In vivo characterization of opioid biased agonists

阿片类偏向激动剂的体内表征

• 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
• 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

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-项目概要/摘要 1持续的阿片类药物危机导致对成瘾性阿片类药物临床处方的重新关注 2种镇痛药。然而，目前没有合适的替代品来治疗严重或恶性疼痛。研究 β-arrestin 2基因缺失小鼠的阿片信号转导机制表明， 4的吗啡在这些小鼠中增强，随后的研究报告说， 5吗啡，包括呼吸抑制，便秘和镇痛耐受性都减少， 6缺乏β-抑制蛋白信号传导。这些发现导致开发新型阿片类药物的努力增加 7，基于它们在体外相对于β-抑制蛋白信号传导优先激活G蛋白信号传导， 8被表征为“偏向性”激动剂。然而，尽管在受体激活的信号传导中有明显的区别， 在体外发现了9种阿片样物质配体，这些细胞差异在多大程度上预测了阿片样物质的不同特征。 10在体内的活性仍然不确定。目前，还没有足够的信息来断定是否存在偏见， 11信号传导确实可以与减少阿片类药物的副作用相关，因此，提高了安全性 12与常规处方阿片类药物相比，“偏向性”激动剂的特征。本申请旨在 13解决了临床前数据的需要，以严格评估这种可能性，并进行了体内研究， 非人灵长类动物中新型阿片类偏向性激动剂的14种效应。在这些研究中，我们将采用成熟的 15和高度转化的药理学方法，以比较作为“平衡”激动剂的处方阿片类药物， 16即，通过G蛋白和β-抑制蛋白途径（吗啡、羟考酮和芬太尼）的信号， 17激动剂PZM 21和两种新的配体，由NIDA IRP的同事提供， 18个体外数据，也可表征为阿片类“偏向性”激动剂。首先，不同阿片类药物的急性影响将 使用经过充分验证的抗伤害感受和操作性能、呼吸功能和 20个潜在的滥用。来自这些研究的数据将使我们能够严格表征和比较 21有益的和不必要的影响的“平衡”和“偏向”激动剂。接下来，将比较相同的药物 22在慢性治疗方案期间。在这些研究中，抗伤害感受和操作性能的测定将 23可用于评价耐受性，其定义为阿片剂量-效应函数的下降或向下移动， 24和呼吸功能和可观察行为的测定以评估阿片样物质依赖的存在， 拮抗剂给药后通气或特征性行为体征增加。的 26后一项研究的结果将提供关于“有偏见”的依赖性责任的关键信息。 27激动剂，在临床实践中，可能会在重复或慢性的基础上给予。最后，认识到性- 28处方阿片类药物的效果相关差异是“平衡”激动剂，我们将进行研究 29在男性和女性受试者，以确定是否类似的性别相关的差异产生的新的 30阿片类“偏向性”激动剂。