Marie H. Deventer, Mattias Persson, Caitlyn Norman, Huiling Liu, Matthew J. Connolly, Niamh Nic Daéid, Craig McKenzie, Henrik Gréen, Christophe P. Stove
{"title":"规避通用禁令的溴化合成大麻素受体激动剂及其类似物的体外大麻素活性分析。","authors":"Marie H. Deventer, Mattias Persson, Caitlyn Norman, Huiling Liu, Matthew J. Connolly, Niamh Nic Daéid, Craig McKenzie, Henrik Gréen, Christophe P. Stove","doi":"10.1002/dta.3592","DOIUrl":null,"url":null,"abstract":"<p>Following the enactment of a generic ban in China in 2021, the synthetic cannabinoid market has been evolving, now encompassing even wider structural diversity. Compounds carrying a brominated core such as ADB-5′Br-BUTINACA (ADMB-B-5Br-INACA) and tail-less analogs, such as ADB-5′Br-INACA (ADMB-5Br-INACA), MDMB-5′Br-INACA, and ADB-INACA (ADMB-INACA), have been detected since late 2021. This study investigated the cannabinoid receptor (CB) activation potential of synthesized (<i>S</i>)-enantiomers of these substances, as well as of two predicted analogs MDMB-5′Br-BUTINACA (MDMB-B-5Br-INACA) and ADB-5′F-BUTINACA (ADMB-B-5F-INACA), using CB<sub>1</sub> and CB<sub>2</sub> β-arrestin 2 recruitment assays and a CB<sub>1</sub> intracellular calcium release assay. Surprisingly, the tail-less (<i>S</i>)-ADB-5′Br-INACA and (<i>S</i>)-MDMB-5′Br-INACA retained CB activity, albeit with a decreased potency compared to their tailed counterparts (<i>S</i>)-ADB-5′Br-BUTINACA and (<i>S</i>)-MDMB-5′Br-BUTINACA, respectively, which were potent and efficacious CB<sub>1</sub> agonists. Also, at CB<sub>2</sub>, tail-less analogs showed a lower potency but increased efficacy. Removing the bromine substitution ((<i>S</i>)-ADB-INACA) resulted in a reduced activity at CB<sub>1</sub>; however, this effect was less prominent at CB<sub>2</sub>. Looking at tailed analogs, replacing the bromine with a fluorine substitution ((<i>S</i>)-ADB-5′F-BUTINACA) resulted in an increased potency and efficacy at both receptors. Furthermore, as ADB-5′Br-INACA and MDMB-5′Br-INACA have been frequently detected together in Scottish prisons, this study also evaluated the CB<sub>1</sub> receptor activation potential of different mixtures of their respective reference standards, showing no unexpected cannabimimetic effect of combining both substances. Lastly, two powders seized by Belgian Customs and confirmed to contain ADB-5′Br-INACA and MDMB-5′Br-INACA, respectively, were assessed for CB activity. Based on the comparison with their reference standards, varying degrees of purity were suspected.</p>","PeriodicalId":160,"journal":{"name":"Drug Testing and Analysis","volume":"16 6","pages":"616-628"},"PeriodicalIF":2.6000,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"In vitro cannabinoid activity profiling of generic ban-evading brominated synthetic cannabinoid receptor agonists and their analogs\",\"authors\":\"Marie H. Deventer, Mattias Persson, Caitlyn Norman, Huiling Liu, Matthew J. Connolly, Niamh Nic Daéid, Craig McKenzie, Henrik Gréen, Christophe P. Stove\",\"doi\":\"10.1002/dta.3592\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Following the enactment of a generic ban in China in 2021, the synthetic cannabinoid market has been evolving, now encompassing even wider structural diversity. Compounds carrying a brominated core such as ADB-5′Br-BUTINACA (ADMB-B-5Br-INACA) and tail-less analogs, such as ADB-5′Br-INACA (ADMB-5Br-INACA), MDMB-5′Br-INACA, and ADB-INACA (ADMB-INACA), have been detected since late 2021. This study investigated the cannabinoid receptor (CB) activation potential of synthesized (<i>S</i>)-enantiomers of these substances, as well as of two predicted analogs MDMB-5′Br-BUTINACA (MDMB-B-5Br-INACA) and ADB-5′F-BUTINACA (ADMB-B-5F-INACA), using CB<sub>1</sub> and CB<sub>2</sub> β-arrestin 2 recruitment assays and a CB<sub>1</sub> intracellular calcium release assay. Surprisingly, the tail-less (<i>S</i>)-ADB-5′Br-INACA and (<i>S</i>)-MDMB-5′Br-INACA retained CB activity, albeit with a decreased potency compared to their tailed counterparts (<i>S</i>)-ADB-5′Br-BUTINACA and (<i>S</i>)-MDMB-5′Br-BUTINACA, respectively, which were potent and efficacious CB<sub>1</sub> agonists. Also, at CB<sub>2</sub>, tail-less analogs showed a lower potency but increased efficacy. Removing the bromine substitution ((<i>S</i>)-ADB-INACA) resulted in a reduced activity at CB<sub>1</sub>; however, this effect was less prominent at CB<sub>2</sub>. Looking at tailed analogs, replacing the bromine with a fluorine substitution ((<i>S</i>)-ADB-5′F-BUTINACA) resulted in an increased potency and efficacy at both receptors. Furthermore, as ADB-5′Br-INACA and MDMB-5′Br-INACA have been frequently detected together in Scottish prisons, this study also evaluated the CB<sub>1</sub> receptor activation potential of different mixtures of their respective reference standards, showing no unexpected cannabimimetic effect of combining both substances. Lastly, two powders seized by Belgian Customs and confirmed to contain ADB-5′Br-INACA and MDMB-5′Br-INACA, respectively, were assessed for CB activity. Based on the comparison with their reference standards, varying degrees of purity were suspected.</p>\",\"PeriodicalId\":160,\"journal\":{\"name\":\"Drug Testing and Analysis\",\"volume\":\"16 6\",\"pages\":\"616-628\"},\"PeriodicalIF\":2.6000,\"publicationDate\":\"2023-10-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Drug Testing and Analysis\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/dta.3592\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMICAL RESEARCH METHODS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Testing and Analysis","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/dta.3592","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMICAL RESEARCH METHODS","Score":null,"Total":0}
In vitro cannabinoid activity profiling of generic ban-evading brominated synthetic cannabinoid receptor agonists and their analogs
Following the enactment of a generic ban in China in 2021, the synthetic cannabinoid market has been evolving, now encompassing even wider structural diversity. Compounds carrying a brominated core such as ADB-5′Br-BUTINACA (ADMB-B-5Br-INACA) and tail-less analogs, such as ADB-5′Br-INACA (ADMB-5Br-INACA), MDMB-5′Br-INACA, and ADB-INACA (ADMB-INACA), have been detected since late 2021. This study investigated the cannabinoid receptor (CB) activation potential of synthesized (S)-enantiomers of these substances, as well as of two predicted analogs MDMB-5′Br-BUTINACA (MDMB-B-5Br-INACA) and ADB-5′F-BUTINACA (ADMB-B-5F-INACA), using CB1 and CB2 β-arrestin 2 recruitment assays and a CB1 intracellular calcium release assay. Surprisingly, the tail-less (S)-ADB-5′Br-INACA and (S)-MDMB-5′Br-INACA retained CB activity, albeit with a decreased potency compared to their tailed counterparts (S)-ADB-5′Br-BUTINACA and (S)-MDMB-5′Br-BUTINACA, respectively, which were potent and efficacious CB1 agonists. Also, at CB2, tail-less analogs showed a lower potency but increased efficacy. Removing the bromine substitution ((S)-ADB-INACA) resulted in a reduced activity at CB1; however, this effect was less prominent at CB2. Looking at tailed analogs, replacing the bromine with a fluorine substitution ((S)-ADB-5′F-BUTINACA) resulted in an increased potency and efficacy at both receptors. Furthermore, as ADB-5′Br-INACA and MDMB-5′Br-INACA have been frequently detected together in Scottish prisons, this study also evaluated the CB1 receptor activation potential of different mixtures of their respective reference standards, showing no unexpected cannabimimetic effect of combining both substances. Lastly, two powders seized by Belgian Customs and confirmed to contain ADB-5′Br-INACA and MDMB-5′Br-INACA, respectively, were assessed for CB activity. Based on the comparison with their reference standards, varying degrees of purity were suspected.
期刊介绍：
As the incidence of drugs escalates in 21st century living, their detection and analysis have become increasingly important. Sport, the workplace, crime investigation, homeland security, the pharmaceutical industry and the environment are just some of the high profile arenas in which analytical testing has provided an important investigative tool for uncovering the presence of extraneous substances.
In addition to the usual publishing fare of primary research articles, case reports and letters, Drug Testing and Analysis offers a unique combination of; ‘How to’ material such as ‘Tutorials’ and ‘Reviews’, Speculative pieces (‘Commentaries’ and ‘Perspectives'', providing a broader scientific and social context to the aspects of analytical testing), ‘Annual banned substance reviews’ (delivering a critical evaluation of the methods used in the characterization of established and newly outlawed compounds).
Rather than focus on the application of a single technique, Drug Testing and Analysis employs a unique multidisciplinary approach to the field of controversial compound determination. Papers discussing chromatography, mass spectrometry, immunological approaches, 1D/2D gel electrophoresis, to name just a few select methods, are welcomed where their application is related to any of the six key topics listed below.
京公网安备 11010802042870号
京ICP备2023020795号-1
分享
求助内容：
应助结果提醒方式：
扫码关注我们
