CYCLIC PRODRUGS OF OPIOID PEPTIDES

阿片肽的环状前药

• 批准号: 2897942
• 负责人: Ronald T Borchardt
• 金额: $ 21.57万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-09 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2897942
• 关键词: P glycoprotein; blood brain barrier; chemical stability; chemical structure; cyclic peptides; drug design /synthesis /production; endogenous opioid; intestinal mucosa; laboratory rat; membrane permeability; opioid receptor; peptide chemical synthesis; pharmacokinetics; prodrugs; protein structure function; synthetic peptide; tissue /cell culture

DESCRIPTION (Applicant's Abstract): In recent years, numerous peptides have been synthesized with high affinity and selectivity for the different types (mu, delta, kappa) of opioid peptides. These opioid receptor-specific peptides have unique pharmacology properties that warrant their development as therapeutic agents. However, in many cases, the clinical development of these opioid peptides has been prevented because of their poor biopharmaceutical properties [e.g., permeation across the intestinal mucosa and blood-brain barrier (BBB)]. During the first two years of this NIDA grant, we have demonstrated that cyclic prodrugs of opioid peptides in general have significantly better cell permeation characteristics than do the opioid peptides themselves. The major objectives of this renewal application include: (i) to demonstrate that the cyclic prodrugs have better oral bioavailability and better permeation of the BBB in vivo than the opioid peptides; (ii) better define how the structure of the "chemical linker" used to cyclize the peptide and the structure of the opioid peptide, itself, influence the permeation characteristics of the prodrugs, particularly their substrate activity for efflux systems (P-glycoproteins), which have been shown to limit their permeation through the intestinal mucosa and the BBB; and (iii) to optimize the bioconversion rates of the prodrugs to the opioid peptides in vivo in order to maximize their pharmacological effects. These studies should lead to the identification of the optimal structural features of the chemical linkers that when employed to make cyclic prodrugs of opioid peptides will afford optimal pharmacological effects after i.v. or p.o. administration.

描述（申请人的摘要）： 近年来，人们合成了大量具有高亲和力的肽 以及对不同类型（mu、delta、kappa）阿片类药物的选择性 肽。 这些阿片受体特异性肽具有独特的药理学 保证它们作为治疗剂开发的特性。 然而， 在许多情况下，这些阿片肽的临床开发已经 由于其较差的生物制药特性而被阻止[例如， 渗透穿过肠粘膜和血脑屏障（BBB）]。 在 NIDA 拨款的头两年中，我们已经证明： 阿片肽的环状前药一般具有明显更好的细胞活性 渗透特性优于阿片肽本身。 这 本次续展申请的主要目标包括： (i) 证明 环状前药具有更好的口服生物利用度和更好的 体内血脑屏障的渗透性高于阿片肽； (二) 更好地定义 “化学连接体”的结构如何用于环化肽以及 阿片肽的结构本身影响渗透 前药的特性，特别是它们的底物活性 外排系统（P-糖蛋白），已被证明限制其 通过肠粘膜和血脑屏障渗透； (iii) 优化 前药在体内向阿片肽的生物转化率 以最大限度地发挥其药理作用。 这些研究应该引导 确定化学物质的最佳结构特征 当用于制备阿片肽的环状前药时，连接体将 静脉注射后提供最佳药理作用或邮政信箱行政。