DYNORPHIN ANALOGS AS KAPPA OPIOID RECEPTOR ANTAGONISTS

描述：（申请人摘要） 由于μ阿片类药物的严重副作用， 在开发其他吗啡的配体方面存在相当大的兴趣。 阿片受体类型作为潜在的治疗剂。 Kappa阿片 受体以高浓度存在于人脑和脊髓中， 并且对开发κ-选择性化合物有相当大的兴趣 作为潜在的神经保护剂和抗惊厥剂， 镇痛剂 κ激动剂也可能用作 免疫调节剂治疗HIV相关脑病。 因此，更好地了解这些受体如何在一个 分子水平以及它们的内源性配体如何与它们相互作用 在新治疗药物的开发中非常重要。 该项目的长期目标是更好地了解 阿片肽与κ阿片受体在分子水平上的相互作用 水平，并开发有效的和选择性的肽类似物作为配体， 这些受体。 本提案侧重于探索 拮抗剂与激动剂构效关系 活性，目标是鉴定具有拮抗剂活性的衍生物 在κ受体。 选择赋予拮抗剂活性的修饰将 集中在肽的N-末端区域。 的中心假设 本研究认为，碱性基团和芳香基团是关键官能团 与kappa受体相互作用，但它是可能的， 将这些药效基团转化为肽的方式 在经典阿片肽中发现并保留κ受体亲和力。 这 该项目包括两个具体目标：1）探索构象 强啡肽的限制性类似物，包含短和长范围 限制，作为kappa受体的配体，和2）探索新的 使用组合方法测定对κ受体的亲和力的序列。 这些研究可能导致配体的鉴定， 具有新颖的结构，对kappa具有高亲和力和选择性， 受体。 这些衍生物可能是有价值的药理学工具， 增加了我们对阿片配体如何与它们相互作用的理解。 分子水平上的受体。

DESCRIPTION: (Applicant's Abstract) Because of the serious side effects associated with mu-opioids such as morphine there is considerable interest in developing ligands for other opioid receptor types as potential therapeutic agents. Kappa opioid receptors are present in human brain and spinal cord in high concentrations, and there is considerable interest in developing kappa-selective compounds as potential neuroprotective and anticonvulsant agents as well as potential analgesic agents. Kappa agonists also potentially could be useful as immunomodulating agents in the treatment of HIV-associate encephalopathy. Therefore a better understanding of how these receptors function at a molecular level and how their endogenous ligands interact with them could be very important in the development of new therapeutic agents. The long term objectives of this project are to better understand the interactions of opioid peptides with kappa opioid receptors at a molecular level and to develop potent and selective peptide analogues as ligand for these receptors. This proposal focuses on the exploration of the structure-and conformation-activity relationships for antagonist vs. agonist activity, with the goal of identifying derivatives with antagonist activity at kappa receptors. Modifications chosen to impart antagonist activity will focus on the N-terminal region of the peptide. The central hypothesis of this research is that basic and aromatic groups are the key functionalities for interaction with kappa receptors, but that it is possible to incorporate these pharmacophoric groups into peptides in ways very different from those found in classical opioid peptides and retain kappa receptor affinity. This project involves two specific aims: 1) To explore conformationally restricted analogues of dynorphin, incorporating both short and longer range constraints, as ligands for kappa receptors, and 2) to explore novel sequences for affinity for kappa receptors using combinatorial approaches. These studies could result in the identification of ligands, potentially with novel structures, with high affinity and selectivity for kappa receptors. Such derivatives could be valuable pharmacological tools in increasing our understanding of how opioid ligands interact with their receptors at a molecular level.