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Enantiospecific synthesis, chiral separation, and biological activity of four indazole-3-carboxamide-type synthetic cannabinoid receptor agonists and their detection in seized drug samples

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Abstract
Synthetic cannabinoid receptor agonists (SCRAs) have been the largest group of illicit psychoactive substances reported to international monitoring and early warning systems for many years. Carboxamide-type SCRAs are amongst the most prevalent and potent. Enantiospecific synthesis and characterization of four indazole-3-carboxamides, AMB-FUBINACA, AB-FUBINACA, 5F-MDMB-PINACA (5F-ADB), and AB-CHMINACA is reported. The interactions of the compounds with CB1 and CB2 receptors were investigated using a G-protein coupled receptor (GPCR) activation assay based on functional complementation of a split NanoLuc luciferase and EC50 (a measure of potency) and E-max (a measure of efficacy) values determined. All compounds demonstrated higher potency at the CB2 receptor than at the CB1 receptor and (S)-enantiomers had an enhanced potency to both receptors over the (R)-enantiomers. The relative potency of the enantiomers to the CB2 receptor is affected by structural features. The difference was more pronounced for compounds with an amine moiety (AB-FUBINACA and AB-CHMINACA) than those with an ester moiety (AMB-FUBINACA and 5F-MDMB-PINACA). An HPLC method was developed to determine the prevalence of (R)-enantiomers in seized samples. Lux (R) Amylose-1 [Amylose tris(3,5-dimethylphenylcarbamate)] has the greatest selectivity for the SCRAs with a terminal methyl ester moiety and a Lux (R) i-Cellulose-5 column for SCRAs with a terminal amide moiety. Optimized isocratic separation methods yielded enantiomer resolution values (Rs) >= 1.99. Achiral GC-MS analysis of seized herbal materials (n = 16), found 5F-MDMB-PINACA (<1.0-91.5 mg/g herbal material) and AMB-FUBINACA (15.5-58.5 mg/g herbal material), respectively. EMB-FUBINACA, AMB-CHMICA, 5F-ADB-PINACA isomer 2, and ADB-CHMINACA were also tentatively identified. Analysis using chiral chromatography coupled to photodiode array and quadrupole time of flight mass spectrometry (chiral HPLC-PDA-QToF-MS/MS) confirmed that the (S)-enantiomer predominated in all samples (93.6-99.3% (S)-enantiomer). Small but significant differences in synthesis precursor enantiopurity may provide significant differences between synthesis batches or suppliers and warrants further study. A method to compare potency between samples containing different SCRAs at varying concentrations was developed and applied in this small preliminary study. A 10-fold difference in the "intrinsic" potency of samples in the study was noted. With the known heterogeneity of SCRA infused materials, the approach provides a simplified method for assessing and communicating the risk of their use.
Keywords
MDMB-FUBINACA, AMB-FUBINACA, PHARMACOLOGICAL EVALUATION, PSYCHOACTIVE, SUBSTANCES, CANNABIMIMETIC INDOLES, DESIGNER DRUGS, AB-FUBINACA, CUMYL-PICA, ADB-PINACA, IDENTIFICATION, synthetic cannabinoid receptor agonists, chiral, pharmacology, bioassay, detection

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MLA
Antonides, Lysbeth H., et al. “Enantiospecific Synthesis, Chiral Separation, and Biological Activity of Four Indazole-3-Carboxamide-Type Synthetic Cannabinoid Receptor Agonists and Their Detection in Seized Drug Samples.” FRONTIERS IN CHEMISTRY, vol. 7, 2019, doi:10.3389/fchem.2019.00321.
APA
Antonides, L. H., Cannaert, A., Norman, C., Vives, L., Harrison, A., Costello, A., … McKenzie, C. (2019). Enantiospecific synthesis, chiral separation, and biological activity of four indazole-3-carboxamide-type synthetic cannabinoid receptor agonists and their detection in seized drug samples. FRONTIERS IN CHEMISTRY, 7. https://doi.org/10.3389/fchem.2019.00321
Chicago author-date
Antonides, Lysbeth H, Annelies Cannaert, Caitlyn Norman, Loelia Vives, Aidan Harrison, Andrew Costello, Niamh Nic Daeid, Christophe Stove, Oliver B Sutcliffe, and Craig McKenzie. 2019. “Enantiospecific Synthesis, Chiral Separation, and Biological Activity of Four Indazole-3-Carboxamide-Type Synthetic Cannabinoid Receptor Agonists and Their Detection in Seized Drug Samples.” FRONTIERS IN CHEMISTRY 7. https://doi.org/10.3389/fchem.2019.00321.
Chicago author-date (all authors)
Antonides, Lysbeth H, Annelies Cannaert, Caitlyn Norman, Loelia Vives, Aidan Harrison, Andrew Costello, Niamh Nic Daeid, Christophe Stove, Oliver B Sutcliffe, and Craig McKenzie. 2019. “Enantiospecific Synthesis, Chiral Separation, and Biological Activity of Four Indazole-3-Carboxamide-Type Synthetic Cannabinoid Receptor Agonists and Their Detection in Seized Drug Samples.” FRONTIERS IN CHEMISTRY 7. doi:10.3389/fchem.2019.00321.
Vancouver
1.
Antonides LH, Cannaert A, Norman C, Vives L, Harrison A, Costello A, et al. Enantiospecific synthesis, chiral separation, and biological activity of four indazole-3-carboxamide-type synthetic cannabinoid receptor agonists and their detection in seized drug samples. FRONTIERS IN CHEMISTRY. 2019;7.
IEEE
[1]
L. H. Antonides et al., “Enantiospecific synthesis, chiral separation, and biological activity of four indazole-3-carboxamide-type synthetic cannabinoid receptor agonists and their detection in seized drug samples,” FRONTIERS IN CHEMISTRY, vol. 7, 2019.
@article{8650062,
  abstract     = {{Synthetic cannabinoid receptor agonists (SCRAs) have been the largest group of illicit psychoactive substances reported to international monitoring and early warning systems for many years. Carboxamide-type SCRAs are amongst the most prevalent and potent. Enantiospecific synthesis and characterization of four indazole-3-carboxamides, AMB-FUBINACA, AB-FUBINACA, 5F-MDMB-PINACA (5F-ADB), and AB-CHMINACA is reported. The interactions of the compounds with CB1 and CB2 receptors were investigated using a G-protein coupled receptor (GPCR) activation assay based on functional complementation of a split NanoLuc luciferase and EC50 (a measure of potency) and E-max (a measure of efficacy) values determined. All compounds demonstrated higher potency at the CB2 receptor than at the CB1 receptor and (S)-enantiomers had an enhanced potency to both receptors over the (R)-enantiomers. The relative potency of the enantiomers to the CB2 receptor is affected by structural features. The difference was more pronounced for compounds with an amine moiety (AB-FUBINACA and AB-CHMINACA) than those with an ester moiety (AMB-FUBINACA and 5F-MDMB-PINACA). An HPLC method was developed to determine the prevalence of (R)-enantiomers in seized samples. Lux (R) Amylose-1 [Amylose tris(3,5-dimethylphenylcarbamate)] has the greatest selectivity for the SCRAs with a terminal methyl ester moiety and a Lux (R) i-Cellulose-5 column for SCRAs with a terminal amide moiety. Optimized isocratic separation methods yielded enantiomer resolution values (Rs) >= 1.99. Achiral GC-MS analysis of seized herbal materials (n = 16), found 5F-MDMB-PINACA (<1.0-91.5 mg/g herbal material) and AMB-FUBINACA (15.5-58.5 mg/g herbal material), respectively. EMB-FUBINACA, AMB-CHMICA, 5F-ADB-PINACA isomer 2, and ADB-CHMINACA were also tentatively identified. Analysis using chiral chromatography coupled to photodiode array and quadrupole time of flight mass spectrometry (chiral HPLC-PDA-QToF-MS/MS) confirmed that the (S)-enantiomer predominated in all samples (93.6-99.3% (S)-enantiomer). Small but significant differences in synthesis precursor enantiopurity may provide significant differences between synthesis batches or suppliers and warrants further study. A method to compare potency between samples containing different SCRAs at varying concentrations was developed and applied in this small preliminary study. A 10-fold difference in the "intrinsic" potency of samples in the study was noted. With the known heterogeneity of SCRA infused materials, the approach provides a simplified method for assessing and communicating the risk of their use.}},
  articleno    = {{321}},
  author       = {{Antonides, Lysbeth H and Cannaert, Annelies and Norman, Caitlyn and Vives, Loelia and Harrison, Aidan and Costello, Andrew and Daeid, Niamh Nic and Stove, Christophe and Sutcliffe, Oliver B and McKenzie, Craig}},
  issn         = {{2296-2646}},
  journal      = {{FRONTIERS IN CHEMISTRY}},
  keywords     = {{MDMB-FUBINACA,AMB-FUBINACA,PHARMACOLOGICAL EVALUATION,PSYCHOACTIVE,SUBSTANCES,CANNABIMIMETIC INDOLES,DESIGNER DRUGS,AB-FUBINACA,CUMYL-PICA,ADB-PINACA,IDENTIFICATION,synthetic cannabinoid receptor agonists,chiral,pharmacology,bioassay,detection}},
  language     = {{eng}},
  pages        = {{20}},
  title        = {{Enantiospecific synthesis, chiral separation, and biological activity of four indazole-3-carboxamide-type synthetic cannabinoid receptor agonists and their detection in seized drug samples}},
  url          = {{http://dx.doi.org/10.3389/fchem.2019.00321}},
  volume       = {{7}},
  year         = {{2019}},
}

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