Investigation of Synthetic Cannabinoid Exposures and Pharmacological Consequences

项目总结 合成大麻素(SC)产生与-9-四氢大麻酚(THC)类似的心理效应 但通常更有效、更有效。值得注意的是，这些物质的使用通常与更多的 毒性。包括美国在内的国际上已经报道了一系列严重的不良反应和死亡。 和新西兰。SC滥用的全球性质表明，需要采取国际方法来解决 有问题。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。通过这件事 合作和多学科的努力，我们将确定分子和药代动力学机制 可能是不同化学成分的SC体内效应的差异的基础，与其滥用潜力和 它们在外周系统中的毒理作用。这项拟议工作的一个基本假设是， 与SC使用相关的行为效应和毒理学效应与它们的差异有关 与THC和其他部分CB1受体相比，与内源性大麻素系统的相互作用 激动剂。这一假说将通过对SC的SAR及其机制的系统研究来验证 它们的中枢和外周活动(即它们的分子指纹)。这项工作将提高能力 预测哪些新化合物可能在它们出现时或之前产生毒理作用 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。 这项研究还将增加对大麻素受体结构-活性关系的了解， 从而加深了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.