Investigation of Synthetic Cannabinoid Exposures and Pharmacological Consequences

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。

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.