Structure-activity relationships of valine, tert-leucine, and phenylalanine amino acid-derived synthetic cannabinoid receptor agonists related to ADB-BUTINACA, APP-BUTINACA, and ADB-P7AICA

Eric Sparkes; Elizabeth A Cairns; Richard C Kevin; Felcia Lai; Katharina Elisabeth Grafinger; Shuli Chen; Marie H Deventer; Ross Ellison; Rochelle Boyd; Lewis J Martin; Iain S McGregor; Roy R Gerona; David E Hibbs; Volker Auwärter; Michelle Glass; Christophe Stove; Samuel D Banister

doi:10.1039/d1md00242b

Structure-activity relationships of valine, tert-leucine, and phenylalanine amino acid-derived synthetic cannabinoid receptor agonists related to ADB-BUTINACA, APP-BUTINACA, and ADB-P7AICA

RSC Med Chem. 2021 Oct 25;13(2):156-174. doi: 10.1039/d1md00242b. eCollection 2022 Feb 23.

Authors

Eric Sparkes^{1

2}, Elizabeth A Cairns^{2

3}, Richard C Kevin^{2

3}, Felcia Lai⁴, Katharina Elisabeth Grafinger⁵, Shuli Chen⁶, Marie H Deventer⁷, Ross Ellison⁸, Rochelle Boyd^{1

2}, Lewis J Martin^{2

3}, Iain S McGregor^{2

3}, Roy R Gerona⁸, David E Hibbs⁴, Volker Auwärter⁵, Michelle Glass⁶, Christophe Stove⁷, Samuel D Banister^{1

2}

Affiliations

¹ School of Chemistry, The University of Sydney NSW 2006 Australia samuel.banister@sydney.edu.au.
² The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney NSW 2050 Australia.
³ School of Psychology, The University of Sydney NSW 2050 Australia.
⁴ School of Pharmacy, The University of Sydney NSW 2006 Australia.
⁵ Institute of Forensic Medicine, Forensic Toxicology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg 79104 Freiburg Germany.
⁶ Department of Pharmacology and Toxicology, University of Otago Dunedin 9016 New Zealand.
⁷ Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University Ottergemsesteenweg 460 9000 Ghent Belgium.
⁸ Clinical Toxicology and Environmental Biomonitoring Laboratory, University of California San Francisco CA 94143 USA.

Abstract

Synthetic cannabinoid receptor agonists (SCRAs) remain one the most prevalent classes of new psychoactive substances (NPS) worldwide, and examples are generally poorly characterised at the time of first detection. We have synthesised a systematic library of amino acid-derived indole-, indazole-, and 7-azaindole-3-carboxamides related to recently detected drugs ADB-BUTINACA, APP-BUTINACA and ADB-P7AICA, and characterised these ligands for in vitro binding and agonist activity at cannabinoid receptor subtypes 1 and 2 (CB₁ and CB₂), and in vivo cannabimimetic activity. All compounds showed high affinity for CB₁ (K _i 0.299-538 nM) and most at CB₂ (K _i = 0.912-2190 nM), and most functioned as high efficacy agonists of CB₁ and CB₂ in a fluorescence-based membrane potential assay and a βarr2 recruitment assay (NanoBiT®), with some compounds being partial agonists in the NanoBiT® assay. Key structure-activity relationships (SARs) were identified for CB₁/CB₂ binding and CB₁/CB₂ functional activities; (1) for a given core, affinities and potencies for tert-leucinamides (ADB-) > valinamides (AB-) ≫ phenylalaninamides (APP-); (2) for a given amino acid side-chain, affinities and potencies for indazoles > indoles ≫ 7-azaindoles. Radiobiotelemetric evaluation of ADB-BUTINACA, APP-BUTINACA and ADB-P7AICA in mice demonstrated that ADB-BUTINACA and ADB-P7AICA were cannabimimetic at 0.1 mg kg^-1 and 10 mg kg^-1 doses, respectively, as measured by pronounced decreases in core body temperature. APP-BUTINACA failed to elicit any hypothermic response up to the maximally tested 10 mg kg^-1 dose, yielding an in vivo potency ranking of ADB-BUTINACA > ADB-P7AICA > APP-BUTINACA.