KININ SYSTEM ANTAGONISTS

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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.