Synthesis and Evaluation of Functionally Biased Opioid Analgesics

功能性阿片类镇痛药的合成与评价

基本信息

批准号：
8422991
负责人：
Thomas D Bannister
金额：
$ 61.39万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-15 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8422991
关键词：
Absence of pain sensation Adverse effects Affinity Agonist Analgesics Animal Model Area Arrestins Attenuated Binding Biological Assay Biological Availability Brain Cells Chemicals Chronic Clinical Collaborations Complex Constipation Coupling Data Dependence Development Drug Exposure Drug Industry Drug Kinetics Enkephalin, Ala(2)-MePhe(4)-Gly(5)-Enkephalins Evaluation Event Family Fentanyl Florida Future G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins Genetic Goals Human Hydrogen Bonding Hydrophobicity In Vitro Indium Intracellular Signaling Proteins Knockout Mice Laboratories Lead Ligands MAPK3 gene Marketing Measurement Mediating Metabolism Methadone Molecular Molecular Weight Morphine Mus Narcotics Opiates Opioid Opioid Analgesics Oxycodone Pain Pain management Penetration Percocet Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Physical Dependence Process Property Proteins Receptor Activation Receptor Signaling Recruitment Activity Regulation Relative (related person)Route Series Signal Pathway Signal Transduction Structure Surface System Testing Therapeutic Uses Ventilatory Depression Vicodin Withdrawal Work addiction analog base central pain clinically relevant combinatorial drug candidate drug discovery electric impedance experience improved in vivo innovation meetings mouse model mu opioid receptors multidisciplinary novel prevent radioligand receptor receptor binding respiratory response scaffold small molecule small molecule libraries

项目摘要

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 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, dependence and constipation. Based on our extensive studies of barrestin regulation of MOR, we believe that the ideal opioid agonist would have little to no efficacy for recruiting barrestin2 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 barrestin2, even under conditions that favor MOR-barrestin 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 barrestin2 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.

描述（由申请人提供）：在人类中的MU阿片受体（MOR）中的阿片类镇痛药，以减轻疼痛。但是，这种受体也是这些药物产生不必要的作用（例如便秘，依赖性和成瘾）的手段。激动剂在受体处的总体效力和疗效不仅可以取决于药物结合受体的能力，还取决于受体与细胞内信号蛋白（例如barrestin2）的接合程度。在过去的十年中，我们的研究使我们假设，如果药物可以激活MOR但不诱导与受体的barreten2相互作用，那么这种药物可能是一种有效的镇痛药，具有有限的副作用，耐受性，依赖性和便秘产生较小的副作用。基于我们对MOR的Barrestin调节的广泛研究，我们认为理想的阿片类药物激动剂对募集Barrestin2的疗效几乎没有疗效，同时对G蛋白偶联或其他细胞信号传导途径具有完全疗效。在此提案中，我们将在药理学上表征和优化来自代表四个不同脚手架的小分子库的化合物。这些化合物是由佛罗里达州斯克里普斯（Scripps Florida）的一位经验丰富的药物师托马斯·班尼斯特（Thomas Bannister）合成的，以前曾在制药行业工作，在许多候选药物中，基于芬太尼的镇痛药。我们的初步数据表明，我们的激动剂在G蛋白偶联，ERK激活和细胞阻抗测定中具有完全符合完全疗效（相对于Enkephalin类似物，DAMGO）的激动剂。值得注意的是，即使在有利于MOR-Barrestin相互作用的条件下，这些类似物中的大多数也不会募集Barrestin2。在这项多学科研究中，Bohn药理学实验室将与Bannister Medicinal Chemistry Laboratory高度合作地工作，以在这4个脚手架上生成和优化多个衍生物（AIM 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，目的是找到具有高效率在信号级联反应中但没有产生与MOR的barrestin2耦合的阿片类药物（AIM 2）。此类化合物将在小鼠模型中进行测试，以确定其信号传导特性是否与它们产生镇痛的能力相关（AIM 3）。最后，与佛罗里达州斯克里普斯的迈克尔·卡梅伦（Michael Cameron）博士合作，我们将评估最佳候选化合物的DMPK属性。从该提案中获得的信息将证明对临床止痛药的未来开发具有有限的副作用。