KININ SYSTEM ANTAGONISTS

激肽系统拮抗剂

• 批准号: 2901048
• 负责人: JOHN M STEWART
• 金额: $ 32.26万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-09-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2901048
• 关键词: antiinflammatory agents; bioassay; bradykinin; chemical models; chemical structure function; computer simulation; drug design /synthesis /production; drug screening /evaluation; guinea pigs; hormone inhibitor; inhibitor /antagonist; laboratory rat; neuropeptide receptor; peptide hormone; receptor binding

DESCRIPTION: The nonapeptide bradykinin (BK) and its homolog kallidin (Lys-BK) are involved in regulation of normal physiology, and are also involved in much pathophysiology. These peptides are produced in tissue injury, ischemia and infection. They are initiators of all, or nearly all, inflammation. Conditions such as asthma, septic shock, adult respiratory distress syndrome (ARDS), trauma-evoked multiple organ failure, inflammatory bowel disease, and inflammatory joint disease (arthritis) are characterized by overproduction of BK. Since the discovery of effective bradykinin antagonists in this laboratory, the PI notes that he has made great progress in developing BK antagonists into potential new anti-inflammatory drugs. This project seeks to make further improvements in development of peptide antagonists for both classes of BK receptors (B1 and B2), and to develop non-peptide (peptidomimetic) BK antagonists. Successful non-peptide BK antagonists should be useful orally active drugs. Computer molecular graphics will be used to model BK receptors and to design antagonists to fit these receptors. The compounds thus designed will be synthesized and tested for biological activity in several assays. Some cancers, notably small cell carcinoma of lung (SCLC) use BK as an autocrine growth stimulant. The PI notes that certain dimers of his potent BK antagonists are selectively cytotoxic to SCLC, in vitro and in vivo. Improved cytotoxic compounds are being developed. These offer potential as anti-cancer drugs.

性状：九肽缓激肽（BK）及其同系物胰激肽 （Lys-BK）参与正常生理学的调节，并且还 参与了许多病理生理学。 这些肽在组织中产生 损伤、局部缺血和感染。 他们是所有，或几乎所有， 炎症 哮喘、感染性休克、成人呼吸道疾病等 窘迫综合征（ARDS），创伤诱发的多器官功能衰竭，炎性 肠道疾病和炎性关节疾病（关节炎）的特点是 由于BK的过度生产。自从发现有效的缓激肽 在这个实验室的拮抗剂，PI指出，他已经取得了很大的进展， 开发BK拮抗剂成为潜在的新型抗炎药。 该项目旨在进一步改善肽的开发 两类BK受体（B1和B2）的拮抗剂，并开发 非肽（肽模拟物）BK拮抗剂。 成功的非肽BK 拮抗剂应该是有用的口服活性药物。 计算机分子 图形将被用来模拟BK受体和设计拮抗剂，以适应 这些受体。 这样设计的化合物将被合成和测试 在几个试验中的生物活性。 一些癌症，特别是小细胞癌 肺癌（SCLC）使用BK作为自分泌生长刺激剂。 的PI 注意到他的有效BK拮抗剂的某些二聚体被选择性地 在体外和体内对SCLC具有细胞毒性。 改进的细胞毒性化合物， 正在开发中。 这些提供了作为抗癌药物的潜力。