In vivo characterization of opioid biased agonists

阿片类偏向激动剂的体内表征

基本信息

批准号：
10062935
负责人：
JACK BERGMAN
金额：
$ 24.56万
依托单位：
MCLEAN HOSPITAL
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：
2019-01-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062935
关键词：
Abstinence Abstinence Syndrome Acute Address Affinity Aftercare Agonist Air Analgesics Animals Atmosphere Attenuated Behavior Behavioral Biological Assay Carbon Dioxide Characteristics Chronic Clinical Constipation Coupling Data Dependence Development Dose Drug Prescriptions Equipment and supply inventories Female Fentanyl GTP-Binding Proteins Genes Goals Hypercapnia In Vitro Intake Knockout Mice Laboratories Ligands Malignant - descriptor Mental Depression Methods Monkeys Morphine Movement Mus Naltrexone National Institute of Drug Abuse Opiate Addiction Opioid Opioid Analgesics Opioid agonist Oxycodone Pain Performance Pharmaceutical Preparations Pharmacologic Substance Pharmacology Plethysmography Procedures Regimen Relapse Reporting Respiration Respiratory physiology Rice Safety Self Administration Sex Differences Signal Transduction Signaling Protein Tail Time Ventilatory Depression Water Withdrawal addiction appropriate dose arrestin 2 base beta-arrestin clinical practice drug seeking behavior experimental study improved in vivo male mu opioid receptors nonhuman primate novel novel therapeutics opioid epidemic optimism pre-clinical prescription opioid programs receptor recruit respiratory response sex side effect ventilation

项目摘要

OTHER PROJECT INFORMATION - SECTION 7 - PROJECT SUMMARY/ABSTRACT 1 The ongoing opioid crisis has led to renewed concerns about the clinical prescription of addictive opioid 2 analgesics. However, there currently are no suitable alternatives for treating severe or malignant pain. Studies 3 of opioid signaling mechanisms in mice lacking the β-arrestin 2 gene indicate that the acute analgesic effects 4 of morphine were enhanced in these mice, and subsequent studies reported that undesirable effects of 5 morphine including respiratory depression, constipation, and analgesic tolerance were all diminished in the 6 absence of β-arrestin signaling. These findings have led to increased efforts in developing novel opioid drugs 7 that, based on their preferential activation of G-protein signaling over β-arrestin signaling in vitro, can be 8 characterized as `biased' agonists. However, although clear distinctions in receptor-activated signaling of 9 opioid ligands are found in vitro, the extent to which these cellular differences predict differing profiles of opioid 10 activity in vivo remains uncertain. Currently, there is not sufficient information to conclude whether biased 11 signaling can indeed be associated with reduced opioid side effects and, consequently, an improved safety 12 profile of `biased' agonists compared to conventional prescription opioids. The present application intends to 13 address the need for preclinical data to rigorous evaluate this possibility with a program of in vivo studies of the 14 effects of novel opioid biased agonists in nonhuman primates. In these studies, we will employ well-established 15 and highly translational pharmacological methods to compare prescription opioids that are `balanced' agonists, 16 i.e., signal through both G-protein and β-arrestin paths (morphine, oxycodone, and fentanyl) with the `biased' 17 agonist PZM21 and two novel ligands that are provided by colleagues at the NIDA IRP and that, based on in 18 vitro data, also can be characterized as opioid `biased' agonists. First, the acute effects of different opioids will 19 be studied using well-validated assays of antinociception and operant performance, respiratory function, and 20 abuse potential. Data from these studies will enable us to rigorously characterize and compare both the 21 beneficial and unwanted effects of the `balanced' and `biased' agonists. Next, the same drugs will be compared 22 during regimens of chronic treatment. In these studies, assays of antinociception and operant performance will 23 be used to evaluate tolerance, defined by rightward or downward movement of the opioid dose-effect function, 24 and assays of respiratory function and observable behavior to evaluate the presence of opioid dependence, 25 evident as increases in ventilation or characteristic behavioral signs following antagonist administration. The 26 results of the latter studies will provide critical information regarding the dependence liability of `biased' 27 agonists that, in clinical practice, might be given on a repeated, or chronic, basis. Finally, cognizant of sex- 28 related differences in the effects of prescription opioids that are `balanced' agonists, we will conduct our studies 29 in both male and female subjects to determine whether similar sex-related differences are produced by novel 30 opioid `biased' agonists.

其他项目信息 - 第7节 - 项目摘要/摘要 1正在进行的阿片类药物危机导致对添加剂阿片类药物的临床处方的重新担忧 2个镇痛药。但是，目前尚无适合治疗严重或恶性疼痛的替代方法。研究缺少β-甲蛋白2基因指示的小鼠中的3个阿片类药物信号传导机制表明急性镇痛作用这些小鼠中有4个吗啡，随后的研究报告说 5个吗啡，包括呼吸抑制，便秘和镇痛耐受性，均降低 6缺乏β-arrestin信号传导。这些发现导致了开发新的阿片类药物的努力 7基于它们的首选G蛋白信号传导优于β-arrestin信号传导，可以是 8被描述为“偏见”激动剂。但是，尽管受体激活的信号的明显区别 9在体外发现了卵形药物配体，这些细胞差异预测了卵样差异的程度 10个体内活性仍然不确定。目前，没有足够的信息来包括是否有偏见 11信号确实可以与阿片类药物副作用减少有关，因此，安全性提高了。与常规处方阿片类药物相比，“偏见”激动剂的12个特征。本申请打算 13解决了临床前数据的需求，以严格评估这种可能性 14新型阿片类药物偏见的激动剂在非人类素数中的影响。在这些研究中，我们将采用良好的 15和高度翻译的药理学方法比较处方阿片类药物的“平衡”激动剂， 16即，通过G蛋白和β-arrest蛋白路径（吗啡，羟考酮和芬太尼）信号，均具有“偏置” 17个激动剂PZM21和两种新型配体由NIDA IRP的同事提供，并基于In 18体外数据，也可以被描述为阿片类药物“偏置”激动剂。首先，不同阿片类药物的急性影响将 19使用抗伤害感受和操作性能，呼吸功能和 20虐待潜力。这些研究的数据将使我们能够严格地表征和比较 21“平衡”和“偏见”激动剂的有益和不必要的影响。接下来，将比较相同的药物 22在慢性治疗方案中。在这些研究中，对抗伤害感受和操作性能的测定将 23用于评估耐受性，该耐受性是由阿片类药物剂量效应函数向右或向下移动定义的， 24和呼吸功能和可观察的行为的测定，以评估阿片类药物依赖性的存在， 25证据是拮抗剂给药后通风或特征行为迹象的增加。这 26后一项研究的结果将提供有关“偏见”依赖性责任的关键信息 27激动剂在临床实践中可能以重复或慢性的基础进行。最后，意识到性 - 28在“平衡”激动剂的处方阿片类药物的作用上的相关差异，我们将进行研究 29在男性和女性受试者中，确定是否通过新颖的性别差异产生相似的性别差异 30 opioid'偏见的激动剂。