A non-peptide antagonist unusually selective for the human form of the bradykinin B sub(2) receptor

Analgesic and anti-inflammatory applications for non-peptide bradykinin (BK) B sub(2) 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 B sub(2) 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 B sub(2) 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 B sub(2) 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 (pA sub(2) values of 5.42, 6.48, 7.42 and 7.53, respectively). In the rabbit jugular vein contractility assay, the pA sub(2) of compound 19c was smaller than 5. Potency at the recombinant rabbit B sub(2) receptor was generally decreasing in the series of four drugs (K sub(i) in a [ super(3)H]BK competition assay to recombinant receptors of 0.78, 0.77, 10.2 and 44.4 nM, respectively); these four compounds did not displace [ super(3)H]Lys-des-Arg super(9)-BK binding from human B sub(1) receptors expressed by smooth muscle cells. The dibenzosuberane compound 19c, verified to functionally antagonize the vascular B sub(2) receptor, is an example of a drug unusually specific for the human form of the receptor.