Effects of two novel non-peptide antagonists at the rabbit bradykinin B(2) receptor.

摘要

Large species differences have been previously observed in the pharmacology of bradykinin (BK) B(2) 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 B(2) receptor (contractility of the jugular vein, competition of [(3)H]BK binding to a B(2) receptor-green fluorescent protein (B(2)R-GFP) conjugate, subcellular distribution of B(2)R-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 B(2)R-GFP from the membrane into the cells. Bradyzide, reportedly very potent at rodent B(2) receptors, was a competitive and reversible antagonist of moderate potency at the rabbit B(2) receptor (contractility pA(2) 6.84, binding competition IC(50) 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 B(2) receptor.