Designer Drugs: The Emerging Face of Drug Abuse

设计药物：药物滥用的新面貌

• 批准号: 8933872
• 负责人: MARILYN A HUESTIS
• 金额: $ 92.98万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8933872
• 关键词: Acute Kidney Failure; Address; Adverse effects; Amphetamines; Appearance; Binding Sites; Biological Assay; Cannabinoids; Collaborations; Communities; Complement; Computer Simulation; Computer software; Data; Designer Drugs; Detection; Development; Docking; Drug Kinetics; Drug abuse; Drug usage; Enzymes; Face; Future; Goals; Half-Life; Hepatocyte; Human; Incubated; Individual; Institutes; Intake; Intoxication; Investigational New Drug Application; Knowledge; Laboratories; Libraries; Link; Liver Microsomes; Marketing; Mass Spectrum Analysis; Metabolic; Metabolism; Methods; Molecular; Monitor; Opioid; Outcome; Paper; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Phase; Piperazines; Procedures; Process; Protocols documentation; Public Health; Publishing; Rattus; Research; Research Design; Resolution; Route; Running; Safety; Seizures; Simulate; Specimen; Stroke; Technology; Testing; Toxicity Tests; analytical method; cathinone; design; drug market; instrument; interest; metabolic abnormality assessment; novel; pre-clinical; preclinical safety; research study

We have designed and implemented metabolite profiling studies, in which we incubate the compounds of interest with human hepatocytes and identify metabolites via high-resolution mass spectrometry (QTOF 5600). This cooperation project with ABSciex and Bristol Myers Squibb has produced an outcome of six published papers describing the metabolism of different new synthetic cannabinoids (XLR-11, AKB-48, RCS-4, RCS-8, STS-135 and PB-22/5F-PB-22) and providing mass spectra for the scientific community to identify use of these drugs. Currently, studies on AH-7921, a new synthetic opioid, and three more synthetic cannabinoids AB-FUBINACA, AB-PINACA/5F-AB-PINACA are performed. Since spring 2014, we also established the analytical procedures for the metabolism identification studies on a second instrument, the Thermo QExactive, and are currently processing four synthetic cathinones alpha-PVT, alpha-PBP, 4-MeO-alpha-PVP and PV8. Complementing the human hepatocyte studies we designed and implemented human liver microsome experiments to assess the metabolic stability (half-life) of new designer drugs, which will provide a first estimate of how quickly the compound is metabolized. In the spring of 2014, we instituted a cooperation with Molecular Discovery, who provide software for in silico prediction of metabolites by simulating 3D docking of molecules in the enzymes catalytic cavity and consider reactive sites in the molecule. Evaluating the softwares potential will help advancing future metabolism studies. We also developed several analytical assays to identify new designer drugs in human specimens: Qualitative assays with library search were validated for 29 synthetic cannabinoids on LC-MS/MS (QTrap 5500) and for an even wider range of synthetic cannabinoids with the new SWATH approach using the QTOF5600. Quantitative assays were validated for 53 synthetic cannabinoids using LC-MS/MS (QTrap 5500) and for 28 cathinones using Orbitrap technology (QExactive). The latter method was recently extended to include 33 cathinones, 3 amphetamines and 8 piperazines. A quantitative analytical method for MDPV and two metabolites was developed to determine MDPV pharmacokinetics in rats after multiple administration routes. Our goal is to continually monitor the appearance of novel psychoactive substances on the US market and worldwide markets and to perform metabolite identification studies on prevalent new compounds. The goal is to publish our findings and provide MS/MS spectra to the scientific community in a timely manner to facilitate development of analytical methods. We also plan to extend the scope of the human liver microsome experiments by performing experiments with individual CYP450 enzymes and elucidate pathways and predict interactions. 3. As part of the collaboration with Dr. Baumann we are developing a quantitative assay for the synthetic cannabinoid AM2201 and its metabolites, which will be used to determine pharmacokinetics of this compound in rats. 4. A long-term goal is to prepare and eventually perform a controlled administration study with a synthetic cannabinoid in humans. To do so, preclinical pharmacology and toxicity tests have to be run first to file for an Investigational New Drug Application, then a protocol can be submitted.

我们已经设计和实施了代谢物分析研究，其中我们将感兴趣的化合物与人肝细胞孵育，并通过高分辨率质谱法（QTOF 5600）鉴定代谢产物。与Absciex和Bristol Myers Squibb的合作项目产生了六篇发表论文的结果，描述了不同新合成大麻素的代谢（XLR-11，AKB-48，RCS-4，RCS-4，RCS-8，RCS-8，RCS-8，STS-135，STS-135和PB-22/5F-PB-PB-22），并确定了以下科学典型的典范。目前，进行了对AH-7921，新的合成阿片类药物和另外三种合成大麻素AB-Fubinaca，AB-Pinaca/5F-AB-Pinaca的研究。自2014年春季以来，我们还建立了第二种仪器（Thermo Qecactive）的代谢鉴定研究的分析程序，目前正在处理四个合成Cathinones alpha-PVT，Alpha-PBP，4-Meo-Alpha-alpha-PVP和PV8。与我们设计和实施的人肝细胞研究的人类肝细胞研究相辅相成，以评估新设计师药物的代谢稳定性（半衰期），这将提供第一个估计化合物代谢速度的速度。在2014年春季，我们与分子发现建立了合作，他们通过模拟酶催化腔中的分子的3D对象来提供用于代谢物的硅硅预测的软件，并考虑分子中的反应性位点。评估软件潜力将有助于进步未来的新陈代谢研究。我们还开发了几种分析测定方法来鉴定人类标本中的新设计师药物：通过LC-MS/MS（QTRAP 5500）在29种合成大麻素（QTRAP 5500）上进行了库搜索的定性测定，并使用QTTOF5600进行了新的Swath方法。使用LC-MS/MS（QTRAP 5500）对53种合成大麻素的定量测定进行了验证，并使用Orbitrap技术（QEXACTIVE）验证了28个Cathinones。后一种方法最近扩展到包括33个Cathinones，3个苯丙胺和8种哌嗪。 开发了针对MDPV和两种代谢产物的定量分析方法，以确定多个给药途径后大鼠中的MDPV药代动力学。我们的目标是不断监测美国市场和全球市场上新型的精神活性物质的外观，并就普遍的新化合物进行代谢物鉴定研究。目的是发布我们的发现，并及时向科学界提供MS/MS Spectra，以促进分析方法的发展。我们还计划通过使用单个CYP450酶进行实验并阐明途径并预测相互作用来扩展人肝微粒体实验的范围。 3。作为与鲍曼博士合作的一部分，我们正在为合成大麻素AM2201及其代谢产物开发一种定量测定，该测定法将用于确定大鼠中这种化合物的药代动力学。 4。长期目标是用人类的合成大麻素准备并最终进行对照管理研究。为此，必须先进行临床前药理学和毒性测试才能进行研究新药物应用，然后可以提交方案。