Development of Specific Mu Opioid Receptor Antagonists to Reverse the Acute and Chronic Toxicity of Fentanyls

项目摘要 本提案是对PAR-20-092：预防和治疗阿片类药物使用的药物开发的回应 疾病和药物过量（UG 3/UH 3）（临床试验可选）。我们建议开发新的莫尔拮抗剂 携带1-苯乙基-N-苯基哌啶-4-胺骨架，能有效特异性逆转急性毒性， 芬太尼及其类似物芬太尼是合成阿片类药物的一个大家族， 阿片类药物滥用和成瘾，因为其中一些药物的效力比吗啡高出10，000倍。 由于它们的高效力和比纳洛酮更长的半衰期，纳洛酮是芬太尼过量的一线治疗药物， 在逆转过程中可能需要多次输注和高剂量的纳洛酮。又一个芬太尼 据报道，成瘾治疗纳洛酮具有患者不依从性和不希望的副作用。 最近，我们已经确定了芬太尼结合和激活其靶蛋白的一种新的分子机制， 莫尔，通过系统的计算化学和生物化学研究。更重要的是，我们发现 一种新的芬太尼衍生物，苯基芬太尼，作为一种有效的莫尔拮抗剂。苯芬太尼与 结构骨架，即1-苯乙基-N-苯基哌啶-4-胺与芬太尼。它具有相当高的亲和力 对莫尔起作用，并且根据最近的研究，对该受体起中性拮抗剂的作用。因此，我们计划 应用这些发现进一步表征具有类似药理作用的苯基芬太尼及其衍生物 在体外和体内的特点，并追求这些线索的临床前开发作为新的逆转 抗芬太尼急性毒性的药物。在UG 3阶段，我们计划实现两个具体目标， 定义具有合理效力和药代动力学特征的新型先导化合物作为芬太尼逆转剂， 在UH 3阶段，我们建议对最有希望的候选人进行IND研究，并最终 在资助期结束前向FDA提交IND。

Project Summary This proposal is in response to PAR-20-092: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional). We propose to develop novel MOR antagonists carrying 1-phenethyl-N-phenylpiperidin-4-amine skeleton to effectively and specifically reverse the acute toxicity of fentanyl and its analogs. The fentanyls are a large family of synthetic opioids and are prominent on the list of opioid abuse and addiction due to the fact that some of them are up to 10,000-fold more potent than morphine. Because of their high potency and longer half-life than naloxone, the front-line treatment for fentanyl overdose, multiple infusions and high doses of naloxone may be required during reversal procedure. Another fentanyl addiction treatment, naltrexone, has been reported with patient non-compliance and unwanted side effects. Recently we have identified a novel molecular mechanism of fentanyl binding and activation on its target protein, the MOR, through systematic computational chemistry and biochemistry studies. More importantly, we identified a new fentanyl derivative, phenylfentanil, as a potent antagonist of the MOR. Phenylfentanil shares the same structural skeleton, i.e. 1-phenethyl-N-phenylpiperidin-4-amine, with fentanyl. It carries reasonably high affinity to the MOR and acts as a neutral antagonist on the receptor based on recent studies. Accordingly, we plan to apply these findings to further characterize phenylfentanil and its derivatives with similar pharmacological characteristics both in vitro and in vivo, and pursue preclinical development on these leads as novel reversal agents against the acute toxicity of fentanyl. In the UG3 phase, we plan to pursue two specific aims in order to define novel leads with reasonable potency and pharmacokinetics profiles as fentanyl reversal agents while in the UH3 phase, we propose to conduct IND-enabling studies on the most promising candidate and eventually file an IND with the FDA by the end of the funding period.