KININ SYSTEM ANTAGONISTS

激肽系统拮抗剂

• 批准号: 2685294
• 负责人: JOHN M STEWART
• 金额: $ 37.62万
• 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/2685294
• 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.

描述：九肽缓激肽(BK)及其同系物Kallidin (Lys-BK)参与正常生理的调节，也 与许多病理生理学有关。这些多肽是在组织中产生的 损伤、缺血和感染。他们是所有的，或者几乎所有的， 发炎。哮喘、感染性休克、成人呼吸道等情况 窘迫综合征(ARDS)，外伤性多器官衰竭，炎症性 肠道疾病和炎症性关节疾病(关节炎)是其特征 由于BK的生产过剩。自发现有效的缓激肽以来 在这个实验室里，PI注意到他已经取得了很大的进步 将BK拮抗剂开发为潜在的新型抗炎药物。 本项目寻求在多肽的开发方面做出进一步的改进 两类BK受体(B1和B2)的拮抗剂，并开发 非肽(模拟多肽)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受体并设计适合的拮抗剂 这些受体。这样设计的化合物将被合成和测试。 在几种化验中用于生物活性。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。《少年派》 注意到他强大的BK拮抗剂的某些二聚体选择性地 体外和体内对小细胞肺癌的细胞毒作用。改进的细胞毒性化合物是 正在开发中。这些药物具有作为抗癌药物的潜力。