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.

偏见的卡帕阿片类动力学家是非添加性镇痛药。处方阿片类药物滥用有所增加在过去的十年中，龙是龙的，现在建立了最大的成长毒品滥用问题美国。这些被滥用的药物是mu oopioid激动剂，疼痛治疗的替代方法是需要。 Kappa阿片类药物受体（Kor）激动剂在人类中是镇痛药，但虐待责任低，但是这些化合物的烦躁和镇静特性排除了其临床实用性和发展。最近，几个小组发现镇痛性特性是通过g-介导的蛋白质信号传导，而镇静和烦躁的作用是通过非G蛋白途径介导的 ßarrestin2或erk1/2。有趣的是，几个小组描述了优先通过βArrestin或ERK1/2途径激活G蛋白途径，称为有偏的Kor激动剂。这些化合物是候选人，是无添加性镇痛药，这些镇痛药将缺乏镇静剂和其他典型的Kor激动剂的烦躁不安。我们最近证明了一种这样的化合物在没有镇静和烦躁不安的迹象的小鼠和大鼠中产生抗伤害感受。此外，这种化合物不会干扰前脑多巴胺神经传递典型的Kor激动剂。使用基于细胞的测定法，在体外确定信号传导偏置的程度和性质。因此，在体外中这种信号传导偏见如何转化为体内的药理学的改善，这并不容易显而易见。这些化合物主要使用非链式相关的疼痛测定法探索为镇痛药，例如作为啮齿动物中的尾部轻弹或热板测试，这些测定通常不能预测临床效率。在这个我们建议使用两个不同化学脚手架，并确定多个的细胞内信号传导偏置之间的关系天然神经元组织（纹状体和背根神经节）中的途径，体内效率不足多巴胺神经化学和抗伤害感受，镇静/烦躁不安以及滥用责任临床相关的炎症，术后和神经性疼痛以及药物自我的啮齿动物模型行政。此外，我们将评估性别在信号偏见效率中的作用，因为女性已经是显示对Kor激动剂的镇痛作用更敏感，对烦躁不安的敏感效果。我们希望确定体外信号传导偏见的轮廓，该偏见转化为改进的可用于进一步的药物开发和机械研究。