Investigation of Synthetic Cannabinoid Exposures and Pharmacological Consequences

合成大麻素暴露和药理学后果的调查

• 批准号: 10704595
• 负责人: RANGAN MAITRA
• 金额: $ 57.94万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704595
• 关键词: Accounting; Acute; Address; Adverse reactions; Aerosols; Affect; Agonist; Animal Model; Behavioral; Behavioral Mechanisms; Biological; Biological Assay; Biological Markers; CNR1 gene; CNR2 gene; Cannabinoids; Cessation of life; Chemicals; Collaborations; Country; Designer Drugs; Detection; Dose; Drug Kinetics; Endocannabinoids; European Union; Evaluation; Exposure to; Female; Forensic Medicine; Goals; Government Agencies; Health; Heart Rate; Heating; Human; In Vitro; Inhalation; International; Intraperitoneal Injections; Investigation; Knowledge; Laboratories; Liver Microsomes; Measures; Metabolic Biotransformation; Molecular; Molecular Profiling; Mus; Nature; New Zealand; Parents; Peripheral; Pharmacology; Physiological; Plasma; Process; Proliferating; Public Health; Reporting; Research; Respiration; Rodent; Route; Sampling; Site; Smoker; Smoking; Stimulus; Structure; Structure-Activity Relationship; System; Temperature; Tetrahydrocannabinol; Time; Toxic effect; Toxicology; Training; Universities; Work; abuse liability; addiction liability; cannabimimetics; cannabinoid receptor; drug discrimination; endogenous cannabinoid system; heart function; in vivo; indexing; insight; male; member; multidisciplinary; natural hypothermia; non-cannabinoid; pharmacologic; psychologic; pulmonary function; substance use; synthetic cannabinoid; vaper; vaping

PROJECT SUMMARY Synthetic cannabinoids (SC) produce psychological effects resembling those of 9-tetrahydrocannabinol (THC) but are usually more potent and efficacious. Notably, the use of these substance is often associated with greater toxicity. Clusters of severe adverse reactions and death have been reported internationally, including in the U.S. and New Zealand. The global nature of SC abuse argues for an international approach to addressing the problem. To this end, one overall goal of this project is to strengthen a nascent international collaboration initiated among laboratories in the U.S. (RTI International) and New Zealand (University of Otago). Through this collaborative and multi-disciplinary effort, we will determine molecular and pharmacokinetic mechanisms that may underlie differences in the in vivo effects of chemically diverse SC related to their abuse potential and to their toxicological effects in peripheral systems. A foundational hypothesis for this proposed work is that the both the behavioral effects and the toxicological effects associated with SC use are related to their differential interactions with the endogenous cannabinoid system, as compared to THC and other partial CB1 receptor agonists. This hypothesis will be evaluated through systematic study of the SAR of SC and the mechanisms underlying their central and peripheral actions (i.e., their molecular fingerprints). This work will enhance ability to predict which new compounds are likely to have toxicological effects when – or before – they appear and will provide a scientific basis for evaluation of potential health concerns associated with use of these compounds. This research also will increase knowledge of the structure-activity relationships at cannabinoid receptors, resulting in deepened understanding of endocannabinoid system functioning.

项目摘要 合成大麻素（SC）产生的心理效应类似于1，9-四氢大麻酚（THC） 但通常更有效。值得注意的是，这些物质的使用往往与更大的 毒性严重不良反应和死亡的集群已在国际上报告，包括在美国。 和新西兰性剥削滥用的全球性质要求采取国际办法来解决这一问题。 问题.为此，该项目的一个总体目标是加强新生的国际合作 在美国（RTI国际）和新西兰（奥塔哥大学）的实验室中发起。通过这个 合作和多学科的努力，我们将确定分子和药代动力学机制， 可能是化学成分不同的SC体内效应差异的基础，这些差异与其滥用潜力有关， 它们在外周系统中的毒性作用。这项工作的基本假设是， 与SC使用相关的行为效应和毒理学效应与其差异有关。 与THC和其他部分CB 1受体相比，与内源性大麻素系统的相互作用 激动剂通过对SC的SAR及其机制的系统研究，将对这一假说进行评价 作为其中心和外围动作的基础（即，分子指纹）。这项工作将提高能力 预测哪些新化合物在出现或出现之前可能具有毒理学效应， 为评估与使用这些化合物相关的潜在健康问题提供科学依据。 这项研究也将增加大麻素受体的结构-活性关系的知识， 从而加深对内源性大麻素系统功能的理解。

项目成果

Preparation and Distribution of Cannabis and Cannabis-Derived Dosage Formulations for Investigational and Therapeutic Use in the United States.

在美国用于研究和治疗用途的大麻和大麻衍生剂量制剂的制备和分销。

• DOI: 10.3389/fphar.2016.00285
• 发表时间: 2016
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Thomas,BrianF;Pollard,GeraldT
• 通讯作者: Pollard,GeraldT

Identification of Eight Synthetic Cannabinoids, Including 5F-AKB48 in Seized Herbal Products Using DART-TOF-MS and LC-QTOF-MS as Nontargeted Screening Methods.

鉴定了八种合成大麻素，包括使用DART-TOF-MS和LC-QTOF-MS作为非目标筛选方法的捕获草药产品中的5F-AKB48。

• DOI: 10.1111/1556-4029.13367
• 发表时间: 2017-09
• 期刊: Journal of forensic sciences
• 影响因子: 1.6
• 作者: Moore KN;Garvin D;Thomas BF;Grabenauer M
• 通讯作者: Grabenauer M

Kinetic and metabolic profiles of synthetic cannabinoids NNEI and MN-18.

合成大麻素 NNEI 和 MN-18 的动力学和代谢特征。

• DOI: 10.1002/dta.2262
• 发表时间: 2018
• 期刊: Drug testing and analysis
• 影响因子: 2.9
• 作者: Kevin,RichardC;Lefever,TimothyW;Snyder,RodneyW;Patel,PurviR;Gamage,ThomasF;Fennell,TimothyR;Wiley,JennyL;McGregor,IainS;Thomas,BrianF
• 通讯作者: Thomas,BrianF

Interactions of Cannabinoids With Biochemical Substrates.

• DOI: 10.1177/1178221817711418
• 发表时间: 2017
• 期刊: Substance abuse : research and treatment
• 作者: Thomas BF

Thermolytic Degradation of Synthetic Cannabinoids: Chemical Exposures and Pharmacological Consequences.

合成大麻素的热解降解：化学暴露和药理学后果。

• DOI: 10.1124/jpet.116.238717
• 发表时间: 2017
• 期刊: The Journal of pharmacology and experimental therapeutics
• 作者: Thomas,BrianF;Lefever,TimothyW;Cortes,RicardoA;Grabenauer,Megan;Kovach,AlexanderL;Cox,AndersonO;Patel,PurviR;Pollard,GeraldT;Marusich,JulieA;Kevin,RichardC;Gamage,ThomasF;Wiley,JennyL
• 通讯作者: Wiley,JennyL