Toward Next Generation Analgesics:Activation Mechanism of the Nociceptin Receptor

迈向下一代镇痛药：伤害感受肽受体的激活机制

基本信息

批准号：
9204309
负责人：
Rebecca Laurie Miller
金额：
$ 1.92万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2017-07-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9204309
关键词：
Absence of pain sensation Adverse effects Affect Agonist American Analgesics Architecture Arrestins Binding Binding Sites Biological Assay Cell membrane Cessation of life Chemicals Cocaine Complex Coupled Crystallization Data Deposition Development Dimensions Drug Targeting Extracellular Space Family G-Protein-Coupled Receptors G-substrate GPER gene GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Goals Heroin Intravenous Laboratories Ligand Binding Ligands Lipids Molecular Molecular Structure Morphine Mutagenesis Mutation Opioid Opioid Receptor Pain Pain management Peptide Receptor Peptides Pharmacology Phase Play Proteins Protocols documentation Pruritus Receptor Activation Receptor Signaling Reporting Research Research Project Grants Resolution Roentgen Rays Role Route Self Administration Signal Transduction Source Structure Temperature Translating Ventilatory Depression combat computer studies design member mu opioid receptors mutant next generation nociceptin nociceptin receptor nonhuman primate novel overdose death predictive modeling prescription opioid prescription opioid abuse public health relevance receptor scaffold small molecule submicron three dimensional structure virtual x-ray free-electron laser

项目摘要

DESCRIPTION (provided by applicant): Prescription opioid abuse affects 2.4 million Americans and poses a societal burden of $55.7 billion annually. These prescription opioids are primarily -opioid receptor (MOR) agonists, and are not only highly addictive but their deadly side effects have caused more overdose deaths than heroin and cocaine combined. Therefore, research to identify analgesics that lack the potential for abuse and severe side effects associated with MOR agonists are urgently needed. Recent studies indicate that targeting the nociceptin receptor (NOP) is a promising alternative route to relieving pain without the deleterious side effects of traditional MOR-activating opioid therapies. In non-human primates, specifically activating NOP induces long lasting, morphine-comparable analgesia without causing pruritus, respiratory depression, or reinforcing effects in an intravenous self-administration paradigm; thus eliminating three serious side-effects of current opioid therapies. Our goal is to develop a mechanistic understanding of NOP signaling through intensive structural studies of NOP and leveraging our newfound understanding of this critical drug target to develop a predictive model for the action of different NOP ligand chemotypes. This goal will be accomplished through the following specific aims: (1) Determine and analyze the three-dimensional molecular structure of activated NOP (2) Delineate the activation mechanism of constitutively active mutants of NOP and finally (3) Define the structure of agonist- bound NOP in complex with effector fragments. The structural and functional data generated throughout this project will be combined and leveraged in computational studies to extend our newfound understanding of NOP activation to the identification of new NOP-activating chemotypes. This potentially high-impact project would pave the way for the development of the next generation of analgesics that lack the abuse liability and serious side effects associated with current opioid therapies.

描述（由适用提供）：处方滥用滥用会影响240万美国人，并每年造成557亿美元的社会焚烧。这些处方oioid是主要的阿片类药物（MOR）激动剂，不仅具有高度添加剂，而且它们的致命副作用导致了比海洛因和可卡因混合的过量服用过量死亡。因此，迫切需要研究缺乏滥用潜力和与MOR激动剂相关的严重副作用的镇痛药的研究。最近的研究表明，靶向Nocteptin受体（NOP）是缓解疼痛的承诺替代途径，而没有传统的MOR激活阿片类药物疗法的有害副作用。在非人类的隐私中，专门激活NOP会引起长期，吗啡可相比的镇痛，而不会引起瘙痒，呼吸抑郁或增强作用，或在静脉内自我给药范式中造成增强作用；因此消除了当前阿片类药物疗法的三种严重副作用。我们的目标是通过对NOP进行密集的结构研究，并利用我们对这一关键药物靶标的新发现的理解来开发一种针对不同NOP配体化学型的作用的预测模型，从而对NOP信号传导有一种机械理解。该目标将通过以下特定目的来实现：（1）确定并分析活化NOP的三维分子结构（2）描绘了NOP的组成型活性突变体的激活机制，最后（3）定义了与效应片段相关的复杂的激动剂结合NOP的结构。在整个项目中生成的结构和功能数据将在计算研究中结合并利用，以将我们对NOP激活的新发现的理解扩展到新的NOP激活化学型的鉴定。这个潜在的高影响力项目将为发展下一代镇痛药的发展铺平道路，这些镇痛药缺乏与当前阿片类药物疗法相关的严重副作用。