Antidotes for Acute Cannabinoid Intoxication

项目概要/摘要-为了响应PAR-16-384，本NIDA/NIH化学品的目标 发现（化学）奖（R21/R33）的建议是发现治疗“急性疟疾”的解毒剂 由Δ9-四氢大麻酚（THC）和下一代合成精神活性物质产生的“中毒” 大麻素（SPC），如JWH-018。大麻成分四氢大麻酚发挥其精神作用 （大麻“高”）主要通过CB 1 R激活。SPC以更高的效力模拟THC的作用， 作为“设计师毒品”非法销售。虽然急性毒性在一般成年人中是良性的， 高剂量四氢大麻酚（草药和合成）本身会出现恶心和呕吐的反复发作 （剧吐综合征），结膜注射，并经历认知，运动技能和精神病受损 在急诊室的症状相比之下，与SPC相关的神经毒性更严重，其中患者 因精神状态改变、嗜睡、心脏毒性、中风、肾损伤和 急性精神病没有解毒剂可用于治疗急性大麻素中毒，强调了 我们需要解决这一关键的公共卫生问题。这个项目的目标是发现解毒剂来抵消 过量CB 1 R活化的致醉作用，并且在紧急情况下在治疗上是有用的。 在这方面，R21阶段将侧重于使用计算机分析、合成和表征 具有良好的药物样安全性特征的化合物。将测试合成的配体的亲和力， 对CB 1 R的选择性和使用cAMP测定的它们的功能性体外功效。随后，配体将 评价其在血浆、全血和肝微粒体中的稳定性。因此，他们 将确定生物化学半衰期和物种间变异。R33阶段将侧重于铅 优化、放大和再合成沿着化合物在小鼠（两种性别）中的体内评价。 将首先使用生理有效剂量静脉内研究配体，以使用 LC/MS/MS.当静脉内给药时，将进行筛查， 快速使由急性剂量的激动剂诱导的持续低温效应正常化的能力。配体 将使用功能观察组合（FOB）进行i. v.测定其能力 以使由CB 1激动剂的“超药理学”剂量产生的神经作用正常化。给定 患者的药物史可能在入院时不知道，这是短效 与CB 1反向激动剂利莫那班（SR）相比，利莫那班拮抗剂的另一个优点是它们不引起生理学上的 大麻依赖者的戒断综合征。为了验证这一假设，将使用先导化合物 给用THC或JWH-018重复处理的小鼠施用，以研究它们是否沉淀 戒断将结果与利莫那班进行比较。数据将以迭代的方式使用，以建立证据- 并最终确定用于治疗急性大麻素中毒的化合物。

PROJECT SUMMARY/ABSTRACT - In response to PAR-16-384, the goal of this NIDA/NIH Chemical Discovery (CHEM) Award (R21/R33) proposal is to discover antidotes for treating “Acute Marijuana Intoxication” produced by Δ9-tetrahydrocannabinol (THC) and the next generation synthetic psychoactive cannabinoids (SPCs) such as JWH-018. The cannabis constituent THC exerts its psychotropic effects (marijuana “high”) mainly via CB1R activation. SPCs mimic the effects of THC with higher potency and are illegally sold as “designer drugs”. Although acute toxicity is benign in the average adult, patients who consume high doses of THC (herbal and synthetic) present themselves with recurrent episodes of nausea and vomiting (Hyperemesis Syndrome), injected conjunctiva, and experience impaired cognition, motor skills and psychotic symptoms in the ER. In comparison, the neurotoxicity associated with SPCs is more severe wherein patients are admitted into the ER for altered mental status, somnolence, cardiotoxicity, stroke, kidney damage and acute psychosis. There are no antidotes available for treating acute cannabinoid poisoning, highlighting the need to address this critical public-health issue. The goal of this project is to discover antidotes to counteract the intoxicating effects of excessive CB1R activation and be therapeutically useful in an emergency setting. In this regard, the R21 phase will focus on use of in silico analysis, synthesis and characterization of compounds with favorable drug-like safety profiles. The synthesized ligands will be tested for their affinity and selectivity for CB1R and for their functional in vitro efficacy using the cAMP assay. Subsequently, ligands will be evaluated for their stability in plasma, whole blood and towards liver microsomes. Accordingly, their biochemical half-lives and interspecies variations will be determined. The R33 phase will focus on lead optimization, scale-up and re-synthesis along with in vivo evaluation of compounds in mice (both genders). Ligands will be first studied using a physiologically effective dose i.v. to quantify relative brain penetration using LC/MS/MS. Compounds exhibiting good brain penetration, when administered i.v., will be screened for their ability to rapidly normalize an on-going hypothermic effect induced by an acute dose of an agonist. Ligands with minimal intrinsic activity will be assayed i.v. using the functional observation battery (FOB) for their ability to normalize the neurological effects produced by “suprapharmacological” doses of the CB1 agonist. Given that the patients’ drug histories may not be known at admission, a key desired characteristic of short-acting antagonists as compared to the CB1 inverse-agonist, rimonabant (SR), is that they not elicit a physical withdrawal syndrome in cannabis-dependent subjects. To test this hypothesis, lead compounds will be administered to mice treated repeatedly with THC or JWH-018, to investigate whether they precipitate withdrawal. Results will be compared to rimonabant. Data will be used in an iterative manner to establish proof- of-concept and ultimately identify compounds for treating acute cannabinoid intoxication.