Biased Kappa Opioid Agonists as Non-addictive Analgesics

偏性Kappa阿片类激动剂作为非成瘾性镇痛药。处方阿片类药物滥用增加 在过去十年中，药物滥用问题急剧增加，现在构成了世界上最大的药物滥用问题。 美国的这些滥用的药物是μ阿片类激动剂，疼痛治疗的替代品是 needed.κ阿片受体（KOR）激动剂在人类中是镇痛剂并且具有低滥用倾向，然而， 这些化合物的烦躁和镇静特性已经排除了它们的临床应用， 发展最近几个研究小组发现，镇痛特性是通过G- 蛋白质信号，而镇静和烦躁不安的影响是通过非G蛋白途径介导的，可能 β抑制蛋白2或ERK 1/2。有趣的是，几个研究组已经描述了KOR激动剂，其优先 激活G蛋白途径而不是β抑制蛋白或ERK 1/2途径，称为偏向性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， 其他典型KOR激动剂的烦躁不安作用。我们最近证明了一种这样的化合物 在小鼠和大鼠中产生抗伤害感受，而没有镇静和烦躁的证据。此外，该化合物 不干扰前脑多巴胺神经传递，被认为是 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倚的程度和性质。 因此，这种体外信号传导偏倚如何转化为体内药理学的改善尚不明显。 这些化合物已被探索为镇痛药，主要使用非临床相关的疼痛测定，如 如啮齿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 我们建议评估KOR激动剂的广泛的信号偏差，使用两种不同的 化学支架，并确定细胞内信号偏差之间的关系，在多个 在天然神经元组织（纹状体和背根神经节）中的通路，在体内对 多巴胺神经化学和产生抗伤害感受，镇静/烦躁不安，和滥用倾向使用 临床相关的炎性、术后和神经性疼痛的啮齿动物模型，以及药物自身 局此外，我们将评估性别在信号偏差有效性中的作用， 显示对KOR激动剂的镇痛作用更敏感，对烦躁不安的 方面的影响.我们希望在体外确定一个信号偏差的概况，转化为一个改进的 可用于进一步药物开发的KOR激动剂的体内药理学特征， 机械研究。

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.