Synthesis and Evaluation of Functionally Biased Opioid Analgesics

阿片类镇痛剂作用于人类的MU阿片受体(MOR)，不仅可以减轻疼痛，还可以产生 便秘、呼吸抑制/过量用药和上瘾等不良影响。整体实力 受体激动剂的疗效不仅取决于药物与受体的结合程度 但也取决于受体与细胞内信号蛋白的结合情况，如Barrest in2。我们的研究 使我们假设，如果一种药物可以激活MOR而不能诱导Barretin 2 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、便秘和过量用药的可能性。在过去的5年里，我们产生了更多 超过50种新的MOR激动剂，它们以高度偏见的方式激活G蛋白信号通路，从而 他们不会招募巴雷斯汀。使用这些化合物，我们检验了我们的假设，并发现 这是一种将体内止痛效果与呼吸抑制相分离的方法。我们 已经确定了主要候选者，并申请了这一系列化合物的专利保护，并正在 目前正在进行临床开发。虽然某些生理副作用是有限的，但没有 到目前为止，有迹象表明这些化合物不会产生奖励或被滥用。在目前的提案中， 我们正在寻求测试它们是否促进药物偏好，并进一步提炼候选化合物和 此外，在额外的受体目标上引入亲和力作为一种手段，将滥用威慑引入 化合物。在我们最初的靶向选择性筛查中，我们注意到D3多巴胺受体在 没有进一步研究的系列(因为我们关注的是MOR的选择性)。然而，鉴于D3多巴胺 受体在维持多巴胺稳态方面起着重要作用，可以极大地影响药物奖赏 门槛，并已被NIDA确定为药物滥用威慑目标，我们将重点优化 D3拮抗，同时在该化合物系列中保持偏向的MOR激动剂。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品 化学实验室生成和优化化合物系列的多种衍生物(目标1)。我们会 使用几种基于细胞的分析方法来表征这些化合物诱导的信号参数 寻找在MOR中维持G蛋白而不是Barrestin信号偏向但也显示D3DAR的阿片类药物的目标 对抗性(目标2)。这些化合物将在小鼠模型中进行测试，以确定它们的信号转导 特性与它们产生止痛的能力相关，呼吸抑制较少，而且如果 避免多巴胺能行为，如运动活动和条件性位置偏爱(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DMPK的属性 我们最好的候选化合物。从这项建议中获得的信息将被证明在临床上是有用的 开发副作用有限的止痛药。

Opiate analgesics act at the mu opioid receptor (MOR) in humans to alleviate pain but also to produce unwanted effects such as constipation, respiratory suppression/overdose 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 barrestin2. Our studies over the last decade have led us to hypothesize that if a drug could activate the MOR yet not induce barrestin2 interactions with the receptor, then such a drug might be an efficacious analgesic with limited side effects, producing less tolerance, constipation and overdose potential. In the last 5 years, we have generated more than 50 new MOR agonists that activate G protein signaling pathways in a highly biased manner, such that they do not recruit barrestins. Using these compounds, we have tested our hypothesis and have found that this is approach will allow for the separation of analgesic efficacy in vivo from respiratory suppression. We have identified lead candidates and have filed for patent protection of this series of compounds and are currently pursuing clinical development. While certain physiological side effects have been limited, there is no indication thus far that the compounds will not produce reward or be subject to abuse. In this current proposal, we are seeking to test whether they promote drug preference and to further refine candidate compounds and also to introduce affinity at an additional receptor target as a means to introduce abuse deterrence into the compounds. In our initial screens for target selectivity, we noted some affinity for D3 dopamine receptors in a series that was not further pursued (as we focused on MOR selectivity). However, given that D3 dopamine receptors play an important role in maintaining dopamine homeostasis, can greatly impact drug reward thresholds, and have been identified as a drug abuse deterrence target by NIDA, we will focus on optimizing D3 antagonism while maintaining biased MOR agonism in this compound series. 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 the compound series (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 maintain G protein over barrestin signaling bias at MOR yet also display D3 DAR antagonism (Aim 2). These compounds will be tested in mouse models to determine if their signaling properties correlate with their ability to produce analgesia with less respiratory suppression and also if dopaminergic behaviors, such as locomotor activity and conditioned place preference are avoided (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 clinical development of pain relievers with limited side effects.