Approaches to Counteract the Harmful Effects of Synthetic Opioid Designer Drugs

 描述（由申请人提供）：合成精神活性药物（SPD）是专门设计用于模拟已知滥用药物作用的物质。然而，SPD通常会绕过非法物质的法律的定义，并且还可能构成公共健康威胁。它可以 有人认为，在药物使用和滥用的整个历史中，一个主要趋势是与使用更强效的药物有关的危险增加，无论是纯化的植物材料还是新的合成化合物。从1979年开始，非法合成毒品已发展到极其复杂的程度。一些过量受害者的死亡归因于海洛因，然而，缉获的样品中不含海洛因，而是受害者从销售“中国白色”的毒贩那里购买，α-甲基芬太尼。芬太尼是一个大家族的高度有效的合成麻醉镇痛剂。它们具有阿片类药物的所有特性，但是，它们的效力比吗啡强50-100倍;然而，它们在化学上不相关，因此不会与阿片类药物筛选试验中使用的试剂发生交叉反应。最近在罗得岛、新泽西、宾夕法尼亚和东南部发生的死亡事件都与最新的“芬太尼”乙酰芬太尼有关，这使这种设计师药物家族再次成为公众关注的焦点。芬太尼重新出现的原因与海洛因纯度下降有关，需要增加效力和成本效益的制备。简单地说，设计师芬太尼可以在一个单一的位置合成，因为它的效力，一克可以配制（切割）成数千，也许一百万剂量。要阻止如此少量的纯毒品的传播是极其困难的。因此，虽然药物管制工作需要继续，但打击SPD滥用/成瘾的努力也需要继续。国家药物开发局发布了一项题为“合成精神活性药物和消除其有害影响的战略方法”的具体方案公告（PAR-14-105）。虽然，抗体疗法已被检查用于治疗滥用药物，如可卡因，尼古丁，甲基苯丙胺和海洛因，但从未尝试过针对SPD的抗体治疗。因此，我们计划研究针对芬太尼及其设计师同系物的抗体。我们将采取两种方法来对抗这些μ受体阿片类药物，然而，这两种方法都将基于独特的半抗原设计，这对于生产不仅对抗芬太尼而且对抗这种合成阿片类药物的常见街道类似物的抗体至关重要。一旦半抗原合成是安全的，我们将研究主动和被动疫苗策略。来自后者的抗体将通过抗体-噬菌体/酵母展示技术的组合来获得，在这里，我们将使用选择过程，其中通过与抗体-酵母FACS筛选和分析偶联的独特的芬太尼标记的荧光团来确保对1-（2-苯乙基）-4-（N-丙酰苯胺基）哌啶药物类别的交叉反应性人抗体。最后，需要一个指标来判断两种疫苗治疗芬太尼生理过程的价值;我们将研究每种疫苗的抗伤害作用，可以以药物剂量依赖的方式进行评估。

 DESCRIPTION (provided by applicant): Synthetic psychoactive drugs (SPDs) are substances that are specifically designed to mimic the actions of known abused drugs. Yet, SPDs typically skirt the legal definition of an illegal substance and can also pose a public health threat. It can be argued that a major trend throughout the history of drug use and abuse is the increased hazards associated with the use of more potent drugs, either purified plant materials or new synthetic compounds. Beginning in 1979, the illicit synthesis of drugs was elevated to an extraordinarily sophisticated level. A number of overdose victim's deaths were attributed to heroin, however, seized samples contained no heroin, rather the victims were buying from drug dealers selling "China White", alpha-methylfentanyl. The fentanyls are a large family of highly potent synthetic narcotic analgesics. They have all the properties of the opiates, however, they are 50-100 times more potent than morphine; yet, are chemically unrelated and therefore do not cross-react with reagents used in opiate screening tests. The recent deaths in Rhode Island, New Jersey, Pennsylvania and the Southeast all associated with the newest "fentanyl", acetyl fentanyl, have brought this designer drug family in the public forefront again. Reasons for fentanyl resurfacing are tied to a decline in heroin purity, a need to increase potency and cost efficient preparation. Simply stated designer fentanyl's can be synthesized at a single location and because of its potency a single gram could be formulated (cut) into many thousand, perhaps a million doses. Preventing the distribution of such small amounts of a pure drug is exceedingly difficult. Thus, while drug control efforts will need to continue, so will efforts to teat SPD abuse/addiction. NIDA has issued a specific program announcement (PAR-14-105) entitled "synthetic psychoactive drugs and strategic approaches to counteract their deleterious effects". Although, antibody therapies have been examined for treating drugs of abuse such as cocaine, nicotine, methamphetamine and heroin no antibody effort has ever been attempted with regards to an SPD. Accordingly, we plan to investigate antibodies against fentanyl and its designer congeners. We will take two approaches to counter these mu-receptor opioid drugs, however, both will be grounded upon unique hapten designs that will be critical in producing antibodies that cannot only counter fentanyl but also the common street analogues of this synthetic opioid. Once hapten synthesis is secure we will examine both active and passive vaccine strategies. Antibodies from the latter will come via a combination of antibody-phage/yeast display technology, here we will use a selection process wherein cross-reactive human antibodies to the 1-(2-phenethyl)-4-(N-propionylanilino) piperidine drug class will be secured through unique fentanyl tagged fluorophores coupled to antibody-yeast FACS screening and analysis. Finally, a metric will be needed to judge the value of both types of vaccines for treating fentanyl's physiological processes; we will look at antinociceptive effects a each vaccine can be evaluated in a drug-dose dependent manner.