scholarly journals Differential activation of G-protein-mediated signalling by synthetic cannabinoid receptor agonists

2019 ◽  
Author(s):  
Shivani Sachdev ◽  
Samuel D. Banister ◽  
Marina Santiago ◽  
Chris Bladen ◽  
Michael Kassiou ◽  
...  
Keyword(s):  
G Protein ◽  
Molecular Mechanisms ◽  
Cannabinoid Receptor ◽  
Rank Order ◽  
Synthetic Cannabinoid ◽  
New Psychoactive Substances ◽  
Differential Activation ◽  
Receptor Agonists ◽  
Synthetic Cannabinoid Receptor Agonists ◽  
Camp Levels

AbstractSynthetic cannabinoid receptor agonists (SCRAs) are new psychoactive substances associated with acute intoxication and even death. However, the molecular mechanisms through which SCRAs may exert their toxic effects remain unclear - including the potential differential activation of G protein subtypes by CB1, a major target of SCRA. We measured CB1-mediated activation of Gαs and Gαi/o proteins by SCRAs by examining stimulation (PTX-treated) as well as inhibition (non-PTX treated) of forskolin-induced cAMP accumulation in HEK cells stably expressing CB1. Real-time measurements of stimulation and inhibition of cAMP levels were made using a BRET biosensor. We found that the maximum concentration of SCRAs tested (10 μM), increased cAMP levels 12 to 45% above that produced by forskolin alone, while the phytocannabinoid THC did not significantly alter cAMP levels in PTX-treated HEK-CB1 cells. All SCRAs had greater potency to inhibit of forskolin-induced cAMP levels than to stimulate cAMP levels. The rank order of potencies for SCRA stimulation of cAMP (Gαs) was PB-22 > 5F-MDMB-PICA > JWH-018 > AB-FUBINACA > XLR-11. By contrast, the potency of SCRAs for inhibition of cAMP (Gαi/o) was 5F-MDMB-PICA > AB-FUBINACA > PB-22 > JWH-018 > XLR-11. The different rank order of potency of the SCRAs to stimulate Gαs-like signalling compared to Gαi/o signalling suggests differences in G protein preference between SCRAs. Understanding the apparent differences among these drugs may contribute to unravelling their complex effects in humans.

scholarly journals Differential activation of G protein‐mediated signaling by synthetic cannabinoid receptor agonists

2020 ◽  
Vol 8 (2) ◽  
Author(s):  
Shivani Sachdev ◽  
Samuel D. Banister ◽  
Marina Santiago ◽  
Chris Bladen ◽  
Michael Kassiou ◽  
...  
Keyword(s):  
G Protein ◽  
Cannabinoid Receptor ◽  
Synthetic Cannabinoid ◽  
Differential Activation ◽  
Receptor Agonists ◽  
Synthetic Cannabinoid Receptor Agonists

An index of fatal toxicity for new psychoactive substances

2018 ◽  
Vol 32 (7) ◽  
pp. 793-801 ◽  
Author(s):  
Leslie A King ◽  
John M Corkery
Keyword(s):  
Cannabinoid Receptor ◽  
Synthetic Cannabinoid ◽  
New Psychoactive Substances ◽  
Death Certificates ◽  
Psychoactive Substances ◽  
Receptor Agonists ◽  
A Value ◽  
Other Substances ◽  
Synthetic Cannabinoid Receptor Agonists ◽  
Original Reference

An index of fatal toxicity for new psychoactive substances has been developed based solely on information provided on death certificates. An updated index of fatal toxicity (Tf), as first described in 2010, was calculated based on the ratio of deaths to prevalence and seizures for the original five substances (amphetamine, cannabis, cocaine/crack, heroin and 3,4-methylenedioxymethylamphetamine)*. These correlated well with the 2010 index. Deaths were then examined for cases both where the substance was and was not found in association with other substances. This ratio (sole to all mentions; S/A) was then calculated for deaths in the period 1993 to 2016. This new measure of fatal toxicity, expressed by S/A, was well-correlated with the index Ln (Tf) of the original reference compounds. The calculation of S/A was then extended to a group of new psychoactive substances where insufficient prevalence or seizure data were available to directly determine a value of Tf by interpolation of a graph of Tf versus S/A. Benzodiazepine analogues had particularly low values of S/A and hence Tf. By contrast, γ-hydroxybutyrate/γ-butyrolactone, α-methyltryptamine, synthetic cannabinoid receptor agonists and benzofurans had a higher fatal toxicity.

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

2021 ◽  
Author(s):  
Eric Sparkes ◽  
Elizabeth Cairns ◽  
Richard Kevin ◽  
Felcia Lai ◽  
Katharina Grafinger ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cannabinoid Receptor ◽  
Synthetic Cannabinoid ◽  
New Psychoactive Substances ◽  
Psychoactive Substances ◽  
Structure Activity Relationships ◽  
Receptor Agonists ◽  
Structure Activity ◽  
Synthetic Cannabinoid Receptor Agonists

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...

scholarly journals Modulation of Human T-type Calcium Channels by Synthetic Cannabinoid Receptor Agonists in vitro

2020 ◽  
Author(s):  
Chris Bladen ◽  
Somayeh Mirlohi ◽  
Marina Santiago ◽  
Mitchell Longworth ◽  
Michael Kassiou ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Molecular Mechanisms ◽  
Cannabinoid Receptor ◽  
Synthetic Cannabinoids ◽  
Synthetic Cannabinoid ◽  
Hek293 Cells ◽  
Channel Activity ◽  
Receptor Agonists ◽  
Synthetic Cannabinoid Receptor Agonists

AbstractBACKGROUND AND PURPOSEConsumption of Synthetic Cannabinoid Receptor agonists (SCRAs) is associated with severe adverse reactions including seizures, arrhythmias and death, but the molecular mechanisms surrounding SCRA toxicity are not yet established. These disease-like symptoms are also synonymous with altered T-type calcium channel activity which controls rhythmicity in the heart and brain. This study examined whether SCRAs alter T-type activity and whether this represents a possible mechanism of toxicity.EXPERIMENTAL APPROACHFluorescence-based and electrophysiology assays were used to screen 16 structurally related synthetic cannabinoids for their ability to inhibit human T-type calcium channels expressed in HEK293 cells. The most potent compounds were then further examined using patch clamp electrophysiology.KEY RESULTSMDMB-CHMICA and AMB-CHMINACA potently blocked Cav3.2 with IC50 values of 1.5 and 0.74 μM respectively. Current inhibition increased from 47 to 80% and 45 to 87% respectively when the channel was in slow-inactivated state. Both SCRAs had little effect on steady state inactivation, however MDMB-CHMICA significantly shifted the half activation potential by −7mV. Neither drug produced frequency dependent block, in contrast to the phytocannabinoid Δ9-THC.CONCLUSIONS and IMPLICATIONSSCRAs are potent agonists of CB1 receptors and can be extremely toxic, but observed toxicity also resembles symptoms associated with altered Cav3.2 activity. Many SCRAs tested were potent modulators of Cav3.2, raising the possibility that SC toxicity may be due in part to Cav3.2 modulation. This potent T-type channel modulation suggests the possibility of SCRAs as a new drug class with potential to treat diseases associated with altered T-type channel activity.

scholarly journals Identification and Analytical Characterization of a Novel Synthetic Cannabinoid-Type Substance in Herbal Material in Europe

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 793
Author(s):  
Emmanouil D. Tsochatzis ◽  
Joao Alberto Lopes ◽  
Margaret V. Holland ◽  
Fabiano Reniero ◽  
Giovanni Palmieri ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cannabinoid Receptor ◽  
Analytical Data ◽  
Synthetic Cannabinoids ◽  
Synthetic Cannabinoid ◽  
Gas Chromatography Mass Spectrometry ◽  
New Psychoactive Substances ◽  
Synthetic Cannabinoid Receptor Agonists ◽  
Analytical Laboratories

The rapid diffusion of new psychoactive substances (NPS) presents unprecedented challenges to both customs authorities and analytical laboratories involved in their detection and characterization. In this study an analytical approach to the identification and structural elucidation of a novel synthetic cannabimimetic, quinolin-8-yl-3-[(4,4-difluoropiperidin-1-yl) sulfonyl]-4-methylbenzoate (2F-QMPSB), detected in seized herbal material, is detailed. An acid precursor 4-methyl-3-(4,4-difluoro-1-piperidinylsulfonyl) benzoic acid (2F-MPSBA), has also been identified in the same seized material. After extraction from the herbal material the synthetic cannabimimetic, also referred to as synthetic cannabinoid receptor agonists or “synthetic cannabinoids”, was characterized using gas chromatography-mass spectrometry (GC-MS), 1H, 13C, 19F and 15N nuclear magnetic resonance (NMR) and high-resolution tandem mass spectrometry (HR-MS/MS) combined with chromatographic separation. A cheminformatics platform was used to manage and interpret the analytical data from these techniques.

scholarly journals Modulation of human T-type calcium channels by synthetic cannabinoid receptor agonists in vitro

2021 ◽  
Vol 187 ◽  
pp. 108478
Author(s):  
Chris Bladen ◽  
Somayeh Mirlohi ◽  
Marina Santiago ◽  
Mitchell Longworth ◽  
Michael Kassiou ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Cannabinoid Receptor ◽  
Synthetic Cannabinoid ◽  
Receptor Agonists ◽  
Synthetic Cannabinoid Receptor Agonists
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