Novel antagonists as fentanyl overdose rescue therapies

摘要 阿片类药物过量死亡是作用于μ阿片受体的化合物的靶向效应的结果 (MOR)导致严重的呼吸抑制芬太尼是一种高效的合成莫尔激动剂。文学 报告显示，美国阿片类药物引起的过量死亡人数急剧上升是由于 芬太尼及其类似物（称为芬太尼）在街头毒品中的流行率。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，最近的DEA新闻稿指出，五分之二的假冒 阿片类药物含有致命剂量的芬太尼。目前的治疗标准和唯一的药物 目前可用于治疗阿片类药物过量的是纳洛酮， 差不多50年前的政府。然而，报告表明，芬太尼诱导的过量是耐药的， 纳洛酮的逆转作用，其效力、快速性或持久性不足，导致过量患者 会再次麻醉并且不太可能存活。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，例如木制胸部， 综合征因此，迫切需要更有效的治疗方法来逆转芬太尼诱导的过量。 我们提出一个假设，即从芬太尼开发的阿片类拮抗剂，因此， 结构上与芬太尼相关，并以类似方式与莫尔结合，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，我们已经鉴定了芬太尼衍生物（R03 DA 048129 和R21 DA 051723），其在体外和体内均充当高亲和力莫尔拮抗剂。的目的 建议是在这些初步线索的基础上开发对莫尔具有高亲和力的专有类似物， 更高的拮抗剂效力以及有利的药代动力学特征，即快速起效， 防止再次麻醉的作用时间长度。总的来说，这项研究可以导致识别和开发 芬太尼过量的有效逆转剂

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.