Peptidic Ligands for Kappa Opioid Receptors

Kappa 阿片受体的肽配体

基本信息

批准号：
7563238
负责人：
Jane V Aldrich
金额：
$ 34.11万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-15 至 2011-02-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7563238
关键词：
Absence of pain sensation Acids Acquired Immunodeficiency Syndrome Address Adverse effects Affect Affinity Agonist Amino Acids Analgesics Anti-Inflammatory Agents Anti-inflammatory Binding Biological Factors C-terminal Cocaine Cocaine Abuse Complex Crime Cyclic Peptides D-Phe-Pro Development Drug abuse Drug user Dynorphin A Dynorphins Evaluation Figs - dietary Goals Head Incidence Individual Laboratories Lead Ligands Mediating Modeling Modification Molecular Morphine N-terminal Needle Sharing Neuroprotective Agents New Agents Opioid Opioid Analgesics Opioid Peptide Opioid Receptor Pain Peptide Receptor Peptides Peripheral Physiological Play Positioning Attribute Protein Precursors Research Research Personnel Role Series Societies Structure-Activity Relationship Tail Therapeutic Therapeutic Agents Ventilatory Depression Work addiction analog arodyn delta opioid receptor design expectation insight interest kappa opioid receptors kappa(1) opioid receptor novel opioid abuse phenylalanyltryptophan prodynorphin programs protein aminoacid sequence receptor rimorphin spatial relationship therapeutic target tool

项目摘要

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.

描述（由申请人提供）：由于与吗啡等MU阿片类镇痛药相关的严重副作用，因此对其他阿片类药物类型的配体开发配体具有相当大的兴趣，因为药理学工具和潜在的治疗剂既是药理工具。 Kappa（K）阿片受体参与了多种生理和药理作用，包括外围和中央介导的镇痛。药物滥用，特别是阿片类药物和可卡因滥用，是一个主要问题，导致个人和社会的后果。喀巴受体激动剂和对手可能分别发现可卡因和阿片类药物滥用的效用。 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以及潜在的艾滋病治疗。配体，尤其是肽的相互作用与喀巴阿片受体的相互作用似乎比配体与MU或Delta阿片受体的相互作用更为复杂。因此，这项研究的长期目标是检查具有高卡帕阿片受体亲和力和选择性的新型肽配体，可以用作药理工具，以更好地了解分子水平上的Kappa受体肽相互作用。该提案结合了方法（合成，构象分析和药理学评估）以及探索结构活性关系（SAR）的迭代策略，并为肽配体的相互作用（激动剂和拮抗剂）与KAPPA受体相互作用开发了药物浮游模型。这项研究具有三个特定的目的：1）探索Dynorphin A类似物的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Kappa受体相互作用的不同肽配体中碱性残基的作用，以及3）研究与具有高kappa受体亲和力的dynorphin A无关的新型小肽。除了确定可用于研究Kappa阿片受体的重要药理工具外，这项研究还应显着提高我们对肽配体如何与这些受体相互作用的理解。这些见解将是对非肽配体发现的见解，并且在开发新的Kappa受体配体（包括具有潜在治疗益处的药物）中可能非常重要。