In vitro cannabinoid activity profiling of generic ban‐evading brominated synthetic cannabinoid receptor agonists and their analogs

Author:

Deventer Marie H.1ORCID,Persson Mattias2ORCID,Norman Caitlyn3ORCID,Liu Huiling4ORCID,Connolly Matthew J.4ORCID,Daéid Niamh Nic3ORCID,McKenzie Craig34ORCID,Gréen Henrik25ORCID,Stove Christophe P.1ORCID

Affiliation:

1. Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences Ghent University Ghent Belgium

2. Department of Forensic Genetics and Forensic Toxicology National Board of Forensic Medicine Linköping Sweden

3. Leverhulme Research Centre for Forensic Science, School of Science and Engineering University of Dundee Dundee UK

4. Chiron AS Trondheim Norway

5. Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences Linköping University Linköping Sweden

Abstract

AbstractFollowing 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.

Funder

Fonds Wetenschappelijk Onderzoek

Leverhulme Trust

Publisher

Wiley

Subject

Spectroscopy,Pharmaceutical Science,Environmental Chemistry,Analytical Chemistry

Reference74 articles.

1. Office of China National Narcotics Control Commission.Announcement on the inclusion of 18 substances including synthetic cannabinoids and fluamine in the Supplementary List of Controlled Narcotic Drugs and Psychotropic Substances with Non‐medical Use.2021. Available at:https://app.mps.gov.cn/gdnps/pc/content.jsp?id=7881703

2. United Nations Office on Drugs and Crime. “News: May 2021– China: announcement to place synthetic cannabinoids under generic control ” Available at:https://www.unodc.org/LSS/Announcement/Details/ff032a29-2e14-4dab-b7d8-ab86d355c809 2021. Accessed on: 31‐10‐2022

3. United Nations Office on Drugs and Crime.World drug report 2022 Vienna n.d. Available at:https://www.unodc.org/unodc/en/data-and-analysis/world-drug-report-2022.html

4. EMCDDA framework and practical guidance for naming synthetic cannabinoids

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