MEN 11270

BACKGROUND AND PURPOSEIcatibant is a well‐known kinin B2receptor antagonist currently used for angiooedema attacks. MEN16132 is a non‐peptide B2receptor antagonist, more potent and long lasting than icatibant in different models. Here we studied the reasons for these differences between the two antagonists.EXPERIMENTAL APPROACHRate of reversibility (over about 3 h) of the functional receptor blockade exerted by the antagonists was compared (inositol phosphates accumulation assay) in CHO cells expressing the human B2receptor and in human synovial cells. Antagonist pretreated cells were washed with medium and the time taken to restore bradykinin (BK) response measured. Antagonist affinity was measured by radioligand binding to wild type and mutated B2receptors.KEY RESULTSRecovery of BK‐induced responses was slower in cells pretreated with MEN16132 than in those treated with icatibant. The affinity of icatibant (for the [3H]‐BK or the B2receptor antagonist [3H]‐MEN11270 binding site) was compared to that of MEN16132 using a panel of point‐mutated receptors with mutations located at the transmembrane regions of the B2receptor, previously shown to decrease MEN16132 high affinity interaction. No consistent decrease of icatibant affinity was observed. From the different affinity of MEN16132 derivatives at wild type and W86A (transmembrane 2 region) receptors, and by evaluating its antagonist profile at the D266A/D284A double mutant receptor, a model of the MEN16132‐B2receptor complex is proposed.CONCLUSIONS AND IMPLICATIONSMEN16132 dissociated from the B2receptor compartment more slowly than icatibant and interacted at a deeper level in transmembrane regions of the receptor.