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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.

摘要