Investigation of Synthetic Cannabinoid Exposures and Pharmacological Consequences

合成大麻素暴露和药理学后果的调查

基本信息

批准号：
9899222
负责人：
JENNY L. WILEY
金额：
$ 45.81万
依托单位：
RESEARCH TRIANGLE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2022-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899222
关键词：
Affinity Animal Model Behavioral Binding Biological Assay CNR1 gene CNR2 gene Cannabinoids Cannabis Chemical Exposure Chemical Structure Chemicals Cigarette Designer Drugs Detection Drug Formulations Drug Kinetics Electronic cigarette Elements Evaluation Exposure to Formulation Goals Health Heating Hepatocyte Human In Vitro Individual Indoles Inhalation Intoxication Investigation Knowledge Ligands Literature Manufacturer Name Marijuana Mass Fragmentography Metabolic Metabolism Mus Outcome Parents Pathway interactions Pattern Pharmaceutical Preparations Pharmacology Pharmacology and Toxicology Plants Preparation Property Receptor Signaling Reporting Research Rodent Route Safety Signal Transduction Smoke Smoking Structure Structure-Activity Relationship Substance abuse problem System Techniques Toxicology Training analog animal data cannabinoid receptor carcinogenicity chemical stability cigarette smoking drug abuser electronic liquid experimental study functional group in vivo in vivo Model mouse model non-cannabinoid novel predictive modeling public health relevance receptor scaffold smoke inhalation synthetic cannabinoid vapor vaporization

项目摘要

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.

描述（由申请人提供）：尽管 JWH-018 和这些非法产品中已发现的其他吲哚衍生大麻素会产生类似大麻的物质，但蒸发或吸食含有合成大麻素的电子液体或草药制剂仍是一个严重的药物滥用问题。中毒，它们在结构上与大麻植物中含有的大麻素不同；因此，人们对它们在使用过程中实际接触的化学物质或其药理学知之甚少，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影响此外，随着个体寻求中毒并避免被发现，这些设计药物制剂中报道的合成大麻素的结构支架和类似物的种类不断增加。，而这些化学品和配方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，以前在科学文献中未将其描述为大麻素的化学物质经常出现在设计药物配方中，此外，其中一些化合物具有已知致癌活性的热不稳定取代基，这些取代基可能在使用过程中释放出来。大麻素制剂和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其药理学结果，重点将放在实际使用场景中吸入或产生的化合物的鉴定上。它们与大麻素 CB1 和 CB2 受体相互作用的程度，以及与非大麻素受体产生的相互作用的程度，以及它们在小鼠模型中提出的体内药理和毒理学作用的程度，从而增加了对结构的了解。大麻素受体的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，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。