Combatting Synthetic Designer Opioids: A Conjugate Vaccine Ablates Lethal Doses of Fentanyl Class Drugs.
Combatting Synthetic Designer Opioids: A Conjugate Vaccine Ablates Lethal Doses of Fentanyl Class Drugs.
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DOI：
10.1002/anie.201511654
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发表时间：
2016-03-07
期刊：
影响因子：
--
通讯作者：
Janda KD
中科院分区：
文献类型：
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作者：
Bremer PT;Kimishima A;Schlosburg JE;Zhou B;Collins KC;Janda KD
芬太尼是一种令人上瘾的处方阿片类药物，其效力是吗啡的80倍以上。芬太尼的合成性质使危险的“设计药物”类似物的创造成为可能，这些类似物逃脱了毒理学筛选，但表现出与母体药物相当的效力。令人震惊的是，大量死亡事件与过量服用芬太尼衍生物有关。在此，我们报告了一种有效的免疫疗法，用于减少芬太尼类药物的精神作用。创建了单一缀合物疫苗，其引起高水平的抗体，其对广泛的芬太尼类似物具有交叉反应性。此外，接种疫苗的小鼠从致死剂量的芬太尼中获得了显着的保护。最后，建立了一种基于表面等离子体共振（SPR）的技术，能够对直接来源于血清的抗体进行药物特异性分析。我们新开发的芬太尼疫苗和分析方法可能有助于打击合成阿片类药物滥用。芬太尼是一种有效的合成阿片类药物，可合法用作II级处方止痛药。然而，芬太尼具有显著的滥用倾向，因为它通过激活大脑中的μ-阿片受体（莫尔）诱导欣快感;与非法的I类阿片类药物海洛因相同的药理学靶点。莫尔的过度激活导致呼吸抑制，这可能是致命的。芬太尼的效力超过海洛因的10倍以上，吗啡超过80倍以上，当从不受管制的来源消费时，会造成过量的重大风险。此外，芬太尼合成的容易性使得非法生产和创造设计师药物类似物成为可能。事实上，这些类似物的药理学尚未得到适当的表征，使它们特别危险，特别是当某些修饰，甚至甲基添加，可以增加效力，特别是在3-位（图1）。
Fentanyl is an addictive prescription opioid that is over 80 times more potent than morphine. The synthetic nature of fentanyl has enabled the creation of dangerous ‘designer drug’ analogues that escape toxicology screening, yet display comparable potency to the parent drug. Alarmingly, a large number of fatalities have been linked to overdose of fentanyl derivatives. Herein, we report an effective immunotherapy for reducing the psychoactive effects of fentanyl class drugs. A single conjugate vaccine was created that elicited high levels of antibodies with cross-reactivity for a wide panel of fentanyl analogues. Moreover, vaccinated mice gained significant protection from lethal fentanyl doses. Lastly, a surface plasmon resonance (SPR)-based technique was established enabling drug specificity profiling of antibodies derived directly from serum. Our newly developed fentanyl vaccine and analytical methods may assist in the battle against synthetic opioid abuse. Fentanyl is an effective synthetic opioid that is used legally as a schedule II prescription pain reliever. However, fentanyl presents a significant abuse liability due to the euphoric feeling it induces via activation of μ-opioid receptors (MOR) in the brain; the same pharmacological target as the illegal schedule I opioid, heroin. Excessive activation of MOR results in respiratory depression which can be fatal. Fentanyl exceeds the potency of heroin by >10-fold, and morphine by >80-fold posing a significant risk of overdose when it is consumed from unregulated sources. Furthermore, the ease of fentanyl synthesis enables illegal production and the creation of designer drug analogues. The fact that the pharmacology of these analogues has yet to be properly characterized makes them particularly dangerous, especially when certain modifications, even methyl additions, can increase potency, notably at the 3-position (Figure 1).