Antidotes for Acute Cannabinoid Intoxication

项目摘要/摘要-响应PAR-16-384，该NIDA/NIH化学公司的目标是 发现(CHEM)奖(R21/R33)的提议是发现治疗急性大麻的解毒剂 Δ-9-四氢大麻酚与新一代合成精神药物“中毒” 大麻(SPC)，如JWH-018。大麻成分THC发挥其精神药效 (大麻“兴奋”)主要通过CB1R激活。SPC以更高的效力模拟THC的效果，并 被非法作为“特制毒品”出售。虽然急性毒性在普通成年人中是良性的，但服用 大剂量的THC(草药和合成的)会出现反复发作的恶心和呕吐。 (剧吐综合征)，结膜注射，并经历认知、运动技能和精神障碍 急诊室的症状。相比之下，与SPC相关的神经毒性更严重，患者 因精神状态改变、嗜睡、心脏毒性、中风、肾脏损害而进入急诊室 急性精神病。目前还没有治疗急性大麻类中毒的解毒剂，这突显了 需要解决这一关键的公共卫生问题。这个项目的目标是寻找解药来抵消 CB1R过度激活的醉人效应，在紧急情况下可用于治疗。 在这方面，R21阶段将集中在电子分析中的应用，合成和表征 具有良好的类药物安全性特征的化合物。将测试合成的配体的亲和力和 CAMP法测定CB1R的选择性及其体外功能效应。随后，配体将 评估其在血浆、全血和肝微粒体中的稳定性。因此，他们的 生化半衰期和种间变异将被确定。R33阶段将重点关注Lead 化合物的优化、放大和重新合成以及在小鼠体内的评估(无论性别)。 首先将使用生理有效剂量静脉注射来研究配体。要量化相对脑渗透率，请使用 LC/MS/MS显示良好的脑透过性的化合物，当静脉注射时，将被筛选其 能够迅速使由急性剂量的激动剂引起的持续降温效应正常化。配体 以最小的内在活性将被静脉注射。使用功能观察电池(FOB)了解他们的能力 使CB1激动剂“超药物”剂量所产生的神经效应正常化。vt.给出 患者的吸毒史在入院时可能不为人所知，这是短效的关键特征 与CB1反向激动剂利莫那班(SR)相比，拮抗剂不会引起物理上的 大麻依赖者中的戒断综合征。为了验证这一假设，先导化合物将是 给反复用THC或JWH-018处理的小鼠，观察它们是否沉淀 戒烟。结果将与利莫那班进行比较。将以迭代的方式使用数据来建立证据- -概念并最终确定用于治疗急性大麻素中毒的化合物。

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.