POTENT, LONG-ACTING BRADYKININ ANTAGONISTS FOR A WIDE-RANGE OF APPLICATIONS

Actions of bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg; BK) are me diated by constitutively expressed B-2 receptors (which require the fu ll BK peptide chain) and by B-1 receptors (which require BK(1-8) as li gand) that are induced in inflammation. BK has many functions in norma l and pathological physiology, including initiation of most, if not al l, inflammation. BK also evidently functions as an autocrine stimulant for growth of small cell lung cancer (SCLC). A new group of BK antago nists containing the novel amino acid alpha-(2-indanyl)glycine (Igl) p rovides both broad-spectrum and selective antagonists for all these fu nctions. As examples, D-Arg-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic-Arg (B94 30) is an extremely potent and long-acting antagonist of both B-1 and B-2 receptors, is stable against endogenous kininase enzymes, and is a ctive in various in vivo models, including by intragastric administrat ion. Acylation of B9430 with dehydroquinuclidine-2-carboxylic acid (Dh q) gives B9562, a highly selective B-2 antagonist. In contrast, Lys-Ly s-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic (B9858) is a highly potent and sel ective B-1 antagonist. The dimer of B9430 linked at the amino terminus with suberimide is a potent selectively cytotoxic agent for SCLC cell s. Results with these peptides suggest that a new generation of antiin flammatory and anticancer drugs may be at hand.