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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：
10448677
负责人：
EMILY M JUTKIEWICZ
金额：
$ 7.11万
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/10448677
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.

该应用为通过后受体提高阿片类镇痛药的安全性提供了一种新的途径