Synthesis and Evaluation of Functionally Biased Opioid Analgesics

功能性阿片类镇痛药的合成与评价

• 批准号: 10596353
• 负责人: Thomas D Bannister
• 金额: $ 21.3万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10596353
• 关键词: Synthesis; Evaluation; Functionally; Biased; Opioid

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.

阿片类镇痛剂作用于人类的μ阿片受体（莫尔）以减轻疼痛，但也产生 不良反应，如便秘、呼吸抑制/过量和成瘾。整体效能 激动剂对受体的效力不仅取决于药物结合受体的程度 还取决于受体与细胞内信号蛋白如barrestin 2的结合程度。我们的研究 在过去的十年中，这些研究使我们假设，如果一种药物可以激活莫尔而不诱导barrestin 2 与受体的相互作用，那么这种药物可能是一种副作用有限的有效镇痛药， 产生更少的耐受性、便秘和过量的可能性。在过去的5年里，我们创造了更多的 超过50种新的莫尔激动剂，以高度偏向的方式激活G蛋白信号通路， 他们不招募Barrestins。使用这些化合物，我们已经测试了我们的假设，并发现， 该方法将允许将体内镇痛功效与呼吸抑制分离。我们 已经确定了这一系列化合物的主要候选物，并已申请专利保护， 目前正在进行临床开发。虽然某些生理副作用有限，但没有 迄今为止的迹象表明，这些化合物不会产生奖励或被滥用。在目前的提案中， 我们正在试图测试它们是否会促进药物偏好，并进一步完善候选化合物， 还可以在另外的受体靶点上引入亲和力，作为将滥用威慑引入所述受体的手段。 化合物.在我们对靶点选择性的初步筛选中，我们注意到D3多巴胺受体在一个细胞中具有一定的亲和力。 没有进一步追求的系列（因为我们专注于莫尔选择性）。然而，考虑到D3多巴胺 受体在维持多巴胺稳态中起重要作用，可极大地影响药物奖赏 阈值，并已被确定为药物滥用威慑目标由NIDA，我们将专注于优化 D3拮抗作用，同时维持该化合物系列中偏向的莫尔激动作用。在这项多学科研究中， 博恩药理学实验室将与班尼斯特医药公司以高度合作的方式开展工作 化学实验室生成和优化化合物系列的多种衍生物（目标1）。我们将 使用几种基于细胞的测定来表征这些化合物诱导的信号传导参数， 目标是找到在莫尔下维持G蛋白超过barrestin信号传导偏好，但也显示D3 DAR的阿片类药物 拮抗作用（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是否 这些性质与它们产生镇痛的能力相关，同时呼吸抑制较少， 避免多巴胺能行为，如自发活动和条件性位置偏爱（目的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DMPK的性质， 最佳候选化合物从该提案中获得的信息将证明在临床上有用 开发副作用有限的止痛药。