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
binding and agonist activity at cannabinoid receptor subtypes 1 and 2 (CB
and CB
), and
cannabimimetic activity. All compounds showed high affinity for CB
(
0.299-538 nM) and most at CB
(
= 0.912-2190 nM), and most functioned as high efficacy agonists of CB
and CB
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 CB
/CB
binding and CB
/CB
functional activities; (1) for a given core, affinities and potencies for
-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
and 10 mg kg
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
dose, yielding an
potency ranking of ADB-BUTINACA > ADB-P7AICA > APP-BUTINACA.