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

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 peptidomim etic related to icatibant) and the thiosemicarbazide bradyzide on the rabbi t B-2 receptor (contractility of the jugular vein, competition of [H-3]BK b inding to a B-2 receptor-green fluorescent protein (B2R-GFP) conjugate, sub cellular 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. Brad yzide, reportedly very potent at rodent B-2 receptors, was a competitive an d reversible antagonist of moderate potency at the rabbit B-2 receptor (con tractility pA(2) 6.84, binding competition IC50 5 nM). The C-terminal regio n 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. (C) 2001 Elsevier Science Inc. All rights reserved.