KININ SYSTEM INHIBITORS

该项目的目标是开发研究 激肽释放酶-激肽（K-K）系统。 这一系统似乎发挥着重要作用 调节血压、炎症、休克、分泌（肾， 唾液，肠道），血液凝固，补体系统，也许 中枢神经系统功能 K-K系统的主要介质 是缓激肽（BK），一种九肽，及其同系物胰激肽（Lys-BK）， Met-Lys-BK。这些肽不存在特异性拮抗剂。 我们希望 发展他们。 BK的结构将以预期的方式进行修改， 增强受体结合但使内在活性最小化。 构象 BK分子的自由度将受到D-氨基掺入的限制 酸和取代的氨基酸，肽的环化， 将它们附着在大分子载体上。 BK受体结合研究 将指导肽的设计。 肽将通过自动固相合成 相合成，通过标准技术纯化并表征。 他们 将在分离的大鼠子宫上测定激动剂和拮抗剂活性， 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谱研究了BK在溶液中的构象。 我们 将试图研究BK分子的构象， 与其膜受体结合。

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.