ORALLY ACTIVE AND SELECTIVE ENKEPHALIN PSEUDOPEPTIDES

口服活性和选择性脑啡肽假肽

• 批准号: 3210209
• 负责人: ARNO F SPATOLA
• 金额: $ 8.82万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1990-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3210209
• 关键词: amides; blood brain barrier; chemical structure function; conformation; cyclic compound; drug design /synthesis /production; opiate alkaloid; oxidation reduction reaction; peptides

Recent findings from this lab and others have demonstrated that backbone modifications render peptides more stable toward enzymatic degradation and often results in increased potency. For example a cyclic pentapeptide containing the psi (CH2S) amide replacement was nearly 10 times more potent than its amide parent in the mu selective guinea pig ileum assay. Most current effort is being directed as finding Mu, delta, or Kappa- selective analogs which regain oral activity. Yet our psi (CH2S) analogs proved to have potency toward both mu and delta receptors and, so far, oral activity has not been demonstrated. Since the specific modification sites and type are so critical to the resulting physical properties of the modified peptides, we propose an expanded study of enkephalin-related cyclic pseudopeptides based on such potent parents as the DiMair- Schiller mu-selective agonist, and the Hruby-Mosberg delta- selective DPDPE. Introduction of psi (CH2S) modifications directly by solid phase synthesis as well as preparation of more polar psi (CH2SO) and psi (CH2SO2) derivatives to probe the Schwyzer hypothesis are also among the objectives of the proposed study. By systemically exploring the changes caused by the peptide backbone modifications on enzymatic stability, transport, selectivity, conformation, and biological activity, it should be possible to design analogs that retain selectivity while processing enhanced metabolic stability and oral activity. In addition hybrid structures between cyclic enkephalins and the kappa-selective dynorphin derivatives will be prepared to test various models of receptor occupancy and selectivity.

这个实验室和其他实验室最近的发现已经证明了这一点