scholarly journals Systematic evaluation of a panel of 30 synthetic cannabinoid receptor agonists structurally related to MMB‐4en‐PICA, MDMB‐4en‐PINACA, ADB‐4en‐PINACA and MMB‐4CN‐BUTINACA using a combination of binding and different CB1 receptor activation assays PART III: The G protein pathway and critical comparison of different assays

2021 ◽  
Author(s):  
Katharina Elisabeth Grafinger ◽  
Marthe M. Vandeputte ◽  
Annelies Cannaert ◽  
Adam Ametovski ◽  
Eric Sparkes ◽  
...  
Keyword(s):  
G Protein ◽  
Cannabinoid Receptor ◽  
Receptor Activation ◽  
Cb1 Receptor ◽  
Synthetic Cannabinoid ◽  
Systematic Evaluation ◽  
Receptor Agonists ◽  
Critical Comparison ◽  
Synthetic Cannabinoid Receptor Agonists

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

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

scholarly journals Human Toxicity Caused by Indole and Indazole Carboxylate Synthetic Cannabinoid Receptor Agonists: From Horizon Scanning to Notification

2018 ◽  
Vol 64 (2) ◽  
pp. 346-354 ◽  
Author(s):  
Simon L Hill ◽  
Michael Dunn ◽  
Céline Cano ◽  
Suzannah J Harnor ◽  
Ian R Hardcastle ◽  
...  
Keyword(s):  
Cannabinoid Receptor ◽  
Synthetic Cannabinoid ◽  
Severe Toxicity ◽  
Accurate Identification ◽  
Receptor Agonists ◽  
Horizon Scanning ◽  
Other Substances ◽  
Using Data ◽  
Synthetic Cannabinoid Receptor Agonists ◽  
The Uk

Abstract BACKGROUND The emergence of novel psychoactive substances (NPS), particularly synthetic cannabinoid receptor agonists (SCRA), has involved hundreds of potentially harmful chemicals in a highly dynamic international market challenging users', clinicians', and regulators' understanding of what circulating substances are causing harm. We describe a toxicovigilance system for NPS that predicted the UK emergence and identified the clinical toxicity caused by novel indole and indazole carboxylate SCRA. METHODS To assist early accurate identification, we synthesized 5 examples of commercially unavailable indole and indazole carboxylate SCRA (FUB-NPB-22, 5F-NPB-22, 5F-SDB-005, FUB-PB-22, NM-2201). We analyzed plasma and urine samples from 160 patients presenting to emergency departments with severe toxicity after suspected NPS use during 2015 to 2016 for these and other NPS using data-independent LC-MS/MS. RESULTS We successfully synthesized 5 carboxylate SCRAs using established synthetic and analytical chemistry methodologies. We identified at least 1 SCRA in samples from 49 patients, including an indole or indazole carboxylate SCRA in 17 (35%), specifically 5F-PB-22 (14%), FUB PB-22 (6%), BB-22 (2%), 5F NPB-22 (20%), FUB NPB-22 (2%), and 5F-SDB-005 (4%). In these 17 patients, there was analytical evidence of other substances in 16. Clinical features included agitation and aggression (82%), reduced consciousness (76%), acidosis (47%), hallucinations and paranoid features (41%), tachycardia (35%), hypertension (29%), raised creatine kinase (24%), and seizures (12%). CONCLUSIONS This toxicovigilance system predicted the emergence of misuse of indole and indazole carboxylate SCRA, documented associated clinical harms, and notified relevant agencies. Toxicity appears consistent with other SCRA, including mental state disturbances and reduced consciousness.

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