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：
10524159
负责人：
John R. Traynor
金额：
$ 73.55万
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/10524159
关键词：
Affinity Animals Back Binding Biological Brain Businesses Canis familiaris Cause of Death Cessation of life Chemicals Chest Clinical Protocols Development Discrimination Documentation Dose Drug Kinetics Electronic Mail Ensure Eye Fentanyl Funding GTP-Binding Proteins Goals Grant Heroin Hour Human In Vitro Individual Investigational New Drug Application Lead Length Life Literature Metabolism Monkeys Mutagenesis Naloxone Narcotics National Institute of Drug Abuse Opioid Opioid Antagonist Opioid agonist Outcome Overdose Overdose reversal Oxycodone Pamphlets Patients Penetration Peripheral Pharmaceutical Preparations Pharmacology 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 Syndrome Toxic effect Training United States United States Food and Drug Administration Ventilatory Depression Work abuse liability analog antagonist base beta-arrestin biodefense clinical candidate cost design effective therapy experimental study fentanyl overdose in vitro Assay in vivo innovation mu opioid receptors novel opioid mortality opioid overdose overdose death pharmacokinetic characteristic 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 阿片类受体的化合物的靶向作用的结果（MOR）导致严重的呼吸抑制。芬太尼是一种高效的合成 MOR 激动剂。文学报告表明，美国阿片类药物过量导致的死亡人数急剧上升是由于街头毒品中芬太尼及其类似物（称为芬他洛类）的流行。事实上，超过 70% 的阿片类药物过量死亡涉及芬太尼或其类似物，美国缉毒局 (DEA) 最近的一份新闻稿称，五分之二的假药阿片类药物含有致死剂量的芬太尼。目前的护理标准和唯一的药物治疗目前可用于治疗阿片类药物过量的是纳洛酮，已获得美国食品和药物管理局批准大约50年前的政府。然而，报告表明芬他洛引起的过量服用对纳洛酮的逆转作用不够有效、快速或持久，导致服用过量的患者可以重新麻醉并且生存的可能性较小。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，进一步受到损害综合症。因此，迫切需要更有效的疗法来逆转芬太尼引起的过量用药。我们提出这样的假设：阿片类拮抗剂是由芬太尼开发的，因此是结构上与芬太尼相关，并以与 MOR 类似的方式结合，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 和 R21 DA051723），在体外和体内均充当高亲和力 MOR 拮抗剂。此举的目的建议在这些初步线索的基础上开发专有的类似物，这些类似物对 MOR 具有高亲和力，并且高拮抗剂效力以及良好的药代动力学特征，即起效快且作用持久防止再次麻醉的作用时间长度。总的来说，这项研究可能导致识别和开发芬太尼过量的有效逆转剂。