title: A non-peptide antagonist unusually selective for the human form of the bradykinin B2 receptor.
abstract: Analgesic and anti-inflammatory applications for non-peptide bradykinin (BK) B2 receptor antagonists have been documented in rats. However, very large species differences in affinity were also noted within this class of drugs, making the preclinical development of relevant drugs difficult. Bradyzide is a potent antagonist at the rat B2 receptor, but a weak one at the human receptor; a series of analogues in which the diphenylmethyl moiety of this drug has been substituted with dibenzosuberane have been reported to gain potency at the human B2 receptor, with some loss of affinity at the rat receptor. The present experiments have been performed in order to verify that the novel series of dibenzosuberane B2 receptor antagonist optimized for affinity in the human species are effective in the isolated human umbilical vein contractility assay. Bradyzide, its analog compound (S)-14c and the dibenzosuberane compounds (S)-14d and 19c surmountably antagonized BK-induced contraction (pA2 values of 5.42, 6.48, 7.42 and 7.53, respectively). In the rabbit jugular vein contractility assay, the pA2 of compound 19c was smaller than 5. Potency at the recombinant rabbit B2 receptor was generally decreasing in the series of four drugs (Ki in a [3H]BK competition assay to recombinant receptors of 0.78, 0.77, 10.2 and 44.4 nM, respectively); these four compounds did not displace [3H]Lys-des-Arg(9)-BK binding from human B1 receptors expressed by smooth muscle cells. The dibenzosuberane compound 19c, verified to functionally antagonize the vascular B2 receptor, is an example of a drug unusually specific for the human form of the receptor.
authors.affiliation: Centre de recherche du Pavillon l'Hôtel-Dieu de Québec, Centre Hospitalier Universitaire de Québec, 11 Côte-du-Palais, Québec, Québec, Canada G1R 2J6. francois.marceau@crhdq.ulaval.ca
authors.forename: François
authors.initials: F
authors.lastname: Marceau
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Fortin
authors.forename: Guillaume
authors.initials: G
authors.lastname: Morissette
authors.forename: Edward K
authors.initials: EK
authors.lastname: Dziadulewicz
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D065094:Bradykinin B2 Receptor Antagonists; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D007601:Jugular Veins / Q000187:drug effects / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D013882:Thiosemicarbazones / Q000737:chemistry / Q000494:pharmacology*; D014162:Transfection; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism
chemical_list: D065094:Bradykinin B2 Receptor Antagonists; D011759:Pyrrolidines; D013882:Thiosemicarbazones; C406475:bradyzide