scholarly journals In Vitro Metabolic Fate of the Synthetic Cannabinoid Receptor Agonists QMPSB and QMPCB (SGT-11) Including Isozyme Mapping and Esterase Activity

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 509
Author(s):  
Matthias J. Richter ◽  
Lea Wagmann ◽  
Tanja M. Gampfer ◽  
Simon D. Brandt ◽  
Markus R. Meyer
Keyword(s):  
Human Liver ◽  
Cannabinoid Receptor ◽  
Ester Hydrolysis ◽  
Synthetic Cannabinoid ◽  
Toxicological Screening ◽  
Metabolic Fate ◽  
Monooxygenase Activity ◽  
Receptor Agonists ◽  
Synthetic Cannabinoid Receptor Agonists

Quinolin-8-yl 4-methyl-3-(piperidine-1-sulfonyl)benzoate (QMPSB) and quinolin-8-yl 4-methyl-3-(piperidine-1-carbonyl)benzoate (QMPCB, SGT-11) are synthetic cannabinoid receptor agonists (SCRAs). Knowing their metabolic fate is crucial for the identification of toxicological screening targets and to predict possible drug interactions. The presented study aimed to identify the in vitro phase I/II metabolites of QMPSB and QMPCB and to study the contribution of different monooxygenases and human carboxylesterases by using pooled human liver S9 fraction (pHLS9), recombinant human monooxygenases, three recombinant human carboxylesterases, and pooled human liver microsomes. Analyses were carried out by liquid chromatography high-resolution tandem mass spectrometry. QMPSB and QMPCB showed ester hydrolysis, and hydroxy and carboxylic acid products were detected in both cases. Mono/dihydroxy metabolites were formed, as were corresponding glucuronides and sulfates. Most of the metabolites could be detected in positive ionization mode with the exception of some QMPSB metabolites, which could only be found in negative mode. Monooxygenase activity screening revealed that CYP2B6/CYP2C8/CYP2C9/CYP2C19/CYP3A4/CYP3A5 were involved in hydroxylations. Esterase screening showed the involvement of all investigated isoforms. Additionally, extensive non-enzymatic ester hydrolysis was observed. Considering the results of the in vitro experiments, inclusion of the ester hydrolysis products and their glucuronides and monohydroxy metabolites into toxicological screening procedures is recommended.

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

In vitro elucidation of the metabolic profile of the synthetic cannabinoid receptor agonists JWH-175 and JWH-176

2016 ◽  
Vol 34 (2) ◽  
pp. 353-362 ◽  
Author(s):  
Mathias Fietzke ◽  
Andreas Thomas ◽  
Justus Beike ◽  
Marcus Alexander Rothschild ◽  
Mario Thevis ◽  
...  
Keyword(s):  
Metabolic Profile ◽  
Cannabinoid Receptor ◽  
Synthetic Cannabinoid ◽  
Receptor Agonists ◽  
Synthetic Cannabinoid Receptor Agonists

scholarly journals Phase I In Vitro Metabolic Profiling of the Synthetic Cannabinoid Receptor Agonists CUMYL-THPINACA and ADAMANTYL-THPINACA

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 470
Author(s):  
Manuela Carla Monti ◽  
Eva Scheurer ◽  
Katja Mercer-Chalmers-Bender
Keyword(s):  
Phase I ◽  
Metabolic Profiling ◽  
Cannabinoid Receptor ◽  
Solid Phase ◽  
Synthetic Cannabinoid ◽  
Screening Methods ◽  
Receptor Agonists ◽  
Synthetic Cannabinoid Receptor Agonists ◽  
Hydroxylated Metabolite

Synthetic cannabinoid receptor agonists (SCRAs) remain popular drugs of abuse. As many SCRAs are known to be mostly metabolized, in vitro phase I metabolic profiling was conducted of the two indazole-3-carboxamide SCRAs: CUMYL-THPINACA and ADAMANTYL-THPINACA. Both compounds were incubated using pooled human liver microsomes. The sample clean-up consisted of solid phase extraction, followed by analysis using liquid chromatography coupled to a high resolution mass spectrometer. In silico-assisted metabolite identification and structure elucidation with the data-mining software Compound Discoverer was applied. Overall, 28 metabolites were detected for CUMYL-THPINACA and 13 metabolites for ADAMATYL-THPINACA. Various mono-, di-, and tri-hydroxylated metabolites were detected. For each SCRA, an abundant and characteristic di-hydroxylated metabolite was identified as a possible in vivo biomarker for screening methods. Metabolizing cytochrome P450 isoenzymes were investigated via incubation of relevant recombinant liver enzymes. The involvement of mainly CYP3A4 and CYP3A5 in the metabolism of both substances were noted, and for CUMYL-THPINACA the additional involvement (to a lesser extent) of CYP2C8, CYP2C9, and CYP2C19 was observed. The results suggest that ADAMANTYL-THPINACA might be more prone to metabolic drug−drug interactions than CUMYL-THPINACA, when co-administrated with strong CYP3A4 inhibitors.

scholarly journals Do Toxic Synthetic Cannabinoid Receptor Agonists Have Signature in Vitro Activity Profiles? A Case Study of AMB-FUBINACA

2019 ◽  
Vol 10 (10) ◽  
pp. 4350-4360 ◽  
Author(s):  
David B. Finlay ◽  
Jamie J. Manning ◽  
Mikkel Søes Ibsen ◽  
Christa E. Macdonald ◽  
Monica Patel ◽  
...  
Keyword(s):  
Cannabinoid Receptor ◽  
Synthetic Cannabinoid ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Receptor Agonists ◽  
Synthetic Cannabinoid Receptor Agonists

scholarly journals A Systematic Study of the In Vitro Pharmacokinetics and Estimated Human In Vivo Clearance of Indole and Indazole-3-Carboxamide Synthetic Cannabinoid Receptor Agonists Detected on the Illicit Drug Market

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1396
Author(s):  
Andrew M. Brandon ◽  
Lysbeth H. Antonides ◽  
Jennifer Riley ◽  
Ola Epemolu ◽  
Denise A. McKeown ◽  
...  
Keyword(s):  
Illicit Drug ◽  
Cannabinoid Receptor ◽  
Liver Microsomes ◽  
Drug Market ◽  
Synthetic Cannabinoid ◽  
Pharmacokinetic Studies ◽  
Receptor Agonists ◽  
Synthetic Cannabinoid Receptor Agonists

In vitro pharmacokinetic studies were conducted on enantiomer pairs of twelve valinate or tert-leucinate indole and indazole-3-carboxamide synthetic cannabinoid receptor agonists (SCRAs) detected on the illicit drug market to investigate their physicochemical parameters and structure-metabolism relationships (SMRs). Experimentally derived Log D7.4 ranged from 2.81 (AB-FUBINACA) to 4.95 (MDMB-4en-PINACA) and all SCRAs tested were highly protein bound, ranging from 88.9 ± 0.49% ((R)-4F-MDMB-BINACA) to 99.5 ± 0.08% ((S)-MDMB-FUBINACA). Most tested SCRAs were cleared rapidly in vitro in pooled human liver microsomes (pHLM) and pooled cryopreserved human hepatocytes (pHHeps). Intrinsic clearance (CLint) ranged from 13.7 ± 4.06 ((R)-AB-FUBINACA) to 2944 ± 95.9 mL min−1 kg−1 ((S)-AMB-FUBINACA) in pHLM, and from 110 ± 34.5 ((S)-AB-FUBINACA) to 3216 ± 607 mL min−1 kg−1 ((S)-AMB-FUBINACA) in pHHeps. Predicted Human in vivo hepatic clearance (CLH) ranged from 0.34 ± 0.09 ((S)-AB-FUBINACA) to 17.79 ± 0.20 mL min−1 kg−1 ((S)-5F-AMB-PINACA) in pHLM and 1.39 ± 0.27 ((S)-MDMB-FUBINACA) to 18.25 ± 0.12 mL min−1 kg−1 ((S)-5F-AMB-PINACA) in pHHeps. Valinate and tert-leucinate indole and indazole-3-carboxamide SCRAs are often rapidly metabolised in vitro but are highly protein bound in vivo and therefore predicted in vivo CLH is much slower than CLint. This is likely to give rise to longer detection windows of these substances and their metabolites in urine, possibly as a result of accumulation of parent drug in lipid-rich tissues, with redistribution into the circulatory system and subsequent metabolism.

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 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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