KININ SYSTEM INHIBITORS

这个项目的目标是开发急需的工具来研究 激肽释放酶-激肽(K-K)系统。这个系统似乎扮演着重要的角色 在调节血压、炎症、休克、分泌(肾、 唾液，肠道)，血液凝结，补体系统，也许 中枢神经系统功能。K-K体系的主要调节者 缓激肽(BK)及其同系物Kallidin(Lys-BK)和 Met-Lys-BK.不存在针对这些多肽的特定拮抗剂。我们希望 开发它们。BK的结构将以预期的方式进行修改 增强受体结合，但最大限度减少内在活性。构象 BK分子的自由将受到D-氨基的掺入的限制 酸和取代氨基酸，多肽和取代氨基酸的环化 将它们附着在大分子载体上。BK受体结合研究 将指导多肽设计。多肽将由自动固体合成 相合成，用标准技术提纯并进行表征。他们 将在分离的大鼠子宫上检测激动剂和拮抗剂的活性， 离体豚鼠回肠和大鼠血压。我们将继续 用圆二色谱和核磁共振研究了BK在溶液中的构象。我们 将尝试研究BK分子的构象，而它是 与它的膜受体结合。

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.