bradyzide and icatibant

Large species differences have been previously observed in the pharmacology of bradykinin (BK) B2 receptor antagonists. We investigated the effect of two novel non-peptide antagonists, compound 9 (a benzodiazepine peptidomimetic related to icatibant) and the thiosemicarbazide bradyzide on the rabbit B2 receptor (contractility of the jugular vein, competition of [3H]BK binding to a B2 receptor-green fluorescent protein (B2R-GFP) conjugate, subcellular distribution of B2R-GFP). While compound 9 is about 9000-fold less potent than icatibant, it shares with the latter peptide drug a selective, insurmountable and largely irreversible antagonist behavior against BK and the capacity to translocate B2R-GFP from the membrane into the cells. Bradyzide, reportedly very potent at rodent B2 receptors, was a competitive and reversible antagonist of moderate potency at the rabbit B2 receptor (contractility pA2 6.84, binding competition IC50 5 nM). The C-terminal region of icatibant, reproduced by compound 9, is likely to be important in the non-equilibrium behavior of icatibant. Bradyzide, a non-peptide antagonist developed on different structural grounds, is competitive at the rabbit B2 receptor.

Topics: Animals; Benzodiazepinones; Binding, Competitive; Bradykinin; Bradykinin Receptor Antagonists; Cells, Cultured; Dose-Response Relationship, Drug; Green Fluorescent Proteins; Guanidines; Humans; Jugular Veins; Luminescent Proteins; Muscle, Smooth; Pyrrolidines; Rabbits; Radioligand Assay; Receptor, Bradykinin B2; Recombinant Fusion Proteins; Structure-Activity Relationship; Thiosemicarbazones; Time Factors; Tissue Distribution; Transfection