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Biased Kappa Opioid Agonists as Non-addictive Analgesics

偏向 Kappa 阿片受体激动剂作为非成瘾性镇痛药

基本信息

批准号：
10348175
负责人：
SARA RAULERSON JONES
金额：
$ 73.46万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
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：
2019-04-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10348175
关键词：
Acute Acute Pain Address Adverse effects Affect Agonist Analgesics Animals Behavioral Biochemical Biological Assay Brain Cells Chemicals Chronic Clinical Corpus striatum structure Cyclic AMP Development Dopamine Female GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Gender Human In Vitro Knockout Mice Lead Light MAPK3 gene Measures Mediating Microdialysis Modeling Molecular Morphine Mus Narcotics Nature Neurons Nucleus Accumbens Opiate Addiction Opioid Opioid Receptor Opioid agonist Overdose Pain Pain Measurement Pain management Pathway interactions Periodicity Pharmaceutical Preparations Pharmacology Phase Phosphotransferases Postoperative Pain Production Property Prosencephalon Psychological reinforcement Rattus Receptor Signaling Regulation Rodent Rodent Model Role Scanning Sedation procedure Self Administration Self Stimulation Sex Differences Signal Pathway Signal Transduction Signaling Protein Slice Spinal Ganglia Substance abuse problem Tail Testing Therapeutic Tissues Translating Triazoles United States Work abuse liability addiction base chronic pain clinical efficacy clinical predictors clinically relevant comparative efficacy design drug development dysphoria heroin use improved in vivo inflammatory pain kappa opioid receptors male mu opioid receptors neurochemistry neurotransmission non-opioid analgesic opioid epidemic opioid user overdose death pain relief painful neuropathy prescription opioid abuse preservation receptor function receptor internalization recruit scaffold sedative side effect therapeutic development therapy outcome tool

项目摘要

Biased Kappa Opioid Agonists as Non-addictive Analgesics. Prescription opioid abuse has increased dramatically over the last decade and now comprises the largest growing substance abuse problem in the United States. These abused medications are mu opioid agonists, and alternatives for pain treatment are needed. Kappa opioid receptor (KOR) agonists are analgesic in humans and have low abuse liability, however the dysphoric and sedating properties of these compounds have precluded their clinical utility and development. Recently several groups have discovered that the analgesic properties are mediated through G- protein signaling, while the sedating and dysphoric effects are mediated through non-G-protein pathways, likely either ßarrestin2 or ERK1/2. Interestingly, several groups have described KOR agonists that preferentially activate G-protein pathways over ßarrestin or ERK1/2 pathways, termed biased KOR agonists. These compounds are promising candidates as non-addictive analgesics that will be devoid of the sedating and dysphoric effects of other typical KOR agonists. We have recently demonstrated that one such compound produces antinociception in mice and rats without evidence of sedation and dysphoria. Further this compound does not interfere with forebrain dopamine neurotransmission, thought to underlie the untoward effects of typical KOR agonists. The extent and nature of signaling bias is determined in vitro, using cell-based assays. As such, it is not readily apparent how this signaling bias in vitro translates into improved pharmacology in vivo. These compounds have been explored as analgesics primarily using non-clinically relevant pain assays, such as tail flick or hot plate tests in rodents, and these assays do not generally predict clinical efficacy. In this application we propose to assess a wide profile of signaling bias for KOR agonists developed using two distinct chemical scaffolds, and to determine the relationship between intracellular signaling bias across multiple pathways in native neuronal tissue (striatum and dorsal root ganglia) with in vivo efficacy in dysregulation of dopamine neurochemistry and production of antinociception, sedation/dysphoria, and abuse liability using clinically relevant rodent models of inflammatory, post-operative, and neuropathic pain, and drug self- administration. Additionally we will assess the role of gender in signaling bias efficacy, as females have been shown to be more sensitive to the analgesic effects of KOR agonists and less sensitive to the dysphoric effects. We hope to determine a profile of signaling bias in vitro that translates into an improved pharmacological profile for KOR agonists in vivo that can be used for further drug development and mechanistic studies.

偏向 Kappa 阿片受体激动剂作为非成瘾性镇痛药。处方阿片类药物滥用有所增加过去十年来，这一问题急剧恶化，目前已成为全球范围内最严重、日益严重的药物滥用问题美国。这些滥用的药物是 mu 阿片类激动剂，疼痛治疗的替代药物是需要。然而，Kappa 阿片受体 (KOR) 激动剂对人类具有镇痛作用，且滥用可能性较低这些化合物的烦躁和镇静特性妨碍了它们的临床应用和发展。最近，几个研究小组发现镇痛特性是通过 G- 介导的蛋白质信号传导，而镇静和烦躁的作用可能是通过非 G 蛋白途径介导的 ßarrestin2 或 ERK1/2。有趣的是，几个研究小组已经描述了 KOR 激动剂，它们优先通过 ßarrestin 或 ERK1/2 途径激活 G 蛋白途径，称为偏向 KOR 激动剂。这些化合物是作为非成瘾性镇痛药的有希望的候选者，其没有镇静作用和其他典型 KOR 激动剂的烦躁效应。我们最近证明了一种这样的化合物对小鼠和大鼠产生镇痛作用，但没有镇静和烦躁的证据。进一步该化合物不会干扰前脑多巴胺神经传递，被认为是不良影响的基础典型的 KOR 激动剂。信号偏差的程度和性质是使用基于细胞的测定在体外确定的。因此，这种体外信号偏向如何转化为体内药理学的改善尚不清楚。这些化合物已被探索作为止痛药，主要使用非临床相关的疼痛测定，例如例如啮齿类动物的甩尾或热板试验，这些试验通常不能预测临床疗效。在这个我们建议评估使用两种不同的方法开发的 KOR 激动剂的广泛信号偏差化学支架，并确定多个细胞内信号传导偏差之间的关系天然神经元组织（纹状体和背根神经节）中的通路，具有体内调节失调的功效多巴胺神经化学和抗伤害、镇静/烦躁和滥用倾向的产生临床相关的炎症、术后和神经性疼痛的啮齿动物模型，以及药物自身行政。此外，我们将评估性别在信号偏差功效中的作用，因为女性已经显示对 KOR 激动剂的镇痛作用更敏感，而对烦躁不安的镇痛作用不太敏感影响。我们希望确定体外信号偏差的概况，从而转化为改进的方法 KOR 激动剂的体内药理学特征，可用于进一步的药物开发和机理研究。