Structure–Activity Relationships, Deuteration, and Fluorination of Synthetic Cannabinoid Receptor Agonists Related to AKB48, 5F-AKB-48, and AFUBIATA

Synthetic cannabinoid receptor agonists (SCRAs) are a growing class of new psychoactive substances (NPS) commonly derived from an N-alkylated indole, indazole, or 7-azaindole scaffold. Diversification of this core (at the 3-position) with amide-linked pendant amino acid groups and modular N-alkylati...

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Published in:ACS chemical neuroscience 2024-06, Vol.15 (11), p.2160-2181
Main Authors: Sparkes, Eric, Maloney, Callan J., Markham, Jack W., Dane, Chianna, Boyd, Rochelle, Gilchrist, Jayson, Moir, Michael, Gordon, Rebecca, Luo, Jia Lin, Pike, Edward, Walker, Katelyn A., Kassiou, Michael, McGregor, Iain S., Kevin, Richard C., Hibbs, David E., Jorgensen, William T., Banister, Samuel D., Cairns, Elizabeth A., Ametovski, Adam
Format: Article
Language:English
Subjects:
Adamantane - analogs & derivatives
Adamantane - chemistry
Adamantane - pharmacology
Animals
Cannabinoid Receptor Agonists - chemical synthesis
Cannabinoid Receptor Agonists - chemistry
Cannabinoid Receptor Agonists - pharmacology
Deuterium
Halogenation
Humans
Indazoles - chemical synthesis
Indazoles - chemistry
Indazoles - pharmacology
Indoles - chemistry
Indoles - pharmacology
Mice
Structure-Activity Relationship
Valine - analogs & derivatives
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Summary:Synthetic cannabinoid receptor agonists (SCRAs) are a growing class of new psychoactive substances (NPS) commonly derived from an N-alkylated indole, indazole, or 7-azaindole scaffold. Diversification of this core (at the 3-position) with amide-linked pendant amino acid groups and modular N-alkylation (of the indole/indazole/7-azaindole core) ensures that novel SCRAs continue to enter the illicit drug market rapidly. In response to the large number of SCRAs that have been detected, pharmacological evaluation of this NPS class has become increasingly common. Adamantane-derived SCRAs have consistently appeared throughout the market since 2011, and as such, a systematic set of these derivatives was synthesized and pharmacologically evaluated. Deuterated and fluorinated adamantane derivatives were prepared to evaluate typical hydrogen bioisosteres, as well as evaluation of the newly detected AFUBIATA.
ISSN:1948-7193
1948-7193
DOI:10.1021/acschemneuro.3c00850