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，但存在严重的靶向副作用。其中原则这些额外的责任和呼吸抑制导致了当前的阿片类药物危机。这些影响再加上其他行为，包括便秘、恶心和呕吐，也会降低药物的有效性。疼痛诊所中的阿片类药物。因此，迫切需要开发新的镇痛药或改进临床镇痛药。现有药物的概况。吗啡和相关阿片类药物通过作用于正位点发挥作用 mu-阿片受体 (MOR) 上的位点，即内源性阿片肽结合的位点。最近的我们对 G 蛋白偶联受体 (GPCR) 结构认识的进步凸显了 GPCR 功能可能由结合在 GPCR 上单独的变构位点的化合物控制的可能性受体。在这方面，作用于 MOR 的正变构调节剂 (PAM) (MOR-PAM) 已被确定。先前的实验表明这些化合物可以变构调节正构位点并因此增加 MOR 激动剂（包括内源性激动剂）的结合亲和力、效力和/或最大反应阿片肽，以探针依赖性方式。初步实验表明 MOR-PAMs 小鼠体内有效的镇痛药，通过增强内源性脑啡肽活性起作用，从而避免对吗啡和羟考酮等阿片类药物的需求。这种体内活性应该保持神经元信号传导的时间和空间特征，从而避免补偿机制由慢性 MOR 激活引起。该应用通过使用结构生物学和借助新开发的计算方法来识别 MOR 上的变构结合位点变构探针使我们能够更清楚地定义变构机制，并进一步探索初步发现变构调节剂在体内可作为有效的疼痛缓解剂。详细的了解 MOR 变构调节剂的作用将提供有关机制的新信息通过它可以控制 MOR 功能，并与高亲和力探针的鉴定一起，将为 MOR 调节剂作为安全利用 MOR 调节剂的新型镇痛药的未来药物开发努力的方向 MOR的镇痛功效无成瘾性和呼吸抑制。相关性（参见说明）：