CYCLIC PRODRUGS OF OPIOID PEPTIDES

近年来，在设计和设计方面取得了巨大的进步 不同类型的高选择性多肽的合成 阿片受体(Mu，Delta，kappa)。然而，一个主要的障碍是 用于临床的合成阿片肽的研究进展 治疗药物一直以来都是通过生物低渗透性 屏障(例如，肠道粘膜、血脑屏障)。不幸的是， 阿片肽的某些结构特征[例如，游离N- 端氨基、C端羧基和侧链羧基 (例如天冬氨酸、谷氨酸)和氨基(例如赖氨酸、精氨酸)具有亲和力 以及该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，从而限制 它的膜通透性。该项目的目标是 阿片肽类环状前体药物的合成及生物活性评价 这将暂时掩盖这些不受欢迎的物理化学性质， 从而提高了它们的膜通透性。新的前药战略 在这项研究中使用的是一种酯酶敏感系统 作为连接物将线性阿片肽转化为环状前体药物。这些 环状前体药物会降低多肽的极性和大小 限制其构象自由，从而增强其膜 渗透性。通过掩蔽的一个或两个终端 阿片肽，阿片肽被体外降解的倾向 而内切酶也应该减少。此外，通过使用 酶触发(酯酶)释放多肽，持续释放 可能会发生系统现象，导致生物半衰期增加- 生活。为了正确评估这一前药系统，各种阿片肽 对不同类型的阿片受体和 已经选择了独特的结构特征和环状前药 这些多肽将被合成。敏感度和选择性分析 线状肽和环状肽的方法将被开发并用于 确定它们的物理化学性质(如分配系数) 以及它们在生物液和组织中的分布。化学物质和 这些环状前体药物的酶(如酯酶、蛋白酶)稳定性 将在体外进行评估。已经设计了实验来评估 环状前体药物的受体结合活性及其能力 在体内产生药理作用。最后，它的渗透性 这些线状和环状阿片肽通过肠粘膜(AN) 大鼠在体肠灌流模型)，并通过血脑 屏障(大鼠在体脑灌流模型)将被确定。如果 被认为是必要的-肠粘膜的细胞培养模型和 血脑屏障将被用来确定内在通透性 并阐明了阿片肽及其环状结构 前药可以穿透这些生物屏障。这项研究的结果 可以为药物化学家提供一种普遍适用的前药 用于增强阿片肽的膜通透性的系统。

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.