Investigation of Synthetic Cannabinoid Exposures and Pharmacological Consequences

 描述（由申请人提供）：含合成大麻素的电子液体或草药制剂的汽化或吸烟是一个严重的药物滥用问题。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中毒，但它们在结构上与大麻植物中含有的大麻素不同;因此，对它们使用过程中发生的实际化学暴露或它们的药理学知之甚少，特别是关于它们对非大麻素受体的作用及其行为和毒理学效应。此外，在这些设计药物制剂中报告的合成大麻素的结构支架和类似物的种类继续增加，因为个人寻求中毒和避免检测，这些化学品和制剂的制造商和分销商似乎很少考虑其产品的化学可靠性或安全性。 事实上，化学物质经常出现在设计药物配方中，这些配方以前在科学文献中没有被描述为大麻素。此外，这些化合物中的一些具有已知致癌活性的热不稳定取代基，其可在使用期间释放。拟议的研究将表征合成大麻素制剂以及储存和使用过程中发生的化学品暴露，并在体外和体内模型中评估其药理学命运。重点将放在识别吸入或实际使用过程中产生的化合物，以及它们与大麻素CB 1和CB 2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学和毒理学效应的程度。因此，拟议的研究将增加对大麻素受体的结构-活性关系以及这些滥用的合成大麻素物质的行为和毒理学影响的了解，并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。

 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.