Synthesis and Evaluation of Functionally Biased Opioid Analgesics

描述(申请人提供)：阿片类镇痛剂作用于人类的Mu阿片受体(MOR)以减轻疼痛。然而，这种受体也是这些药物产生诸如便秘、依赖和成瘾等不良影响的手段。受体激动剂的总体效力和效果不仅取决于药物与受体结合的程度，还取决于受体与细胞内信号蛋白的结合程度，如？arrestin2。我们在过去十年中的研究使我们假设，如果一种药物可以激活MOR而不能诱导与受体相互作用，那么这种药物可能是一种副作用有限的有效止痛剂，产生较少的耐受性、依赖性和便秘。基于我们对？arrestin调节MOR的广泛研究，我们认为，理想的阿片类激动剂在招募？arrestin2方面几乎没有效果，而对G蛋白偶联或其他细胞信号通路则完全有效。在这项提案中，我们将从代表四个不同支架的小分子库中对化合物进行药理学表征和优化。这些化合物是由佛罗里达州斯克里普斯公司经验丰富的药物化学家托马斯·班尼斯特博士合成的，他之前曾在制药行业工作，生产过许多候选药物，其中包括基于芬太尼的止痛药。我们的初步数据显示，我们的激动剂在G蛋白偶联、ERK激活和细胞阻抗分析中具有部分或全部疗效(相对于脑啡肽类似物DAMGO)。值得注意的是，这些类似物中的大多数甚至在有利于莫尔-阿雷斯汀相互作用的条件下也不会招募。在这项多学科研究中，博恩药理实验室将以高度合作的方式与班尼斯特药物化学实验室合作，在这4种支架上产生和优化多种衍生物(目标1)。我们将使用几种基于细胞的分析来表征这些化合物诱导的信号参数，目的是寻找在信号级联中具有高效率但不会产生与MOR偶联的阻止蛋白2的阿片类药物(目标2)。这些化合物将在小鼠模型中进行测试，以确定它们的信号特性是否与它们产生副作用较少的止痛能力相关(目标3)。最后，我们将与佛罗里达州斯克里普斯的迈克尔·卡梅隆博士合作，评估我们最好的候选化合物的DMPK性质。从这项建议中获得的信息将被证明对副作用有限的临床止痛药的未来发展有用。

DESCRIPTION (provided by applicant): Opiate analgesics act at the mu opioid receptor (MOR) in humans to alleviate pain. However, this receptor is also the means by which these drugs produce unwanted effects such as constipation, dependence and addiction. The overall potency and efficacy of an agonist at the receptor may be determined not only by how well the drug binds the receptor but also by how well the receptor engages with intracellular signaling proteins, such as ßarrestin2. Our studies over the last decade have led us to hypothesize that if a drug could activate the MOR yet not induce ßarrestin2 interactions with the receptor, then such a drug might be an efficacious analgesic with limited side effects, producing less tolerance, dependence and constipation. Based on our extensive studies of ßarrestin regulation of MOR, we believe that the ideal opioid agonist would have little to no efficacy for recruiting ßarrestin2 while having full efficacy for G protein coupling or other cellular signaling pathways. In this proposal, we will pharmacologically characterize and optimize compounds from a small molecule library representing four distinct scaffolds. These compounds have been synthesized by Dr. Thomas Bannister, an experienced medicinal chemist at Scripps Florida who has previously worked in the pharmaceutical industry generating, among many drug candidates, analgesics based on fentanyl. Our preliminary data shows that we have agonists that possess partial to full efficacy (relative to the enkephalin analog, DAMGO) in G protein coupling, ERK activation, and cellular impedance assays. Remarkably, most of these analogs do not recruit ßarrestin2, even under conditions that favor MOR-ßarrestin interactions. In this multidisciplinary study, the Bohn pharmacology laboratory will work in a highly collaborative manner with the Bannister medicinal chemistry laboratory to generate and optimize multiple derivatives on these 4 scaffolds (Aim 1). We will use several cell-based assays to characterize the signaling parameters induced by these compounds with the goal of finding opiates that possess high efficacy in signaling cascades yet produce no ßarrestin2 coupling to MOR (Aim 2). Such compounds will be tested in mouse models to determine if their signaling properties correlate with their ability to produce analgesia with fewer side effects (Aim 3). Finally, in collaboration with Dr. Michael Cameron of Scripps Florida, we will evaluate the DMPK properties of our best candidate compounds. The information garnered from this proposal will prove useful in the future development of clinical pain relievers with limited side effects.