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

Eric Sparkes; Callan J Maloney; Jack W Markham; Chianna Dane; Rochelle Boyd; Jayson Gilchrist; Michael Moir; Rebecca Gordon; Jia Lin Luo; Edward Pike; Katelyn A Walker; Michael Kassiou; Iain S McGregor; Richard C Kevin; David E Hibbs; William T Jorgensen; Samuel D Banister; Elizabeth A Cairns; Adam Ametovski

doi:10.1021/acschemneuro.3c00850

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

ACS Chem Neurosci. 2024 Jun 5;15(11):2160-2181. doi: 10.1021/acschemneuro.3c00850. Epub 2024 May 20.

Authors

Eric Sparkes^{1

2}, Callan J Maloney^{1

2}, Jack W Markham^{1

2

3}, Chianna Dane², Rochelle Boyd^{1

3}, Jayson Gilchrist², Michael Moir⁴, Rebecca Gordon^{1

3}, Jia Lin Luo^{1

5}, Edward Pike^{1

2

6}, Katelyn A Walker^{1

5}, Michael Kassiou², Iain S McGregor^{1

5}, Richard C Kevin^{1

7

8}, David E Hibbs³, William T Jorgensen², Samuel D Banister^{1

2}, Elizabeth A Cairns^{1

3}, Adam Ametovski^{1

2}

Affiliations

¹ Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia.
² School of Chemistry, Faculty of Science, The University of Sydney, Sydney, NSW 2006, Australia.
³ Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia.
⁴ National Deuteration Facility, Australian Nuclear Science and Technology Organisation, Sydney, NSW 2234, Australia.
⁵ School of Psychology, Faculty of Science, The University of Sydney, Sydney, NSW 2006, Australia.
⁶ Department of Chemistry, University of York, York YO10 5DD, U.K.
⁷ Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital Sydney, Sydney, NSW 2010, Australia.
⁸ School of Clinical Medicine, The University of New South Wales, Sydney, NSW 2052, Australia.

PMID: 38766866
DOI: 10.1021/acschemneuro.3c00850

Abstract

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.

Keywords: SAR; SCRA; adamantane; cannabinoid; deuteration; pharmacology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Cannabinoid Receptor Agonists
Indazoles
Indoles
methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamido)-3-methylbutanoate
methyl 2-(1-(cyclohexylmethyl)-1H-indole-3-carboxamido)-3,3-dimethylbutanoate
Adamantane
Deuterium
Valine