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Development of G protein beta gamma subunit inhibitors to improve the safety and efficacy of opioid analgesics

开发G蛋白βγ亚基抑制剂以提高阿片类镇痛药的安全性和有效性

基本信息

批准号：
9894965
负责人：
EMILY M JUTKIEWICZ
金额：
$ 69.91万
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：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894965
关键词：
ADRBK1 gene Absence of pain sensation Acute Acute Pain Address American Analgesics Animal Disease Models Animals Arrestins Binding Brain Characteristics Chemicals Chemistry Chemosensitization Chronic Chronic inflammatory pain Constipation Coupled Data Development Dyes Electrophysiology (science)Family Feedback G protein coupled receptor kinase G-protein Beta gamma GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Goals Gold Knock-out Knockout Mice Laboratories Lead Mediating Modeling Morphine Mus Opioid Opioid Analgesics Opioid Receptor Opioid agonist Pain Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phospholipase C Phosphorylation Phosphotransferases Physical Dependence Potassium Channel Process Property Protein Inhibition Protein Subunits Proteins Publishing Rattus Receptor Signaling Regulation Reporting Rewards Role Safety Scheme Self Administration Series Signal Transduction Slice Synaptic Membranes Testing Therapeutic Time Ventilatory Depression Vesicle addiction arrestin 2 base chronic pain cost gallein high throughput screening improved in vitro testing in vivo inhibitor/antagonist lead candidate mouse model mu receptors neurotransmitter release novel novel drug class novel strategies novel therapeutics opioid use phospholipase C gamma prototype receptor scaffold side effect small molecule inhibitor standard care therapeutic development

项目摘要

This application proposes a novel approach to improving the safety of opioid analgesics by post-receptor pharmacological targeting of G protein  subunits to modify the actions of -opioid receptors (MORs). Our laboratory has identified small molecule inhibitors of G protein  subunits that demonstrate in vivo efficacy in various animal models of disease. Relevant to this application, we identified two related G inhibitors, M119 and gallein that increase MOR agonist analgesic potency in mice without potentiating side effects that include development of tolerance, respiratory depression, constipation or addiction. Thus co-administration of G inhibitors with opioid analgesics has the potential to improve their safety profile by opening up the therapeutic window between analgesic efficacy and deleterious side effects. We propose that gallein and M119 modify opioid action by blocking specific feedback pathways downstream of MORs while leaving pro-analgesic pathways intact. MORs couple to the Gi family of G proteins and promote analgesia through G protein-dependent inhibition of neurotransmitter release via G-dependent regulation of K+ (GIRK) channels, N-type Ca2+ channels and inhibition of vesicle fusion with synaptic membranes. At the same time G activates feedback pathways including phospholipase C (PLC) and G protein-coupled receptor kinases (GRKs), which limit opioid receptor activity. Gallein and M119 block G-dependent regulation of PLC and GRK2 without blocking GIRK or N-type Ca2+ channels and thereby biasing MORs toward pro-analgesic signaling. Gallein and M119 have been powerful probe compounds to validate the idea that pharmacological G blockade could improve the properties of opioid analgesics, but the chemical characteristics of the molecules makes them unsuitable for therapeutic development. Data with new chemical series’ derived from our high throughput screening (HTS) campaign support a G on-target mechanism of action. The primary goal of this application is to develop and mechanistically characterize novel “drug like” G inhibitors that can be utilized to improve the safety of opioid analgesics. This application is divided into 3 specific aims 1) We will diversify the chemistry of promising lead compounds derived from HTS with the goal of improving potency and “drug like” characteristics. We expect that upon completion of this aim we will identify a high potency “drug like” G inhibitor that can be a strong lead candidate for therapeutic development. 2) We will use whole animal PLC and -arrestin-2 knockout models, and brain slice electrophysiology to examine the roles of blocking feedback inhibition of MOR signaling by PLC, PKC and -arrestin pathways in the potentiating actions of G inhibitors. 3) There is a significant need to find an opioid analgesic for the treatment of chronic pain without abuse potential and adverse side effects. We will explore the utility of G inhibition in chronic opioid use in a mouse model of chronic inflammatory pain, with both chronic and acute administration and use a rat model of morphine self-administration.

这项应用为通过受体后提高阿片类镇痛剂的安全性提供了一种新的方法药物靶向G蛋白亚基以改变-阿片受体(MORs)的作用。我们的实验室已经确定了G蛋白亚基的小分子抑制剂，它们在体内显示了对各种疾病的动物模型。与这一应用相关的是，我们确定了两种相关的G抑制剂M119 和帆船可以增加小鼠的MOR激动剂的止痛效力，而不会增强副作用，包括出现耐受性、呼吸抑制、便秘或成瘾。因此，G的共同管理含有阿片类镇痛剂的抑制剂有可能通过打开治疗药物来改善其安全性止痛效果和有害副作用之间的窗口。我们认为Gallein和M119对阿片类药物有修饰作用阻断MORS下游的特定反馈通路，同时离开前镇痛通路的作用完好无损。MORS与G蛋白的Gi家族偶联，通过G蛋白依赖的抑制促进镇痛神经递质的释放通过G-依赖的K+通道、N型钙通道和抑制囊泡与突触膜的融合。同时，G-激活反馈通路包括磷脂酶C(PLC)和G蛋白偶联受体激酶(GRKs)，它们限制阿片受体活动。Gallein和M119在不阻断Girk或N型的情况下阻断G依赖的PLC和GRK2的调节 Ca~(2+)通道，从而使MORS偏向于前镇痛信号。帆船和M119一直很强大探索化合物以验证药理G阻滞剂可改善阿片类药物特性的想法止痛药，但分子的化学特性使它们不适合治疗发展。来自我们的高通量筛选(HTS)活动的新化学系列数据支持G目标上的行动机制。此应用程序的主要目标是开发和可用于提高阿片类药物安全性的新型“类药物”G-抑制剂的机械表征止痛药。这项应用分为三个具体目标1)我们将使有前途的铅的化学成分多样化从HTS衍生的化合物，目标是提高效力和“类药物”特性。我们期待着在完成这一目标后，我们将确定一种高效的类似药物的G抑制剂，它可能是一个强有力的先导治疗开发的候选人。2)我们将使用全动物PLC和-arrestin-2基因敲除模型，和脑片电生理学检测PLC阻断MOR信号反馈抑制的作用， PKC和-arrestin通路在G-抑制剂增强作用中的作用3)有很大的需要找到一种阿片类止痛剂，用于治疗慢性疼痛，没有滥用潜力和不良副作用。我们会探讨G抑制在慢性阿片类药物慢性炎症性疼痛小鼠模型中的应用慢性和急性给药，并使用吗啡自我给药的大鼠模型。