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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：
10449233
负责人：
EMILY M JUTKIEWICZ
金额：
$ 67.55万
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/10449233
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 abuse liability addiction arrestin 2 base chronic pain chronic pain management cost gallein high throughput screening improved in vitro testing in vivo inhibitor 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.

本申请提出了一种新的方法，以提高阿片类镇痛药的安全性，通过后受体药理学靶向G蛋白β亚基以改变β-阿片受体（MORs）的作用。我们一个实验室已经鉴定出G蛋白酪氨酸酶亚基的小分子抑制剂，各种疾病的动物模型。与本申请相关的是，我们鉴定了两种相关的G蛋白酶抑制剂，M119 和gallein，其增加小鼠中的莫尔激动剂镇痛效力，而不增强副作用，包括耐受性、呼吸抑制、便秘或成瘾的发展。因此，联合给药的G 抑制剂与阿片类镇痛药联合使用，有可能通过开放治疗途径来改善其安全性。镇痛效果和有害副作用之间的窗口。我们建议gallein和M119修饰阿片样物质通过阻断MORs下游的特异性反馈通路，同时留下促镇痛通路来发挥作用完整MORs与G蛋白Gi家族偶联，通过G蛋白依赖性抑制促进镇痛通过G蛋白依赖性调节K+（GIRK）通道、N型Ca 2+通道和抑制囊泡与突触膜融合。与此同时，G蛋白激活反馈通路，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阻断G蛋白依赖的PLC β 2和GRK 2调节，而不阻断GIRK或N型 Ca 2+通道，从而使MORs偏向镇痛信号传导。Gallein和M119的威力探针化合物，以验证药理学G受体阻滞剂可以改善阿片样物质性质的想法镇痛剂，但分子的化学特性使它们不适合治疗发展来自我们高通量筛选（HTS）活动的新化学系列数据支持一个全球目标行动机制。该应用程序的主要目标是开发和机械地表征可用于改善阿片类药物安全性的新型“药物样”G β抑制剂，止痛药这项申请分为3个具体目标1）我们将多样化的化学有前途的铅衍生自HTS的化合物，目的是提高效力和“药物样”特征。我们预计完成这一目标后，我们将确定一种高效的“药物样”G抑制剂，它可以成为强有力的领导者治疗开发的候选人。2)我们将使用全动物PLC抑制蛋白和β-arrestin-2敲除模型，和脑切片电生理学检查PLC阻断莫尔信号反馈抑制的作用， PKC和β-arrestin途径在G β抑制剂增强作用中的作用。3)我们需要找到一种用于治疗慢性疼痛而没有滥用可能性和不良副作用的阿片类镇痛剂。我们将在慢性炎症性疼痛的小鼠模型中，探索G蛋白抑制在慢性阿片类药物使用中的效用，慢性和急性给药，并使用吗啡自我给药的大鼠模型。