Peptidic Ligands for Kappa Opioid Receptors

描述（由申请人提供）：由于与μ阿片类镇痛药（如吗啡）相关的严重副作用，因此对开发其他阿片类受体类型的配体作为药理学工具和潜在治疗剂具有相当大的兴趣。κ（k）阿片受体参与多种生理和药理作用，包括外周以及中枢介导的镇痛。药物滥用，特别是阿片类药物和可卡因滥用，是一个严重问题，对个人和社会都造成了后果。κ受体激动剂和拮抗剂可分别用于治疗可卡因和阿片类药物滥用。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和潜在的艾滋病治疗。配体，特别是肽，与κ阿片受体的相互作用似乎比配体与μ或δ阿片受体的相互作用更复杂。因此，本研究的长期目标是研究具有高κ阿片受体亲和力和选择性的新型肽配体，其可用作药理学工具以更好地理解分子水平上的κ受体-肽相互作用。该提案使用的方法（合成，构象分析和药理学评价）和迭代策略的组合，探索结构-活性关系（SAR）和开发的肽配体，激动剂和拮抗剂，与κ受体的相互作用的药效模型。本研究有三个具体目标：1）探索强啡肽A类似物N-末端序列的SAR; 2）探索这些肽的C-末端序列的修饰，以了解不同肽配体中碱性残基对Kappa受体相互作用的作用; 3）研究与强啡肽A无关的具有高Kappa受体亲和力的新型小肽。除了确定可用于研究Kappa阿片受体的重要药理学工具外，这项研究还应显着促进我们对肽配体如何与这些受体相互作用的理解。这些见解将是互补的那些发现的非肽配体，并可能是非常重要的新的κ受体配体，包括具有潜在的治疗效益的代理商的发展。

DESCRIPTION (provided by applicant): 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 (k) 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 Kappa 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 kappa opioid receptor affinity and selectivity that can be used as pharmacological tools to better understand Kappa 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 kappa 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 Kappa receptor interaction, and 3) to study novel small peptides unrelated to dynorphin A that have high kappa receptor affinity. In addition to identifying important pharmacological tools that can be used to study Kappa 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 kappa receptor ligands, including agents with potential therapeutic benefit.