Novel antagonists as fentanyl overdose rescue therapies

作为芬太尼过量救援疗法的新型拮抗剂

基本信息

批准号：
10666669
负责人：
John R. Traynor
金额：
$ 72.9万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10666669
关键词：
Affinity Animals Binding Biological Brain Businesses Canis familiaris Cause of Death Cessation of life Chemicals Clinical Protocols Development Discrimination Documentation Dose Drug Kinetics Electronic Mail Ensure Fentanyl Funding GTP-Binding Proteins Goals Grant Heroin Hour Human In Vitro Individual Investigational New Drug Application Lead Length Life Literature Metabolism Microsomes Monkeys Mutagenesis Naloxone Narcotics National Institute of Drug Abuse Opioid Opioid Antagonist Opioid Receptor Opioid agonist Outcome Overdose Overdose reversal Oxycodone Pamphlets Patients Penetration Peripheral Pharmaceutical Preparations Phase Physiological Plasma Positron-Emission Tomography Preparation Press Releases Prevalence Property Rattus Reporting Research Research Personnel Resistance Respiratory Failure Resuscitation Risk Schedule Self Administration Signal Transduction Small Business Technology Transfer Research Street Drugs Toxic effect Training United States United States Food and Drug Administration Ventilatory Depression Wooden Chest Syndrome Work abuse liability analog antagonist antinociception beta-arrestin biodefense clinical candidate cost design effective therapy experimental study fentanyl analog fentanyl overdose fentanyl self-administration in vitro Assay in vivo innovation manufacture mu opioid receptors novel opioid mortality opioid overdose overdose death pharmacokinetic characteristic pharmacologic pre-IND studies prescription opioid prevent preventable death scale up sex standard of care

项目摘要

Abstract Opioid overdose deaths are the result of an on-target effect of compounds acting at the mu opioid receptor (MOR) causing severe respiratory depression. Fentanyl is a highly potent synthetic MOR agonist. Literature reports indicate the drastic rise in opioid-induced overdose deaths in the United States is due to the increased prevalence of fentanyl and its analogs (known as fentalogs) in street drugs. Indeed, more than 70% of opioid overdose deaths involve fentanyl or its analogs and a recent DEA press release stated that 2 in 5 counterfeit opioid medications contain a lethal dose of fentanyl. The current standard of care and the only medication currently available currently to treat opioid overdose is naloxone which was approved by the US Food and Drug Administration almost 50 years ago. However, reports suggest that fentalog-induced overdose is resistant to reversal by naloxone, which is not sufficiently potent, rapid, or long lasting with the result that overdose patients can re-narcoticize and are less likely to survive. In addition, there is evidence that successful resuscitation is further compromised because fentanyl produces unique physiological outcomes, for example wooden chest syndrome. Therefore, the is an urgent need for more effective therapies to reverse fentanyl-induced overdose. We propose the hypothesis that that an opioid antagonist that is developed from fentanyl and is therefore structurally related to fentanyl and binds in an analogous way to MOR, will reverse all aspects of opioid overdose caused by fentanyl and its illicit analogs. To this end we have identified fentanyl derivatives (R03 DA 048129 and R21 DA051723) that act as high affinity MOR antagonists both in vitro and in vivo. The objective of this proposal is to build on these initial leads to develop proprietary analogues, that have high affinity for MOR, and high antagonist potency together with favorable pharmacokinetic characteristics, i.e. rapid onset and with a length of action that prevents re-narcotization. Overall, this study could lead to the identification and development of an efficient reversal agent for fentanyl overdose.

抽象的阿片类药物过量死亡是作用于MU阿片受体的化合物的靶向作用的结果（MOR）导致严重的呼吸抑郁症。芬太尼是一种高度有效的合成剂激动剂。文学报告表明，美国阿片类药物诱发的过量死亡的急剧增加是由于增加芬太尼及其类似物（称为脾气暴躁）的患病率在街头毒品中。确实，超过70％的阿片类药物过量的死亡涉及芬太尼或其类似物，最近的DEA新闻稿指出，五分之一的伪造阿片类药物含有致命的芬太尼剂量。当前的护理标准和唯一的药物目前可用于治疗阿片类药物过量的纳洛酮目前可用于治疗阿片类药物过量大约50年前的行政管理。但是，报告表明，训练诱导的用药过量对纳洛酮的逆转，不足以有效，快速或持久，导致患者过量可以重新解释，并且不太可能生存。此外，有证据表明成功的复苏是由于芬太尼产生独特的生理结果，例如木箱综合征。因此，迫切需要更有效的疗法逆转芬太尼诱导的过量。我们提出了以下假设：从芬太尼发展的阿片类药物拮抗剂，因此是结构上与芬太尼相关并以类似方式与MOR结合，将逆转阿片类药物过量的所有方面由芬太尼及其非法类似物引起。为此，我们确定了芬太尼衍生物（R03 DA 048129 R21 DA051723）在体外和体内充当高亲和力的拮抗剂。这个目的提议是建立在这些初始线索的基础上，以发展对MOR和MOR具有很高亲和力的专有类似物，并且高拮抗剂的效力以及有利的药代动力学特征，即快速发作和动作长度可防止重新纳入。总体而言，这项研究可能导致识别和发展芬太尼过量的有效逆转剂。