Peptidic Ligands for Kappa Opioid Receptors

由于与吗啡等阿片类止痛药相关的严重副作用， 开发其他阿片受体类型的配体作为药理工具和 潜在的治疗剂。Kappa(_：)阿片受体参与多种生理和 药理作用，包括外周和中枢介导的镇痛。滥用药物， 特别是阿片类药物和可卡因的滥用，是一个重大问题，对个人造成的后果 和社会。Kappa受体激动剂和拮抗剂可用于治疗可卡因和阿片类药物 分别是虐待。Kappa受体配体还具有许多其他潜在的治疗应用， 包括作为神经保护剂，并可能用于艾滋病的治疗。 配体，特别是多肽，与K阿片受体的相互作用似乎更为复杂 而不是配体与Mu或Delta阿片受体的相互作用。因此，这一计划的长期目标是 研究目的是检测具有高r_阿片受体亲和力和选择性的新型多肽配体 作为药理学工具，在分子水平上更好地了解K受体-多肽的相互作用。这 提案综合运用了多种方法(合成法、构象分析法和药理学法 评价)和探索结构-活性关系(SAR)的迭代战略 激动剂和拮抗剂的多肽配体与_：相互作用的药理学模型： 感受器。本研究有三个具体目的：1)探索猪细小病毒N-端序列的SAR 强啡肽A类似物；2)探索这些多肽C-末端序列的修饰以了解 不同多肽配体碱性残基在K受体相互作用中的作用；3)研究新的小分子 与强啡肽A无关的具有高c受体亲和力的多肽。除了确定重要的 可以用来研究K阿片受体的药理学工具，这项研究应该会取得重大进展 我们对多肽配体如何与这些受体相互作用的理解。这些见解将是免费的。 与那些发现的非肽配体有关，在新受体的开发中可能非常重要 配体，包括具有潜在治疗益处的试剂。

Because of the serious side effects associated with mu opioid analgesics such as morphine there is considerable interest in developing ligands for other opioid receptor types as both pharmacological tools and potential therapeutic agents. Kappa (_:) opioid receptors are involved in a variety of physiological and pharmacological effects, including peripheral as well as centrally mediated analgesia. Drug abuse, particularly opioid and cocaine abuse, is a major problem, resulting in consequences for both the individual and society. Kappa receptor agonists and antagonists may find utility in the treatment of cocaine and opioid abuse, respectively. Kappa receptor ligands also have a number of other potential therapeutic applications, including as neuroprotective agents and potentially in the treatment of AIDS. The interactions of ligands, particularly peptides, with K opioid receptors appear to be more complex than the interactions of ligands with mu or delta opioid receptors. Therefore the long-term objectives of this research are to examine novel peptidic ligands with high r_ opioid receptor affinity and selectivity that can be used as pharmacological tools to better understand K receptor-peptide interactions at a molecular level. This proposal uses a combination of approaches (synthesis, conformational analysis, and pharmacological evaluation) and an iterative strategy to explore structure-activity relationships (SAR) and develop pharmacophoric models for the interactions of peptide ligands, both agonists and antagonists, with _: receptors. This research has three specific aims: 1) to explore the SAR of the N-terminal sequences of dynorphin A analogs; 2) to explore modifications in the C-terminal sequence of these peptides to understand the roles of basic residues in different peptide ligands for K receptor interaction, and 3) to study novel small peptides unrelated to dynorphin A that have high _c receptor affinity. In addition to identifying important pharmacological tools that can be used to study K opioid receptors, this research should significantly advance our understanding of how peptide ligands interact with these receptors. These insights will be complimentary to those found for non-peptide ligands and could be very important in the development of new _: receptor ligands, including agents with potential therapeutic benefit.