Investigation of Synthetic Cannabinoid Exposures and Pharmacological Consequences

 描述(由申请人提供)：含有大麻素的合成电子液体或草药制剂的蒸发或吸烟是一个严重的物质滥用问题。虽然在这些非法产品中发现的JWH-018和其他吲哚衍生的大麻素会产生大麻样的中毒作用，但它们在结构上不同于大麻植物中所含的大麻素；因此，人们对它们在使用期间实际接触的化学物质或其药理，特别是它们对非大麻素受体的作用及其行为和毒理的影响知之甚少。此外，这些特制药物配方中报告的结构支架和合成大麻素类似物的种类继续增加，因为个人试图陶醉并逃避检测，而这些化学品和制剂的制造商和经销商似乎对其产品的化学可靠性或安全性漠不关心。 事实上，化学物质经常出现在以前没有在科学文献中被描述为大麻的特制药物配方中。此外，其中一些化合物具有热不稳定的已知致癌活性的取代基，可以在使用过程中释放出来。这项拟议的研究将表征合成大麻素制剂以及在储存和使用过程中发生的化学暴露，并在体外和体内模型中评估它们的药理命运。重点将放在识别在实际使用情况下吸入或产生的化合物，以及它们与大麻素CB1和CB2受体以及非大麻素受体相互作用的程度，以及它们在小鼠模型中产生体内药理和毒理效应的程度。因此，拟议的研究将增加对大麻素受体构效关系的了解，以及这些滥用的合成大麻素物质的行为和毒理学影响，并为评估与使用这些化合物有关的潜在健康问题提供科学基础。

 DESCRIPTION (provided by applicant): Vaporization or smoking of synthetic cannabinoid-containing e-liquids or herbal formulations is a significant substance abuse problem. Although JWH-018 and other indole-derived cannabinoids that have been identified in these illicit products produce marijuana-like intoxication, they are structurally distinct from cannabinoids contained in the cannabis plant; hence, very little is known about the actual chemical exposures that occur during their use, or their pharmacology, particularly with regards to their actions at non-cannabinoid receptors and their behavioral and toxicological effects. Furthermore, the variety of structural scaffolds and analogs of synthetic cannabinoids that are being reported in these designer drug formulations continues to increase as individuals seek to become intoxicated and avoid detection, and the manufacturers and distributors of these chemicals and formulations appear to have little regard for the chemical reliability or safety of their products. Indeed, chemicals are frequently appearing in designer drug formulations that have not been previously described as cannabinoids in the scientific literature. Moreover, some of these compounds possess thermally unstable substituents of known carcinogenic activity that may be liberated during use. The proposed research will characterize synthetic cannabinoid formulations and the chemical exposures that occur during storage and use, and evaluate their pharmacological fate in in vitro and in vivo models. Emphasis will be placed on the identification of the compounds that are inhaled or produced during actual use scenarios, and the extent to which they can interact with cannabinoid CB1 and CB2 receptors, as well as with non-cannabinoid receptors, and the degree to which they produce in vivo pharmacological and toxicological effects in mouse models. The proposed studies will thereby increase knowledge of the structure-activity relationships at cannabinoid receptors and the behavioral and toxicological effects of these abused synthetic cannabinoid substances, and provide a scientific basis for evaluation of potential health concerns associated with use of these compounds.