR-90 human fibroblast membranes with a Ki value of 0.26±0.02 nM. In IMR-90 cells expressing native bradykinin B1 receptor, ELN-441958 led to a dose-dependent antagonism of DAKD-induced calcium mobilization with a KB value of 0.12±0.02 nM. The rank order potency for ELN-441958 antagonism of bradykinin B1 receptors was human ~ rhesus (KB = 0.24±0.01 nM) > rat (KB = 1.5±0.4 nM) > mouse (KB = 14±4 nM). In MDR1 knockout mice, ELN-441958 achieved low micromolar brain levels five minutes after an i.v. administration of 2.5 mg/kg. ELN441958 at 2.5 mg/kg also showed a moderate volume of distribution (2.7 L/kg) and a moderate clearance (0.96 L/h/kg) in rats. A 30-min pretreatment with ELN441958 (10 mg/kg, s.c.) completely inhibited carrageenan-Induced hyperalgesia after 1–1.5 h post injection[2].
作用机制
ELN-441958 is a potent antagonist of bradykinin B1 receptor activation. It competitively inhibits the binding of the B1 agonist ligand to B1 receptor and antagonized agonist-induced calcium mobilization in native and recombinant cells[2].
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