Development of Long Lasting Stable Fentanyl Antagonist to Reverse Opioid Overdose

开发长效稳定芬太尼拮抗剂以逆转阿片类药物过量

基本信息

批准号：
10197869
负责人：
Jessica Priya Anand
金额：
$ 19.5万
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：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197869
关键词：
Adverse effects Affinity Aftercare Agonist Analgesics Animal Model Binding Binding Proteins Biological Assay Blood Brain Cessation of life Clinic Data Development Dose Drug Kinetics Evaluation Fentanyl GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Goals Half-Life Healthcare Heroin Illicit Drugs In Vitro Lead Literature Maintenance Therapy Metabolic Metabolism Morphine Naloxone Opioid Opioid Antagonist Opioid Receptor Opioid agonist Overdose Pain Patients Penetration Pharmaceutical Preparations Pharmacodynamics Pharmacology Plasma Prevalence Productivity Property Reporting Respiration Resuscitation Rodent Sampling Structure Structure-Activity Relationship Testing United States Vehicle crash Ventilatory Depression Work absorption addiction analog base beta-arrestin blood-brain barrier penetration cost design drug market drug of abuse fentanyl overdose high risk improved in vivo in vivo evaluation mu opioid receptors novel opioid mortality opioid overdose opioid therapy overdose death pharmacokinetics and pharmacodynamics predictive modeling prescription opioid preventable death protein B recruit response scaffold standard of care

项目摘要

Project Abstract 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 analogs (fentalogs) are increasingly found cut into illicit drug samples, both where the primary drug of abuse is an opioid and in cases where it is not. The prevalence of fentalogs in the illicit drug market is thought to be the primary driver of increased opioid-related overdose deaths since 2016. The standard opioid overdose rescue therapy, naloxone is often insufficient to reverse opioid overdoses caused by fentalog agonists under current treatment paradigms. It has been reported that naloxone is either not potent enough or has too short a duration of action to effectively reverse fentalog overdose and resuscitate patients. The objective of this proposal is to design novel opioid antagonists on the fentanyl scaffold based on previously identified fentalog antagonists and improve their pharmacokinetic properties (limited metabolism, high blood-brain penetration, and rapid absorption) relative to naloxone. We propose that the fentanyl scaffold is a good starting point as fentanyl and its analogs already bind tightly to MOR and display rapid onset of action in vivo. The overarching hypothesis is that antagonists on the fentalog scaffold will be more effective than naloxone in blocking opioid overdose. We will explore this hypothesis in two aims: 1) we will examine the ability of two lead fentalog antagonists to block fentanyl induced antinociception and respiratory depression and examine their distribution and metabolism in whole animal models and 2) design novel metabolically stable analogs which we will characterize both in vitro and in vivo. Overall, this project will develop new fentalog antagonists for the treatment of opioid overdose and characterize their in vitro and in vivo pharmacological properties.

项目摘要阿片类药物相关的过量占美国药物过量死亡的几乎一半州并每年造成可预防的死亡，而不是汽车撞车。芬太尼，高度有效的MU阿片受体（MOR）激动剂及其类似物（Fenalyogs）越来越被发现切割进入非法药物样本，既是滥用的主要药物是阿片类药物不是。非法毒品市场中疾病的流行被认为是自2016年以来，与阿片类药物相关的过量死亡增加。标准阿片类药物过量救援疗法，纳洛酮通常不足以逆转疾病激动剂引起的阿片类药物过量剂量在当前的治疗范例下。据报道，纳洛酮不是有效的足够或行动时间太短，无法有效地逆转疾病过量和复苏患者。该提议的目的是设计新颖的阿片类药物拮抗剂芬太尼支架基于先前确定的疾病拮抗剂并改善其药代动力学特性（有限的新陈代谢，高血脑渗透和快速吸收）相对于纳洛酮。我们建议芬太尼支架是一个很好的起点由于芬太尼及其类似物已经与MOR紧密结合并在体内表现出快速的作用开始。总体假设是，训练脚架上的拮抗剂将更有效在阻止阿片类药物过量的情况下，纳洛酮比纳洛酮。我们将以两个目的探讨这一假设：1）我们将检查两个铅疾病拮抗剂阻断芬太尼诱导的抗伤害感受的能力和呼吸抑郁症并检查其在整个动物中的分布和代谢模型和2）设计新型代谢稳定的类似物，我们将在体外表征这两个类似物和体内。总体而言，该项目将为治疗阿片类药物开发新的疾作拮抗剂过量并表征其体外和体内药理特性。