title: Cyclic and linear bradykinin analogues: implications for B2 antagonist design.
abstract: Bradykinin (BK, Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) antagonists are potentially useful for treating inflammation, pain and severe trauma. To identify what chemical features might promote effective antagonism, we replaced Arg1 and Pro7 with structurally constrained and proteolytic-resistant residues, such as Bip (biphenylalanine), Dip (diphenylalanine) or 2Ind (indane amino acid). To determine which BK folding might lead to favourable interactions with receptors, the effects of cyclo(3,8) vs. cyclo(5,8) analogues were compared. The resulting BK analogues were examined for their agonistic and antagonistic activities in guinea pig ileum, rat uterus and depressor 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 Dip1 may mimic a folded Arg1 side chain to elicit agonistic activities, with Bip1 mimicking an extended Arg1 side chain to elicit inhibitory activities. However, ileal and uterine receptors 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 pA2.
authors.affiliation: Department of Biochemistry, University of Colorado School of Medicine, Denver 80262, USA.
authors.forename: K H
authors.initials: KH
authors.lastname: Hsieh
authors.forename: J M
authors.initials: JM
authors.lastname: Stewart
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000819:agonists; D014599:Uterus / Q000187:drug effects / Q000502:physiology
chemical_list: D065168:Bradykinin Receptor Antagonists; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D001920:Bradykinin