Conformation - Selectivity Relations of Opioid Peptides

阿片肽的构象-选择性关系

基本信息

批准号：
7924273
负责人：
HENRY Isaac MOSBERG
金额：
$ 8.07万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2010-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7924273
关键词：
Achievement Affinity Agonist Binding Binding Sites Biological Assay C-terminal Clinical Complement Complex Data Dependence Development Evaluation Grant In Vitro Investigation Lead Ligands Modeling Modification Molecular Conformation Mutagenesis ORL1 receptor Opioid Opioid Peptide Opioid Receptor Orphan Parents Peptides Pharmaceutical Preparations Process Property Proteins Publishing Recruitment Activity Series Site Structure Study models Testing Validation analog base delta opioid receptor design efficacy testing follow-up improved in vivo insight interest kappa opioid receptors member peptide structure peptidomimetics pharmacophore public health relevance receptor scaffold success

Achievement Affinity Agonist Binding Binding Sites Biological Assay C-terminal Clinical Complement Complex Data Dependence Development Evaluation Grant In Vitro Investigation Lead Ligands Modeling Modification Molecular Conformation Mutagenesis ORL1 receptor Opioid Opioid Peptide Opioid Receptor Orphan Parents Peptides Pharmaceutical Preparations Process Property Proteins Publishing Recruitment Activity Series Site Structure Study models Testing Validation analog base delta opioid receptor design efficacy testing follow-up improved in vivo insight interest kappa opioid receptors member peptide structure peptidomimetics pharmacophore public health relevance receptor scaffold success

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项目摘要

DESCRIPTION (provided by applicant): The rational design of opioid drugs requires a detailed understanding of the precise interactions between opioid ligand and opioid receptor that underlie ligand selectivity for a particular opioid receptor and that distinguish agonist from antagonist function. During the current grant period our efforts to gain that understanding have focused on the refinement and validation of models of ligand/receptor complexes for the mu and delta opioid receptors (MOR and DOR) and elucidation of the precise features of ligand-receptor interaction that differentiate binding to MOR and DOR. In the next grant period, we propose to extend these studies by applying the insights gained from initial cyclic KOR (kappa opioid receptor) peptide ligands that display high affinity but are nonselective, and from our ligand-receptor interaction models for MOR, DOR, and KOR to design new KOR ligands within the same series that achieve KOR selectivity through KOR-specific receptor interactions. We will also begin a similar process of structure based ligand design for the orphan receptor, ORL1, using a cyclic pentapeptide scaffold. If successful, these studies would represent the considerable achievement of structure-based design of structurally related selective ligands for all 4 classes of opioid receptors, two of which (KOR and ORL1) typically bind only larger peptide ligands. Further, we will follow-up exciting initial results that point to features that determine efficacy. Success in these studies would be a clear indicator of the accuracy of the ligand/receptor interaction models and the applicability of our approaches to a wide array of GPCRs. Finally, we will continue our efforts aimed at transferring peptide-derived pharmacophore information to peptidomimetic scaffolds that hold much greater potential as possible CNS active clinical agents. PUBLIC HEALTH RELEVANCE: The interaction of opioid drugs with their protein targets initiates the desirable and undesirable effects of these drugs. Gaining a precise understanding of these interactions is the first step toward the design and development of opioid drugs with more tailored actions, especially opioids with reduced tolerance, dependence liability, and abuse potential.

描述（由申请人提供）：阿片类药物的合理设计需要详细了解阿片类配体和阿片类药物受体之间的精确相互作用，这是特定阿片类药物受体的配体选择性的基础，并将激动剂与拮抗剂功能区分开来。在当前赠款期间，我们为获得理解的努力集中在MU和Delta阿片受体（MOR和DOR）的配体/受体复合物模型（MOR和DOR）的改进和验证，以及阐明配体 - 受体相互作用的精确特征，这些特征将与MOR与MOR和DOR区分开。在下一个赠款期内，我们建议通过应用从最初的环状库（Kappa阿片受体）肽配体获得的见解来扩展这些研究，这些肽配体具有很高的亲和力，但是非选择性的，并且是从MOR，DOR和KOR中的配体 - 受体相互作用模型中，从而在同一系列中设计新的kor Ligands通过Kor Specection来设计新的Kor Ligands。我们还将使用环状五肽支架开始针对孤儿受体ORL1的基于结构的配体设计的类似过程。如果成功，这些研究将代表所有4种阿片类药物受体的结构相关选择配体的基于结构相关的选择配体的实现，其中两个（Kor和Orl1）通常仅结合较大的肽配体。此外，我们将跟进令人兴奋的初始结果，以指出确定功效的功能。在这些研究中的成功将明确表明配体/受体相互作用模型的准确性以及我们方法适用于广泛的GPCR。最后，我们将继续努力将肽来源的药效团信息转移到肽型脚手架上，这些脚手架具有更大的潜力。公共卫生相关性：阿片类药物与其蛋白质靶标的相互作用启动了这些药物的理想和不良作用。对这些相互作用的确切了解是朝着设计和开发阿片类药物的第一步，其量身定制的动作，尤其是耐受性，依赖责任和滥用潜力的阿片类药物。