The goal of this project is to develop much-needed tools for study of the kallikrein-kinin (K-K) system. This system appears to play important roles in regulation of blood pressure, inflammation, shock, secretion (renal, salivary, intestinal), blood clotting, the complement system and perhaps central nervous system function. The principal mediators of the K-K system are bradykinin (BK), a nonapeptide, and its homologs kallidin (Lys-BK) and Met-Lys-BK. No specific antagonists exist for these peptides. We hope to develop them. The structure of BK will be modified in ways expected to enhance receptor binding but minimize intrinsic activity. Conformational freedom of the BK molecule will be restricted by incorporation of D-amino acids and substituted amino acids, cyclization of the peptides and attachment of them to macromolecular carriers. BK receptor binding studies will guide peptide design. Peptides will be synthesized by automatic solid phase synthesis, purified by standard techniques and characterized. They will be assayed for agonist and antagonist activity on isolated rat uterus, isolated guinea pig ileum and rat blood pressure. We will continue to study the conformation of BK in solution by CD and NMR spectroscopy. We will attempt to study the conformation of the BK molecule while it is combined with its membrane receptors.
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