Examining Novel Fentalogs: Pharmacological Characteristics and Reversibility

检查新型 Fentalogs：药理学特征和可逆性

基本信息

批准号：
9901497
负责人：
Jessica Priya Anand
金额：
$ 7.8万
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：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2021-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9901497
关键词：
Affinity Agonist Binding Binding Proteins Biological Assay Cessation of life Characteristics Clinic Collaborations Communities Cyclic AMP Data Dose Fentanyl Forensic Medicine GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Goals Guidelines Healthcare Hydrocodone In Vitro Law Enforcement Light Literature Maintenance Therapy Mediating Morphine Naloxone Names Narcan Opioid Opioid Analgesics Opioid Antagonist Opioid Receptor Opioid agonist Overdose Pain Patients Pharmaceutical Preparations Pharmacology Play Productivity Property Radioactive Reporting Resuscitation Role Sampling Seizures Specialist Street Drugs Structure-Activity Relationship Testing Time United States Vehicle crash Ventilatory Depression Work addiction analog automobile accident cost delta opioid receptor design in vitro Model in vivo insight kappa opioid receptors mu opioid receptors novel opioid epidemic opioid mortality opioid overdose overdose death prevent preventable death protein degradation receptor receptor function scaffold standard care

项目摘要

Opioid analgesics, such as morphine and hydrocodone, are widely used for the treatment of moderate to severe pain but are also widely misused and abused. Opioid-related overdoses account for almost half of all drug overdose deaths in the United States and cause more preventable deaths every year than car crashes. Fentanyl, a highly potent mu opioid receptor (MOR) agonist, and its analogues (fentalogs) are increasingly found in drug samples from search and seizure by law enforcement and are thought to contribute to the drastic increase in opioid-induced overdose deaths since 2016. In fact, the number of deaths and drug seizures involving fentalogs is likely an underestimate, as the rapid rate at which new fentalogs are synthesized makes it difficult for law enforcement and forensic specialists to keep up. As many of these compounds are novel analogs, very little is known about their basic pharmacology in terms of receptor affinity or activity at the opioid receptors. The objective of this proposal is to evaluate novel fentalogs, many of which have been identified in illicit samples, in terms of binding affinity and receptor function at the three classical opioid receptors: MOR, the delta opioid receptor (DOR), and the kappa opioid receptor (KOR). This will be accomplished using standard competitive radioactive ligand binding and G protein turnover assays. The ability of a standard rescue therapy, naloxone (trade name Evzio or Narcan), to reverse the agonist activity of the most potent and efficacious fentalogs will also be examined; real time cAMP accumulation will be used to determine agonist function and reversal by antagonists, such as naloxone. The overarching hypothesis is that many of these novel fentalogs are more potent and efficacious than traditional opioid agonists and that standard treatments for opioid overdose may be insufficient when fentalogs are involved. Overall, this project will characterize the in vitro pharmacological properties of novel fentalogs found in street drugs and has the potential to inform best practices for preventing opioid overdose and related deaths.

阿片类镇痛药，例如吗啡和氢可酮，被广泛用于治疗中度至重度疼痛，但也被广泛滥用和滥用。阿片类药物有关过量占美国药物过量死亡的几乎一半每年造成可预防的死亡，而不是汽车撞车。芬太尼，高度有效 MU阿片受体（MOR）激动剂及其类似物（Fenalyogs）越来越多地发现在执法部门搜查和扣押中的毒品样本中，被认为是自2016年以来，阿片类药物诱发的过量死亡的急剧增加。涉及脾气病毒的死亡和毒品癫痫发作的数量可能是低估的，因为合成新的疾病的快速速度使法律困难执法和法医专家跟上。这些化合物中的许多都是新颖的类似物，关于受体亲和力的基本药理学知之甚少或在阿片受体上的活性。该提议的目的是评估小说在具有约束力的亲和力方面和受体功能在三个经典阿片类药物受体上：MOR，三角洲阿片类药物受体（DOR）和Kappa阿片受体（Kor）。这将使用标准的竞争放射性配体结合和G蛋白周转测定。能力标准救援疗法Naloxone（商品名EVZIO或NARCAN），以扭转还将检查最有效和有效的疾病的激动剂活动；真实的时间训练营的积累将用于确定激动剂功能和逆转拮抗剂，例如纳洛酮。总体假设是这些小说中的许多与传统的阿片类药物激动剂相比当涉及疾病时，阿片类药物过量的标准治疗可能不足。总体而言，该项目将表征新颖的体外药理特性在街头毒品中发现的疾病，并有可能为最佳实践提供信息防止阿片类药物过量和相关死亡。