Synthesis and Evaluation of Functionally Biased Opioid Analgesics

描述（由申请方提供）：阿片类镇痛药作用于人体μ阿片受体（莫尔），以缓解疼痛。然而，这种受体也是这些药物产生便秘、依赖和成瘾等不良影响的手段。激动剂对受体的总体效力和功效不仅可以通过药物与受体结合的程度来确定，还可以通过受体与细胞内信号传导蛋白如β抑制蛋白2结合的程度来确定。我们在过去十年的研究使我们假设，如果一种药物可以激活莫尔，但不诱导β抑制蛋白2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，产生更少的耐受性，依赖性和便秘。基于我们对莫尔的β抑制蛋白调节的广泛研究，我们认为理想的阿片激动剂对募集β抑制蛋白2几乎没有功效，而对G蛋白偶联或其他细胞信号传导途径具有完全功效。在这个提议中，我们将从一个代表四种不同支架的小分子库中重新表征和优化化合物。这些化合物是由托马斯班尼斯特博士合成的，班尼斯特是佛罗里达斯克里普斯的一位经验丰富的药物化学家，他以前曾在制药行业工作，在许多候选药物中产生基于芬太尼的镇痛剂。我们的初步数据显示，我们有激动剂，具有部分到全部的效力（相对于脑啡肽类似物，DAMGO）在G蛋白偶联，ERK激活，和细胞阻抗测定。值得注意的是，即使在有利于莫尔-β抑制蛋白相互作用的条件下，这些类似物中的大多数也不募集β抑制蛋白2。在这项多学科研究中，Bohn药理学实验室将与班尼斯特药物化学实验室高度合作，在这4种支架上生成和优化多种衍生物（目标1）。我们将使用几种基于细胞的测定来表征由这些化合物诱导的信号传导参数，目的是找到在信号传导级联中具有高功效但不产生β抑制蛋白2与莫尔偶联的阿片类药物（目的2）。这些化合物将在小鼠模型中进行测试，以确定它们的信号传导特性是否与它们产生具有较少副作用的镇痛作用的能力相关（目标3）。最后，与佛罗里达斯克里普斯的迈克尔卡梅隆博士合作，我们将评估我们最好的候选化合物的DMPK特性。从这一建议中获得的信息将被证明是有用的，在未来的发展，临床止痛药有限的副作用。

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.