title: Effects of two novel non-peptide antagonists at the rabbit bradykinin B2 receptor.
abstract: 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.
authors.affiliation: Centre Hospitalier Universitaire de Québec, Centre de recherche du Pavillon l'Hôtel-Dieu de Québec, G1R 2J6, Québec, Canada. francois.marceau@crhdq.ulaval.ca
authors.forename: F
authors.initials: F
authors.lastname: Marceau
authors.forename: S
authors.initials: S
authors.lastname: Houle
authors.forename: J
authors.initials: J
authors.lastname: Bouthillier
authors.forename: N B
authors.initials: NB
authors.lastname: Said
authors.forename: P J
authors.initials: PJ
authors.lastname: Garratt
authors.forename: E K
authors.initials: EK
authors.lastname: Dziadulewicz
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D065168:Bradykinin Receptor Antagonists; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D049452:Green Fluorescent Proteins; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D007601:Jugular Veins / Q000166:cytology / Q000502:physiology; D008164:Luminescent Proteins / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D043782:Receptor, Bradykinin B2; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D014018:Tissue Distribution; D014162:Transfection
chemical_list: C441739:3-benzyl-1-(4-guanidinylphenyl)-4-phenyl-2H-1,4-benzodiazepin-2-one; D001570:Benzodiazepinones; D065168:Bradykinin Receptor Antagonists; D006146:Guanidines; D008164:Luminescent Proteins; D011759:Pyrrolidines; D043782:Receptor, Bradykinin B2; D011993:Recombinant Fusion Proteins; D013882:Thiosemicarbazones; C406475:bradyzide; D049452:Green Fluorescent Proteins; C065679:icatibant; D001920:Bradykinin