CYCLIC PRODRUGS OF OPIOID PEPTIDES

阿片肽的环状前药

• 批准号: 2443485
• 负责人: Ronald T Borchardt
• 金额: $ 21.07万
• 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: 1995-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2443485
• 关键词: blood brain barrier; chemical stability; cyclic peptides; drug design /synthesis /production; endogenous opioid; esterase; intestinal mucosa; laboratory rat; membrane permeability; peptide chemical synthesis; prodrugs; receptor binding; slow release drug; synthetic peptide; tissue /cell culture

In recent years tremendous progress has been made in the design and synthesis of peptides with high selectivities for the different types (mu, delta, kappa) of opioid receptors. However, a major obstacle to the development of these synthetic opioid peptides as clinically useful therapeutic agents has been their low permeability through biological barriers (e.g., intestinal mucosa, blood brain barrier). Unfortunately, some of the structural features of an opioid peptide [e.g., free N- terminal amino and C-terminal carboxyl groups and side chain carboxyl (e.g., Asp, Glu) and amino (e.g., Lys, Arg) groups] that bestow affinity and specificity of the molecule for the different opioid receptors, also bestow on the molecule undesirable physicochemical properties which limit its membrane permeability. The objectives of this project are to synthesize and biologically evaluate cyclic prodrugs of opioid peptides which will transiently mask these undesirable physicochemical properties, thereby enhancing their membrane permeability. The novel prodrug strategy employed in this study takes advantage of an esterase sensitive system as a linker to convert linear opioid peptides to cyclic prodrugs. These cyclic prodrugs will decrease the polarity and size of the peptide and restrict its conformational freedom, thus, enhancing its membrane permeability. Through the masking of one or both of the terminal ends of an opioid peptide, the propensity of the peptide to be degraded by exo and endo peptidase should also be reduced. In addition, by employing an enzyme trigger (esterase) to release the peptide, a sustained release system phenomena may occur resulting in an increased biological half- life. To properly evaluate this prodrug system, various opioid peptides with high selectivities for different types of opioid receptors and unique structural features have been selected and cyclic prodrugs of these peptides will be synthesized. Sensitive and selective analytical methods for the linear and cyclic peptides will be developed and used to determine their physicochemical properties (e.g., partition coefficients) and their disposition in biological fluids and tissues. The chemical and enzymatic (e.g., esterase, protease) stability of these cyclic prodrugs will be evaluated in vitro. Experiments have been designed to evaluate the receptor binding activity of the cyclic prodrugs and their ability to elicit pharmacological effects in vivo. Finally, the permeability of these linear and cyclic opioid peptides through the intestinal mucosa (an in situ rat intestinal perfusion model) and through the blood brain barrier (an in situ rat brain perfusion model) will be determined. If deemed necessary, -cell culture models of the intestinal mucosa and the blood brain barrier will be used to determine intrinsic permeabilities and elucidate pathways by which the opioid peptides and their cyclic prodrug penetrate these biological barriers. The results of this study could provide medicinal chemists with a generally applicable prodrug system for enhancing the membrane permeability of opioid peptides.

近年来在设计和制造方面取得了巨大进步 对不同类型具有高选择性的肽合成 （mu、delta、kappa）阿片受体。然而，一个主要障碍是 开发这些具有临床用途的合成阿片肽 治疗剂的生物渗透性低 屏障（例如肠粘膜、血脑屏障）。很遗憾， 阿片肽的一些结构特征 [例如，游离 N- 末端氨基和C末端羧基以及侧链羧基 （例如，Asp、Glu）和氨基（例如，Lys、Arg）基团]赋予亲和力 以及分子对不同阿片受体的特异性 赋予分子不良的物理化学性质，限制 它的膜渗透性。该项目的目标是 阿片肽环状前药的合成和生物学评价 这将暂时掩盖这些不良的物理化学特性， 从而增强其膜的通透性。新颖的前药策略 本研究中采用的方法利用了酯酶敏感系统 作为将线性阿片肽转化为环状前药的连接体。这些 环状前药会降低肽的极性和大小 限制其构象自由度，从而增强其膜 渗透性。通过掩盖一个或两个终端 阿片肽，肽被外切酶降解的倾向 内肽酶也应减少。此外，通过采用 酶触发剂（酯酶）释放肽，持续释放 系统现象可能会发生，导致生物半数增加 生活。为了正确评估该前药系统，各种阿片肽 对不同类型的阿片受体具有高选择性 选择了独特的结构特征和环状前药 这些肽将被合成。灵敏、选择性分析 将开发线性和环状肽的方法并用于 确定它们的物理化学性质（例如分配系数） 及其在生物体液和组织中的分布。化学和 这些环状前药的酶（例如酯酶、蛋白酶）稳定性 将在体外进行评估。实验旨在评估 环状前药的受体结合活性及其能力 从而在体内产生药理作用。最后，渗透率 这些线性和环状阿片肽通过肠粘膜（ 原位大鼠肠道灌注模型）和通过血脑 将确定屏障（原位大鼠脑灌注模型）。如果 被认为是必要的， -肠粘膜和细胞培养模型 血脑屏障将用于确定内在渗透性 并阐明阿片肽及其环状化合物的途径 前药穿透这些生物屏障。本研究结果 可以为药物化学家提供普遍适用的前药 增强阿片肽膜通透性的系统。