In vitro cannabinoid activity profiling of generic ban-evading brominated synthetic cannabinoid receptor agonists and their analogs

• Following the enactment of a generic ban in China in 2021, the synthetic cannabinoid market has been evolving, now encompassing even wider structural diversity. Compounds carrying a brominated core such as ADB-5 Br-BUTINACA (ADMB-B-5Br-INACA) and tail-less analogs, such as ADB-5 Br-INACA (ADMB-5Br-INACA), MDMB-5 Br-INACA, and ADB-INACA (ADMB-INACA), have been detected since late 2021. This study investigated the cannabinoid receptor (CB) activation potential of synthesized (S)-enantiomers of these substances, as well as of two predicted analogs MDMB-5 Br-BUTINACA (MDMB-B-5Br-INACA) and ADB-5 F-BUTINACA (ADMB-B-5F-INACA), using CB1 and CB2 beta-arrestin 2 recruitment assays and a CB1 intracellular calcium release assay. Surprisingly, the tail-less (S)-ADB-5 Br-INACA and (S)-MDMB-5 Br-INACA retained CB activity, albeit with a decreased potency compared to their tailed counterparts (S)-ADB-5 Br-BUTINACA and (S)-MDMB-5 Br-BUTINACA, respectively, which were potent and efficacious CB1 agonists. Also, at CB2, tail-less analogs showed a lower potency but increased efficacy. Removing the bromine substitution ((S)-ADB-INACA) resulted in a reduced activity at CB1; however, this effect was less prominent at CB2. Looking at tailed analogs, replacing the bromine with a fluorine substitution ((S)-ADB-5 F-BUTINACA) resulted in an increased potency and efficacy at both receptors. Furthermore, as ADB-5 Br-INACA and MDMB-5 Br-INACA have been frequently detected together in Scottish prisons, this study also evaluated the CB1 receptor activation potential of different mixtures of their respective reference standards, showing no unexpected cannabimimetic effect of combining both substances. Lastly, two powders seized by Belgian Customs and confirmed to contain ADB-5 Br-INACA and MDMB-5 Br-INACA, respectively, were assessed for CB activity. Based on the comparison with their reference standards, varying degrees of purity were suspected. The enactment of the Chinese generic ban (2021) has majorly impacted the SCRA market, exemplified by the recent emergence of tail-less compounds and substances with a brominated core. CB1 and CB2 cannabinoid activity of six analogs was assessed using beta arr2 recruitment and Ca2+ release assays. Absence of a tail moiety still yielded cannabinoid activity albeit with lower potency, whereas tailed analogs were highly efficacious.image

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medicinal Chemistry (hsv//eng)

Nyckelord

ADB-5Br-BUTINACA; ADB-5Br-INACA; brominated synthetic cannabinoid receptor agonists; CB1 cannabinoid receptor; MDMB-5Br-INACA

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