Linking in vitro and ex vivo CB1 activity with serum concentrations and clinical features in 5F-MDMB-PICA users to better understand SCRAs and their metabolites

Janssens, Liesl K.; Hudson, Simon; Wood, David M.; Wolfe, Caitlin; Dargan, Paul I.; Stove, Christophe

doi:10.1007/s00204-022-03355-6

Cited by 5 publications

(2 citation statements)

References 31 publications

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“…Among them, 5F-MDMB-PICA, a schedule-I drug, has been identified as one of the most prevalent SCRAs in United States, as of 2019 [66]. Fatal events have been associated with the use of this drug [67,68], as well as reports of notably strong depressant effects [69], and other toxic interactions [70]. Our present findings suggest that even minor structural modifications in newly emerging SCRAs, particularly in relation to the presence of substituted head moieties, can strongly increase SCRA efficacy, and potentially contribute to the adverse effects occurring with human consumption of these illicit compounds.…”

Section: Discussionmentioning

confidence: 99%

A subtle structural modification of a synthetic cannabinoid receptor agonist drastically increases its efficacy at the CB1 receptor

Yano

Chitsazi

Lucaj

et al. 2023

Preprint

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The emergence of synthetic cannabinoid receptor agonists (SCRAs) as illicit psychoactive substances has posed considerable public health risks that include fatalities. Many SCRAs exhibit much higher efficacy and potency, compared with the phytocannabinoid Δ9-tetrahydrocannabinol (THC), at the cannabinoid receptor 1 (CB1R), a G protein-coupled receptor involved in modulating neurotransmitter release. In this study, we investigated structure activity relationships (SAR) of aminoalkylindole SCRAs at CB1Rs, focusing on 5F-pentylindoles containing an amide linker attached to different head moieties. Using in vitro bioluminescence resonance energy transfer (BRET) assays, we identified a few of SCRAs exhibiting significantly higher efficacy in engaging the Gi protein and recruiting β-arrestin than the reference CB1R full agonist CP55940. Importantly, adding a methyl group at the head moiety of 5F-MMB-PICA yielded 5F-MDMB-PICA, an agonist exhibiting a large increase in efficacy and potency at the CB1R. This pharmacological observation was supported by a functional assay of the effects of these SCRAs on glutamate field potentials recorded in hippocampal slices. Molecular modeling and simulations of the CB1R bound with either of the SCRAs revealed critical structural determinants contributing to the higher efficacy of 5F-MDMB-PICA, and how these subtle differences propagated to the receptor-G protein interface. Thus, we find that apparently minor structural changes in the head moiety of SCRAs can cause major changes in efficacy. Our results highlight the need for close monitoring of structural modifications of newly emerging SCRAs and their potential for toxic drug responses in humans.

show abstract

Section: Discussionmentioning

confidence: 99%

A subtle structural modification of a synthetic cannabinoid receptor agonist drastically increases its efficacy at the CB1 receptor

Yano

Chitsazi

Lucaj

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…5,17,45 Among them, 5F-MDMB-PICA, a schedule-I drug, has been identified as one of the most prevalent SCRAs in the United States, as of 2019. 46 Fatal events have been associated with the use of this drug, 47,48 as well as reports of notably strong depressant effects, 49 and other toxic interactions. 50 Our present findings suggest that even minor structural modifications in newly emerging SCRAs, particularly in relation to the presence of substituted head moieties, can strongly increase SCRA efficacy and potentially contribute to the adverse effects occurring with human consumption of these illicit compounds.…”

Section: ■ Discussionmentioning

confidence: 99%

Subtle Structural Modification of a Synthetic Cannabinoid Receptor Agonist Drastically Increases its Efficacy at the CB1 Receptor

Yano,

Chitsazi,

Lucaj

et al. 2023

ACS Chem. Neurosci.

View full text Add to dashboard Cite

The emergence of synthetic cannabinoid receptor agonists (SCRAs) as illicit psychoactive substances has posed considerable public health risks, including fatalities. Many SCRAs exhibit much higher efficacy and potency compared with the phytocannabinoid Δ9-tetrahydrocannabinol (THC) at the cannabinoid receptor 1 (CB1R), leading to dramatic differences in signaling levels that can be toxic. In this study, we investigated the structure–activity relationships of aminoalkylindole SCRAs at CB1Rs, focusing on 5F-pentylindoles containing an amide linker attached to different head moieties. Using in vitro bioluminescence resonance energy transfer assays, we identified a few SCRAs exhibiting significantly higher efficacy in engaging the Gi protein and recruiting β-arrestin than the reference CB1R full agonist CP55940. Importantly, the extra methyl group on the head moiety of 5F-MDMB-PICA, as compared to that of 5F-MMB-PICA, led to a large increase in efficacy and potency at the CB1R. This pharmacological observation was supported by the functional effects of these SCRAs on glutamate field potentials recorded in hippocampal slices. Molecular modeling and simulations of the CB1R models bound with both of the SCRAs revealed critical structural determinants contributing to the higher efficacy of 5F-MDMB-PICA and how these subtle differences propagated to the receptor-G protein interface. Thus, we find that apparently minor structural changes in the head moiety of SCRAs can cause major changes in efficacy. Our results highlight the need for close monitoring of the structural modifications of newly emerging SCRAs and their potential for toxic drug responses in humans.

show abstract

Interpreting mono- and poly-SCRA intoxications from an activity-based point of view: JWH-018 equivalents in serum as a comparative measure

Janssens,

Sommer,

Grafinger

et al. 2024

Arch Toxicol

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Linking in vitro and ex vivo CB1 activity with serum concentrations and clinical features in 5F-MDMB-PICA users to better understand SCRAs and their metabolites

Cited by 5 publications

References 31 publications

A subtle structural modification of a synthetic cannabinoid receptor agonist drastically increases its efficacy at the CB1 receptor

A subtle structural modification of a synthetic cannabinoid receptor agonist drastically increases its efficacy at the CB1 receptor

Subtle Structural Modification of a Synthetic Cannabinoid Receptor Agonist Drastically Increases its Efficacy at the CB1 Receptor

Interpreting mono- and poly-SCRA intoxications from an activity-based point of view: JWH-018 equivalents in serum as a comparative measure

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