Antidotes for Acute Cannabinoid Intoxication

急性大麻素中毒的解毒剂

• 批准号: 9788399
• 负责人: Alexandros Makriyannis
• 金额: $ 23.1万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788399
• 关键词: Acute; Address; Admission activity; Adrenergic beta-Antagonists; Adult; Affinity; Agonist; Anti-Arrhythmia Agents; Antidotes; Antipsychotic Agents; Award; Benign; Benzodiazepines; Biochemical; Biological Assay; Brain; CNR1 gene; Cannabidiol; Cannabinoids; Cannabis; Carboxylic Acids; Cardiotoxicity; Cell membrane; Cells; Characteristics; Chemicals; Clinic; Complex; Computer Simulation; Consumption; Crystallization; Cyclic AMP; Data; Designer Drugs; Docking; Dose; Drowsiness; Evaluation; Exhibits; Free Energy; Gender; Goals; Human; Impaired cognition; In Vitro; Ingestion; Intervention; Intoxication; Lead; Ligands; Liver Microsomes; Marijuana; Mission; Molecular; Monkeys; Motor Skills; Mus; Naloxone; Naltrexone; Narcan; National Institute of Drug Abuse; Nausea and Vomiting; Neurologic Effect; Overdose; Patients; Penetration; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Phase; Physiological; Plasma; Poisoning; Property; Psychotic Disorders; Public Health; Pyrrolidinones; Recording of previous events; Recurrence; Rodent; Safety; Saline; Stroke; Structure; Substance Withdrawal Syndrome; Supportive care; Syndrome; Testing; Tetrahydrocannabinol; Therapeutic; Time; Toxic effect; Toxicokinetics; Translating; United States National Institutes of Health; Variant; Whole Blood; Withdrawal; acute toxicity; azetidine; base; clinical candidate; computer studies; conjunctiva; design; emergency settings; esterase; experience; gamma-Aminobutyric Acid; improved; in vivo; in vivo evaluation; lead optimization; liquid chromatography mass spectrometry; mental state; neurotoxicity; next generation; nonhuman primate; novel; opioid overdose; preclinical study; psychotic symptoms; renal damage; response; rimonabant; scale up

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.

项目摘要/摘要 - 响应PAR-16-384，这是NIDA/NIH化学的目标 Discovery（Chem）奖（R21/R33）提案是发现治疗“急性大麻的解毒剂 δ9-四氢大麻酚（THC）和下一代合成精神活性产生的中毒” 大麻素（SPC），例如JWH-018。大麻构成THC发挥其精神作用 （大麻“高”）主要通过CB1R激活。 SPC模仿THC具有更高效力的影响，并且是 非法出售为“设计师毒品”。尽管急性毒性在平均成年人中是良性的，但食用的患者 高剂量的THC（草药和合成）表现出复发性的恶心和呕吐发作 （综合症综合征），注入结膜，并经历认知，运动技能和精神病的经历 ER中的症状。相比之下，与SPC相关的神经毒性更为严重，患者患者 被录取到急诊室，以改变心理状况，脾气暴躁，心脏毒性，中风，肾脏损害和 急性精神病。没有可用于治疗急性大麻素中毒的解毒剂 需要解决这个关键的公共卫生问题。该项目的目的是发现解毒剂来抵消 过量的CB1R激活的醉人作用，在紧急情况下热有用。 在这方面，R21阶段将集中于用于计算机分析，合成和表征的使用 具有良好毒品的安全性概况的化合物。合成配体的亲和力将测试 CB1R的选择性及其使用CAMP分析的实用性效率。随后，配体会 可以评估其在血浆，全血和肝微粒体中的稳定性。据他们说 将确定生化半衰期和种间变化。 R33阶段将集中于铅 优化，扩大和重新合成以及对小鼠的化合物的体内评估（两种性别）。 配体将首先使用具有物理有效剂量i.v.使用 LC/MS/MS。当静脉内给药时，将筛选出表现出良好脑穿透的化合物 急性剂量激动剂引起的持续的低温作用的能力。配体 随着固有活性的最低，将分配静脉内。使用功能观察电池（FOB）的能力 为了使CB1激动剂的“超磷酸药物”剂量产生的神经系统作用正常化。给出 入院时可能不知道患者的毒品病史，这是短效的关键所需特征 与CB1反激动剂Rimonabant（SR）相比，拮抗剂不引起物理 大麻依赖性受试者的戒断综合征。为了检验该假设，铅化合物将是 用THC或JWH-018反复治疗的小鼠给药，以调查它们是否珍贵 提取。结果将与Rimonabant进行比较。数据将以迭代方式使用以建立证明 - 概念并最终确定了治疗急性大麻素中毒的化合物。