Synthesis and functional evaluation of synthetic cannabinoid receptor agonists related to ADB-HEXINACA
- Author
- Eric Sparkes, Axelle Timmerman (UGent) , Jack W. Markham, Rochelle Boyd, Rebecca Gordon, Katelyn A. Walker, Richard C. Kevin, David E. Hibbs, Samuel D. Banister, Elizabeth A. Cairns, Christophe Stove (UGent) and Adam Ametovski
- Organization
- Project
- Abstract
- ADB-HEXINACA has been recently reported as a synthetic cannabinoid receptor agonist (SCRA), one of the largest classes of new psychoactive substances (NPSs). This compound marks the entry of the n-hexyl tail group into the SCRA landscape, which has continued in the market with recent, newly detected SCRAs. As such, a proactive characterization campaign was undertaken, including the synthesis, characterization, and pharmacological evaluation of ADB-HEXINACA and a library of 41 closely related analogues. Two in vitro functional assays were employed to assess activity at CB1 and CB2 cannabinoid receptors, measuring G(beta gamma)-coupled agonism through a fluorescence-based membrane potential assay (MPA) and beta-arrestin 2 (beta arr2) recruitment via a live cell-based nanoluciferase complementation reporter assay. ADB-HEXINACA was a potent and efficacious CB1 agonist (CB1 MPA pEC(50) = 7.87 +/- 0.12 M; E-max = 124 +/- 5%; beta arr2 pEC(50) = 8.27 +/- 0.14 M; E-max = 793 +/- 42.5), as were most compounds assessed. Isolation of the heterocyclic core and alkyl tails allowed for the comprehensive characterization of structure-activity relationships in this compound class, which were rationalized in silico via induced fit docking experiments. Overall, most compounds assessed are possibly emerging NPSs.
- Keywords
- Cell Biology, Cognitive Neuroscience, Physiology, Biochemistry, General Medicine, cannabinoid, pharmacology, ADB-HEXINACA, SCRA, NPS, PHARMACOLOGY, FUBINACA, PROTEIN, ACTIVATION, BRAIN
Downloads
-
(...).pdf
- full text (Published version)
- |
- UGent only
- |
- |
- 5.64 MB
Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-01HVK1KYPP68MAXWNJH0KQKX50
- MLA
- Sparkes, Eric, et al. “Synthesis and Functional Evaluation of Synthetic Cannabinoid Receptor Agonists Related to ADB-HEXINACA.” ACS CHEMICAL NEUROSCIENCE, vol. 15, no. 9, 2024, pp. 1787–812, doi:10.1021/acschemneuro.3c00818.
- APA
- Sparkes, E., Timmerman, A., Markham, J. W., Boyd, R., Gordon, R., Walker, K. A., … Ametovski, A. (2024). Synthesis and functional evaluation of synthetic cannabinoid receptor agonists related to ADB-HEXINACA. ACS CHEMICAL NEUROSCIENCE, 15(9), 1787–1812. https://doi.org/10.1021/acschemneuro.3c00818
- Chicago author-date
- Sparkes, Eric, Axelle Timmerman, Jack W. Markham, Rochelle Boyd, Rebecca Gordon, Katelyn A. Walker, Richard C. Kevin, et al. 2024. “Synthesis and Functional Evaluation of Synthetic Cannabinoid Receptor Agonists Related to ADB-HEXINACA.” ACS CHEMICAL NEUROSCIENCE 15 (9): 1787–1812. https://doi.org/10.1021/acschemneuro.3c00818.
- Chicago author-date (all authors)
- Sparkes, Eric, Axelle Timmerman, Jack W. Markham, Rochelle Boyd, Rebecca Gordon, Katelyn A. Walker, Richard C. Kevin, David E. Hibbs, Samuel D. Banister, Elizabeth A. Cairns, Christophe Stove, and Adam Ametovski. 2024. “Synthesis and Functional Evaluation of Synthetic Cannabinoid Receptor Agonists Related to ADB-HEXINACA.” ACS CHEMICAL NEUROSCIENCE 15 (9): 1787–1812. doi:10.1021/acschemneuro.3c00818.
- Vancouver
- 1.Sparkes E, Timmerman A, Markham JW, Boyd R, Gordon R, Walker KA, et al. Synthesis and functional evaluation of synthetic cannabinoid receptor agonists related to ADB-HEXINACA. ACS CHEMICAL NEUROSCIENCE. 2024;15(9):1787–812.
- IEEE
- [1]E. Sparkes et al., “Synthesis and functional evaluation of synthetic cannabinoid receptor agonists related to ADB-HEXINACA,” ACS CHEMICAL NEUROSCIENCE, vol. 15, no. 9, pp. 1787–1812, 2024.
@article{01HVK1KYPP68MAXWNJH0KQKX50,
abstract = {{ADB-HEXINACA has been recently reported as a synthetic cannabinoid receptor agonist (SCRA), one of the largest classes of new psychoactive substances (NPSs). This compound marks the entry of the n-hexyl tail group into the SCRA landscape, which has continued in the market with recent, newly detected SCRAs. As such, a proactive characterization campaign was undertaken, including the synthesis, characterization, and pharmacological evaluation of ADB-HEXINACA and a library of 41 closely related analogues. Two in vitro functional assays were employed to assess activity at CB1 and CB2 cannabinoid receptors, measuring G(beta gamma)-coupled agonism through a fluorescence-based membrane potential assay (MPA) and beta-arrestin 2 (beta arr2) recruitment via a live cell-based nanoluciferase complementation reporter assay. ADB-HEXINACA was a potent and efficacious CB1 agonist (CB1 MPA pEC(50) = 7.87 +/- 0.12 M; E-max = 124 +/- 5%; beta arr2 pEC(50) = 8.27 +/- 0.14 M; E-max = 793 +/- 42.5), as were most compounds assessed. Isolation of the heterocyclic core and alkyl tails allowed for the comprehensive characterization of structure-activity relationships in this compound class, which were rationalized in silico via induced fit docking experiments. Overall, most compounds assessed are possibly emerging NPSs.}},
author = {{Sparkes, Eric and Timmerman, Axelle and Markham, Jack W. and Boyd, Rochelle and Gordon, Rebecca and Walker, Katelyn A. and Kevin, Richard C. and Hibbs, David E. and Banister, Samuel D. and Cairns, Elizabeth A. and Stove, Christophe and Ametovski, Adam}},
issn = {{1948-7193}},
journal = {{ACS CHEMICAL NEUROSCIENCE}},
keywords = {{Cell Biology,Cognitive Neuroscience,Physiology,Biochemistry,General Medicine,cannabinoid,pharmacology,ADB-HEXINACA,SCRA,NPS,PHARMACOLOGY,FUBINACA,PROTEIN,ACTIVATION,BRAIN}},
language = {{eng}},
number = {{9}},
pages = {{1787--1812}},
title = {{Synthesis and functional evaluation of synthetic cannabinoid receptor agonists related to ADB-HEXINACA}},
url = {{http://doi.org/10.1021/acschemneuro.3c00818}},
volume = {{15}},
year = {{2024}},
}
- Altmetric
- View in Altmetric
- Web of Science
- Times cited: