Antidotes for Acute Cannabinoid Intoxication

急性大麻素中毒的解毒剂

• 批准号: 10460623
• 负责人: Alexandros Makriyannis
• 金额: $ 36.88万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460623
• 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; 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; Psychoses; 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; antagonist; azetidine; base; clinical candidate; computer studies; conjunctiva; design; emergency settings; esterase; experience; gamma-Aminobutyric Acid; improved; in silico; in vivo; in vivo evaluation; lead optimization; liquid chromatography mass spectrometry; marijuana use; 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，该 NIDA/NIH 化学品的目标 发现（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物质产生的“中毒” 大麻素 (SPC)，例如 JWH-018，大麻成分 THC 发挥其精神作用。 （大麻“高”）主要通过 CB1R 激活来模仿 THC 的效果，并且具有更高的效力。 尽管急性毒性对普通成年人来说是良性的，但服用该药物的患者却被非法出售。 高剂量的 THC（草药和合成）会导致反复发作的恶心和呕吐 （呕吐综合症），结膜注射，认知、运动技能受损和精神病 相比之下，与 SPC 相关的神经毒性对患者来说更为严重。 因精神状态改变、嗜睡、心脏毒性、中风、肾脏损伤和 急性精神病没有可用于治疗急性大麻素中毒的解毒剂。 需要解决这一关键的公共卫生问题，该项目的目标是找到解决方案。 CB1R 过度激活的中毒效应，在紧急情况下具有治疗作用。 在这方面，R21阶段将重点关注使用计算机分析、合成和表征 将测试合成配体的亲和力和安全性。 随后，配体将使用 cAMP 测定对 CB1R 进行选择性及其体外功能功效。 评估它们在血浆、全血和肝微粒体中的稳定性。 R33 阶段将重点关注铅的生化半衰期和种间差异。 优化、放大和重新合成以及小鼠（男女）体内化合物的体内评估。 首先将使用生理有效剂量静脉注射来研究配体，以量化相对脑渗透率。 LC/MS/MS 将筛选静脉注射时表现出良好脑渗透性的化合物。 快速使由急性剂量的激动剂引起的持续低温效应正常化的能力。 具有最小内在活性的，将使用功能观察电池（FOB）进行静脉内分析。 使“超药理学”剂量的 CB1 激动剂产生的神经学效应正常化。 入院时可能不知道患者的用药史，这是短效药物的一个关键期望特征 与 CB1 反向激动剂利莫那班 (SR) 相比，拮抗剂的优点是它们不会引起物理作用 为了检验这一假设，将研究先导化合物。 给予反复接受 THC 或 JWH-018 治疗的小鼠，以研究它们是否沉淀 结果将与利莫那班进行比较，以迭代的方式建立证据。 概念并最终确定用于治疗急性大麻素中毒的化合物。