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<p>Synthetic cannabinoid receptor agonists (SCRAs) are a group of new psychoactive substances (NPS) that bind to and activate the cannabinoid 1 and 2 (CB<sub>1</sub> and CB<sub>2</sub>) receptors. Following the introduction of SCRA analog controls in China in July 2021, new SCRAs with a bromine at the 5 position on the indazole core emerged on the recreational drug market. In this study, the in vitro CB<sub>1</sub> receptor activity of 19 different SCRAs with a halogenated indazole core was systematically examined using a AequoScreen<sup>®</sup> CB<sub>1</sub> assay alongside four available non-halogenated analogs, ADB-BUTINACA, MDMB-BUTINACA, MDMB-4en-PINACA, and MDMB-INACA, and the newly emerged MDMB-5′Me-INACA (MDMB-5-methyl-INACA). Of SCRAs with a substitution at the 5 position on the indazole core, analogs with a fluorine had the lowest EC<sub>50</sub> values. For SCRAs with a methyl ester head moiety (MMB or MDMB), chlorinated analogs had the next lowest EC<sub>50</sub> values followed by brominated analogs; however, the opposite relationship was observed for SCRAs with an amide head moiety (AB or ADB). All halogenated compounds had similar potency to their non-halogenated analog, except the brominated <i>tert</i>-leucine methyl ester SCRAs, which had significantly reduced potency. Of the different head moieties, <i>tert</i>-leucine methyl ester SCRAs were the most potent, followed by <i>tert</i>-leucinamide, valinamide, and valine methyl ester. The potencies of the SCRAs with pentyl (ADB-5′Br-PINACA/ADMB-5′Br-PINACA/ADB-P-5′Br-INACA), pent-4-enyl (ADB-4en-5′Br-PINACA/ADMB-4en-5′Br-PINACA/ADB-4en-P-5′Br-INACA and MDMB-4en-5′Br-PINACA/MDMB-4en-P-5′Br-INACA), and butyl tails (ADB-5′Br-BUTINACA/ADMB-5′Br-BUTINACA/ADB-B-5′Br-INACA) were not significantly different, whereas fluorobenzyl (ADB-5′Br-FUBINACA), tail-less (ADB-5′Br-INACA), and decyl tail (ADB-5′Br-DECINACA/ADMB-5′Br-DECINACA/ADB-D-5′Br-INACA) analogs were significantly less potent.</p>

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In vitro CB1 receptor activity of halogenated indazole synthetic cannabinoid receptor agonists

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月18日

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  • Henrik Green,
  • Craig McKenzie,
  • Elias Hamra,
  • Tobias Rautio,
  • Xiongyu Wu,
  • Emma Juneskog,
  • Rebecka Sandblom,
  • Manuela Carla Monti,
  • Mattias Persson,
  • Caitlyn Norman

摘要

Synthetic cannabinoid receptor agonists (SCRAs) are a group of new psychoactive substances (NPS) that bind to and activate the cannabinoid 1 and 2 (CB1 and CB2) receptors. Following the introduction of SCRA analog controls in China in July 2021, new SCRAs with a bromine at the 5 position on the indazole core emerged on the recreational drug market. In this study, the in vitro CB1 receptor activity of 19 different SCRAs with a halogenated indazole core was systematically examined using a AequoScreen® CB1 assay alongside four available non-halogenated analogs, ADB-BUTINACA, MDMB-BUTINACA, MDMB-4en-PINACA, and MDMB-INACA, and the newly emerged MDMB-5′Me-INACA (MDMB-5-methyl-INACA). Of SCRAs with a substitution at the 5 position on the indazole core, analogs with a fluorine had the lowest EC50 values. For SCRAs with a methyl ester head moiety (MMB or MDMB), chlorinated analogs had the next lowest EC50 values followed by brominated analogs; however, the opposite relationship was observed for SCRAs with an amide head moiety (AB or ADB). All halogenated compounds had similar potency to their non-halogenated analog, except the brominated tert-leucine methyl ester SCRAs, which had significantly reduced potency. Of the different head moieties, tert-leucine methyl ester SCRAs were the most potent, followed by tert-leucinamide, valinamide, and valine methyl ester. The potencies of the SCRAs with pentyl (ADB-5′Br-PINACA/ADMB-5′Br-PINACA/ADB-P-5′Br-INACA), pent-4-enyl (ADB-4en-5′Br-PINACA/ADMB-4en-5′Br-PINACA/ADB-4en-P-5′Br-INACA and MDMB-4en-5′Br-PINACA/MDMB-4en-P-5′Br-INACA), and butyl tails (ADB-5′Br-BUTINACA/ADMB-5′Br-BUTINACA/ADB-B-5′Br-INACA) were not significantly different, whereas fluorobenzyl (ADB-5′Br-FUBINACA), tail-less (ADB-5′Br-INACA), and decyl tail (ADB-5′Br-DECINACA/ADMB-5′Br-DECINACA/ADB-D-5′Br-INACA) analogs were significantly less potent.