Are noscapine and raloxifene ligands of the bradykinin B2 receptor? An assessment based on the human umbilical vein contractility assay

The centrally acting antitussive opiate derivative, noscapine, has been claimed to be a non-competitive bradykinin B2 receptor antagonist. Raloxifene, a selective estrogen receptor modulator, was predicted to bind the bradykinin B2 receptor and to exert a partial agonist activity. These intriguing claims suggest that new molecular scaffolds (chemotypes) may be identified for small molecule ligands of kinin receptors and that some off-target effects of noscapine or raloxifene may be mediated by bradykinin B2 receptors. An established contractile bioassay for ligands of the bradykinin B2 receptor, the isolated human umbilical vein, was exploited to characterize the inhibitory effect of noscapine and raloxifene on the B2 receptor-mediated contractile response to bradykinin. Observed effects were compared with those of the peptide antagonist icatibant, a potent, selective and competitive B2 receptor antagonist. Our results indicate that neither noscapine (2.5 mu M) nor raloxifene (20 mu M) behave as B2 receptor antagonists in concentrations that vastly exceeded an effective concentration of the control antagonist, icatibant; further, none of these drugs had direct contractile effects. It is suggested that the previously reported B2 receptor inhibitory effect of noscapine, a putative sigma-receptor agonist, might result from an indirect physiological antagonism, while raloxifene did not appear to have any significant affinity for the B2 receptors.

Automated summary

Noscapine and raloxifene were claimed to be bradykinin B2 receptor antagonists, but our study showed that they do not possess this inhibitory effect. This suggests that previous reports might contain misleading information.