Synthesis and Evaluation of Functionally Biased Opioid Analgesics

描述（由申请人提供）：阿片类镇痛药作用于人类的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不良影响的手段，如便秘、依赖和成瘾。受体激动剂的总体效力可能不仅取决于药物与受体的结合程度，还取决于受体与细胞内信号蛋白（如ßarrestin2）的结合程度。我们在过去十年的研究让我们假设，如果一种药物可以激活MOR而不诱导ßarrestin2与受体的相互作用，那么这种药物可能是一种有效的镇痛药，副作用有限，产生较少的耐受性，依赖性和便秘。基于我们对ßarrestin2调控MOR的广泛研究，我们认为理想的阿片类激动剂在招募ßarrestin2时几乎没有效果，而对G蛋白偶联或其他细胞信号通路具有完全功效。在本提案中，我们将从代表四种不同支架的小分子文库中对化合物进行药理学表征和优化。这些化合物是由托马斯·班尼斯特博士合成的，他是佛罗里达州斯克里普斯研究所经验丰富的药物化学家，曾在制药行业工作，在许多候选药物中，芬太尼为基础的镇痛药。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完全的功效（相对于脑啡肽类似物DAMGO）。值得注意的是，即使在有利于MOR- arstin2相互作用的条件下，大多数这些类似物也不招募ßarrestin2。在这项多学科研究中，Bohn药理学实验室将与Bannister药物化学实验室高度合作，在这4种支架上生成并优化多种衍生物（目的1）。我们将使用几种基于细胞的试验来表征这些化合物诱导的信号参数，目的是找到在信号级联中具有高效但不产生与MOR的ßarrestin2偶联的阿片类药物（目的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较少副作用的镇痛能力相关（目的3）。最后，我们将与佛罗里达州Scripps的Michael Cameron博士合作，评估我们的最佳候选化合物的DMPK特性。从该建议中获得的信息将证明对未来开发副作用有限的临床止痛药有用。

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.