Synthesis and Functional Evaluation of Synthetic Cannabinoid Receptor Agonists Related to ADB-HEXINACA

Eric Sparkes; 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; Adam Ametovski

doi:10.1021/acschemneuro.3c00818

Synthesis and Functional Evaluation of Synthetic Cannabinoid Receptor Agonists Related to ADB-HEXINACA

ACS Chem Neurosci. 2024 May 1;15(9):1787-1812. doi: 10.1021/acschemneuro.3c00818. Epub 2024 Apr 10.

Authors

Eric Sparkes^{1

2}, Axelle Timmerman³, Jack W Markham^{1

2

4}, Rochelle Boyd^{1

4}, Rebecca Gordon^{1

4}, Katelyn A Walker^{1

5}, Richard C Kevin^{1

6

7}, David E Hibbs⁴, Samuel D Banister^{1

2}, Elizabeth A Cairns^{1

4}, Christophe Stove³, Adam Ametovski^{1

2}

Affiliations

¹ Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales 2050, Australia.
² School of Chemistry, The University of Sydney, Sydney, New South Wales 2050, Australia.
³ Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, 9000 Ghent, Belgium.
⁴ Sydney Pharmacy School, The University of Sydney, Sydney, New South Wales 2050, Australia.
⁵ School of Psychology, The University of Sydney, Sydney, New South Wales 2050, Australia.
⁶ Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital Sydney, Sydney, New South Wales 2010, Australia.
⁷ School of Clinical Medicine, The University of New South Wales, Sydney, New South Wales 2052, Australia.

PMID: 38597712
DOI: 10.1021/acschemneuro.3c00818

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_βγ-coupled agonism through a fluorescence-based membrane potential assay (MPA) and β-arrestin 2 (βarr2) recruitment via a live cell-based nanoluciferase complementation reporter assay. ADB-HEXINACA was a potent and efficacious CB₁ agonist (CB₁ MPA pEC₅₀ = 7.87 ± 0.12 M; E_max = 124 ± 5%; βarr2 pEC₅₀ = 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: ADB-HEXINACA; NPS; SCRA; cannabinoid; pharmacology.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cannabinoid Receptor Agonists* / chemical synthesis
Cannabinoid Receptor Agonists* / pharmacology
HEK293 Cells
Humans
Receptor, Cannabinoid, CB1* / agonists
Receptor, Cannabinoid, CB1* / metabolism
Receptor, Cannabinoid, CB2* / agonists
Receptor, Cannabinoid, CB2* / metabolism
Structure-Activity Relationship

Substances

Cannabinoid Receptor Agonists
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2