Cyclic and linear bradykinin analogues: implications for B-2 antagonist design

Bradykinin (BK, Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) antagonists are potent ially useful for treating inflammation, pain and severe trauma. To identify what chemical features might promote effective antagonism, we replaced Arg (1) and Pro(7) with structurally constrained and proteolytic-resistant resi dues, such as Bip (biphenylalanine), Dip (diphenylalanine) or 21nd (indane amino acid). To determine which BK folding might lead to favourable interac tions with receptors, the effects of cyclo((3.8)) vs. cyclo((5.8)) analogue s were compared. The resulting BK analogues were examined for their agonist ic and antagonistic activities in guinea pig ileum, rat uterus and depresso r assays. The results suggest that co-planarity of the residue-7 side chain with its backbone NH is important for potent agonism as well as antagonism , and a D-directed side chain is crucial for antagonism. For residue-1 an L -orientation is important, and Dip(1) may mimic a folded Arg(1) side chain to elicit agonistic activities, with Bip(1) mimicking an extended Arg(1) si de chain to elicit inhibitory activities. However, ileal and uterine recept ors appear to prefer differently folded BK. For ileum, a BK conformation in which residues-3 and -8 are proximal to each other, but apart from residue -5, led to improved pA(2).