Non‐competitive pharmacological antagonism at the rabbit B1 receptor

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Abstract
The B1 receptor for kinins, stimulated by kinin metabolites without the C‐terminal Arg residue (e.g., des‐Arg9‐bradykinin (BK) and Lys‐des‐Arg9‐BK), is an increasingly recognized molecular target for the development of analgesic and anti‐inflammatory drugs. Recently developed antagonists of this receptor were compared to a conventional antagonist, Ac‐Lys‐[Leu8]‐des‐Arg9‐BK, in pharmacological assays based on the rabbit B1 receptor. B‐9858 (Lys‐Lys‐[Hyp3, Igl5, D‐Igl7, Oic8]des‐Arg9‐BK) and three other analogues possessing the α‐2‐indanylglycine5 (Igl5) residue (order of potency B‐9858 ∼ B‐10146>B‐10148>B‐10050) were partially insurmountable antagonists of des‐Arg9‐BK in the contractility assay based on rabbit aortic rings. B‐9858‐induced depression of the maximal effect was more pronounced in tissues treated with the protein synthesis inhibitor cycloheximide to block the spontaneous increase of response attributed to the post‐isolation formation of B1 receptors, and only partly reversible on washing. By comparison, Ac‐Lys‐[Leu8]des‐Arg9‐BK was a surmountable antagonist (pA2 7.5), even in cycloheximide‐treated tissues. B‐9958 (Lys‐[Hyp3, CpG5, D‐Tic7, CpG8]des‐Arg9‐BK) was also surmountable (pA2 8.5). The binding of [3H]‐Lys‐des‐Arg9‐BK to recombinant rabbit B1 receptors expressed in COS‐1 cells was influenced by two of the antagonists: while Ac‐Lys‐[Leu8]des‐Arg9‐BK competed for the radioligand binding without affecting the Bmax, B‐9858 decreased the Bmax in a time‐dependent and washout‐resistant manner. B‐9858 and analogues possessing Igl5 are the first reported non‐competitive, non‐equilibrium antagonists of the kinin B1 receptor. British Journal of Pharmacology (2000) 131, 885–892; doi:10.1038/sj.bjp.0703656