Cumyl‐PEGACLONE: A comparatively safe new synthetic cannabinoid receptor agonist entering the NPS market?

Synthetic cannabinoid receptor agonists (SCRAs) first appeared on the international recreational drug market in the early 2000s in the form of SCRA‐containing herbal blends. Due to the cannabimimetic effects associated with the consumption of SCRAs, they have acquired an ill‐informed reputation for being cheap, safe, and legal alternatives to illicit cannabis. Possessing high potency and affinity for the human cannabinoid receptor subtype‐1 (CB1) and ‐2 (CB2), it is now understood that the recreational use of SCRAs can have severe adverse health consequences. The major public health problem arising from SCRA use has pressed legislators around the world to employ various control strategies to curb their recreational use. To circumvent legislative control measures, SCRA manufacturers have created a wide range of SCRA analogs that contain, more recently, previously unencountered azaindole, γ‐carbolinone, or carbazole heterocyclic scaffolds. At present, little information is available regarding the chemical syntheses of these newly emerging classes of SCRA, from a clandestine perspective. When compared with previous generations of indole‐ and indazole‐type SCRAs, current research suggests that many of these heterocyclic SCRA analogs maintain high affinity and efficacy at both CB1 and CB2 but largely evade legislative control. This review highlights the importance of continued research in the field of SCRA chemistry and pharmacology, as recreational SCRA use remains a global public health issue and represents a serious control challenge for law enforcement agencies.

Section: Ernst Et Al Reported the Identification Of Cumyl-pegamentioning

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Adding more “spice” to the pot: A review of the chemistry and pharmacology of newly emerging heterocyclic synthetic cannabinoid receptor agonists

Alam

Keating

2020

“…Structurally, it contains a γ‐carbolinone core, which is unique among SCs with the exception of its analog, 5F‐CUMYL‐PEGACLONE. CUMYL‐PEGACLONE is a full CB1 and CB2 receptor agonist, and thus a potent drug; however, it has been suggested that it may not be as acutely toxic as some other SCs . More data is needed to confirm this observation.…”

Section: Introductionmentioning

confidence: 99%

Identification of a thermal degradation product of CUMYL‐PEGACLONE and its detection in biological samples

Nash

Glowacki

Gerostamoulos

et al. 2019

The structural diversity of synthetic cannabinoids makes it a challenging task to have a comprehensive screening method for this class of drugs. The difficulty is increased by the fact that some synthetic cannabinoids undergo thermal decomposition during common routes of administration, such as smoking or vaping. CUMYL‐PEGACLONE is a relatively new synthetic cannabinoid which has a structural variant from most other synthetic cannabinoids: a γ‐carbolinone core. To investigate its thermal stability, CUMYL‐PEGACLONE was heated in an oven at temperatures ranging from 200 to 350oC, and a major thermal degradation product, N‐pentyl‐γ‐carbolinone, was subsequently identified. Unlike some other synthetic cannabinoids, the thermal degradation product of CUMYL‐PEGACLONE is not one of its known metabolites, nor were any known metabolites detected during the thermal stability experiments. The degradation product was formed in significant amounts at temperatures above 250°C, and has been detected (along with CUMYL‐PEGACLONE) in case samples, including post‐mortem blood and urine, and residue found at a scene.

In vitro activity profiling of Cumyl‐PEGACLONE variants at the CB₁ receptor: Fluorination versus isomer exploration

Janssens

Cannaert

Connolly

et al. 2020

Synthetic cannabinoid receptor agonists (SCRAs) are one of the largest groups of new psychoactive substances monitored in Europe. SCRAs are known to typically exert higher cannabinoid activity than tetrahydrocannabinol from cannabis, thereby entailing a greater health risk. Both Cumyl‐PEGACLONE and 5F‐Cumyl‐PEGACLONE were not controlled by the national legislation upon their first detection in Germany in 2016 and 2017, respectively, and have been linked to several fatalities. In this study, the CB1 receptor activity of these compounds, together with two newly synthesized structural isomers (Cumyl‐PEGACLONE ethylbenzyl isomer and n‐propylphenyl isomer), was assessed using two different in vitro receptor‐proximal bioassays, monitoring the recruitment of either β‐arrestin2 (β‐arr2) or a modified G protein (mini‐Gαi) to the activated CB1 receptor. In terms of both potency and relative efficacy, Cumyl‐PEGACLONE and 5F‐Cumyl‐PEGACLONE were found to exert strong CB1 activation, with sub‐nanomolar EC50 values and efficacy values exceeding those of the reference agonist JWH‐018 threefold (β‐arr2 assay) or almost twofold (mini‐Gαi assay). The ethylbenzyl and n‐propylphenyl isomers exhibited a strongly reduced CB1 activity (EC50 values >100 nM; efficacy <40% relative to JWH‐018), which is hypothesized to originate from steric hindrance in the ligand‐binding pocket. None of the evaluated compounds exhibited significant biased agonism. In conclusion, the functional assays applied here allowed us to demonstrate that 5‐fluorination of Cumyl‐PEGACLONE is not linked to an intrinsically higher CB1 activation potential and that the ethylbenzyl and n‐propylphenyl isomers yield a strongly reduced CB1 activation.