Allosteric Modulation of the Mu-Opioid Receptor

Mu-阿片受体的变构调节

基本信息

批准号：
10161762
负责人：
John R. Traynor
金额：
$ 69.53万
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：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10161762
关键词：
Absence of pain sensation Acute Pain Affinity Agonist Allosteric Site Amino Acids Analgesics Arrestins Behavior Behavioral Binding Binding Sites Characteristics Chemicals Chemistry Chronic Clinical Collaborations Computing Methodologies Constipation Coupled Coupling Cryoelectron Microscopy Cyclic AMP-Dependent Protein Kinases Data Development Drug Design Effectiveness Enkephalins Epidemic Exposure to Funding Future G protein coupled receptor kinase G-Protein-Coupled Receptors GTP-Binding Proteins Heterotrimeric GTP-Binding Proteins In Vitro Instruction Knowledge Ligands Methionine Enkephalin Modeling Molecular Morphine Mus Mutate Nausea and Vomiting Opioid Opioid Analgesics Opioid Antagonist Opioid Peptide Opioid Rotation Opioid agonist Oxycodone Pain Clinics Pathway interactions Patients Pharmaceutical Preparations Property Protein Kinase Receptor Activation Regulation Relapse Role Side Signal Transduction Site Structure System Testing Translating Transmembrane Domain Ventilatory Depression Work addiction chronic pain density diverse data drug development endogenous opioids experimental study extracellular gamma-Aminobutyric Acid improved in vivo models and simulation mu opioid receptors neurotransmission novel opioid epidemic pain relief positive allosteric modulator preservation prevent receptor receptor binding receptor function recruit respiratory response side effect small molecule structural biology

项目摘要

Opioid drugs are highly effective analgesics but suffer from serious on-target side-effects. Principle among these are addition liability and respiratory depression that have led to the current opioid crisis. These effects together with other actions, including constipation and nausea and vomiting, also reduce the effectiveness of opioids in the pain clinic. Thus, there is a vital need to develop new analgesics or to improve the clinical profile of existing medications. Morphine and related opioids exert their effects by acting at the orthosteric site on the mu-opioid receptor (MOR), i.e. the site where the endogenous opioid peptides bind. Recent advances in our knowledge of the structure of G-protein coupled receptors (GPCRs) have highlighted the possibility that GPCR function may be controlled by compounds binding at a separate, allosteric, site on the receptors. In this regard positive allosteric modulators (PAMs) that act at MOR (MOR-PAMs) have been identified. Previous experiments show these compounds act to allosterically modulate the orthosteric site and so increase the binding affinity, potency and/or maximal response of MOR agonists, including endogenous opioid peptides, in a probe-dependent manner. Preliminary experiments demonstrate that MOR- PAMs are effective antinociceptive agents in vivo in the mouse and act by enhancing endogenous enkephalin activity, thus avoiding the need for opioid drugs such as morphine and oxycodone. This in vivo activity should preserve the temporal and spatial characteristics of neuronal signaling and so avoid compensatory mechanisms induced by chronic MOR activation. This application moves the field forward by using structural biology and computational methods to identify the allosteric binding site on MOR, aided by the development of new allosteric probes to allow us to more clearly define the mechanism of allosterism, and further exploration of preliminary findings that allosteric modulators work as effective pain relieving agents in vivo. Detailed understanding of the actions of allosteric modulators of MOR will provide new information on mechanisms by which MOR function may be controlled and, together with the identification of high affinity probes, will pave the way for future drug development efforts of MOR modulators as novel analgesics that safely harness the analgesic efficacy of MOR without addiction and respiratory depression. RELEVANCE (See instructions):

阿片类药物是高效的镇痛药，但患有严重的靶向副作用。原则这些是导致当前阿片类药物危机的额外责任和呼吸抑郁症。这些影响以及其他行动，包括便秘，恶心和呕吐，还降低了疼痛诊所中的阿片类药物。因此，至关重要的是开发新的镇痛药或改善临床现有药物的概况。吗啡和相关的阿片类药物通过在直角处作用发挥作用位于Mu-阿片受体（MOR）的位置，即内源性阿片类肽结合的部位。最近的我们对G蛋白偶联受体（GPCR）结构的了解的进步已经强调了 GPCR函数可以通过在单独的变构位点结合的化合物来控制的可能性受体。在这方面确定。以前的实验表明，这些化合物的作用是在变构调节正常位点，并且因此，增加了MOR激动剂的结合亲和力，效力和/或最大反应，包括内源性阿片类肽，以探针依赖性方式。初步实验表明morpam是在小鼠体内有效抗伤害感受剂，并通过增强内源性enkephalin活性来起作用，因此避免了需要阿片类药物（例如吗啡和羟考酮）。这种体内活动应保留神经元信号的时间和空间特征，因此避免了代偿机制由慢性MOR激活诱导。该应用程序通过使用结构生物学和在MOR上识别变构结合位点的计算方法，由新的发展变构探针使我们能够更清楚地定义了变构主义的机制，并进一步探索定构调节剂在体内可缓解疼痛剂的初步发现。详细的了解MOR的变构调节剂的作用将提供有关机制的新信息可以控制MOR功能，并与高亲和力探针的识别一起铺路 MOR调节剂将来的药物开发工作的方式作为新型的镇痛药，可以安全地利用 MOR没有成瘾和呼吸抑郁的镇痛功效。相关性（请参阅说明）：