Examining Novel Fentalogs: Pharmacological Characteristics and Reversibility

阿片类镇痛剂，如吗啡和氢可酮，被广泛用于治疗 可用于中度至重度疼痛，但也被广泛误用和滥用。阿片类药物相关 服药过量占美国所有服药过量死亡的近一半， 每年造成的可预防的死亡人数比车祸还多。芬太尼，一种高效的 MU阿片受体(MOR)激动剂及其类似物(芬太洛)的发现越来越多 在被执法部门搜查和扣押的毒品样本中被认为 这是自2016年以来阿片类药物过量死亡大幅增加的原因之一。事实上, 与芬太洛有关的死亡和缉获毒品的数量可能被低估了，因为 合成新芬太尼的速度太快，这让法律很难 执法和法医专家要跟上。因为这些化合物中的许多都是新的 类似物，就受体亲和力而言，人们对其基本药理知之甚少 或阿片受体的活动。这项建议的目的是评价小说 芬太罗，其中许多已在非法样本中发现，就结合亲和力而言 受体在三个经典的阿片受体上发挥作用：MOR，增量阿片受体 受体(DOR)和kappa阿片受体(KOR)。这将通过以下方式完成 标准竞争性放射性配基结合试验和G蛋白周转试验。一种能力 标准的抢救疗法，纳洛酮(商标是Evzio或Narcan)，以逆转 最有效和最有效的芬太洛的激动剂活性也将被检查；真实 时间cAMP积累将被用来确定激动剂的功能和逆转 拮抗剂，如纳洛酮。最重要的假设是，这些小说中的许多 芬太洛比传统的阿片激动剂更有效，而且 当涉及芬太洛时，阿片类药物过量的标准治疗可能是不够的。 总体而言，本项目将表征新药的体外药理特性 在街头毒品中发现的芬太罗，并有可能成为 预防阿片类药物过量和相关死亡。

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.