In Vitro Metabolic Fate of the Synthetic Cannabinoid Receptor Agonists QMPSB and QMPCB (SGT-11) Including Isozyme Mapping and Esterase Activity
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...
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MDPI AG
2021-08-01
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| author | Matthias J. Richter Lea Wagmann Tanja M. Gampfer Simon D. Brandt Markus R. Meyer |
| author_facet | Matthias J. Richter Lea Wagmann Tanja M. Gampfer Simon D. Brandt Markus R. Meyer |
| author_sort | Matthias J. Richter |
| collection | DOAJ |
| description | 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. |
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| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-10T08:36:21Z |
| publishDate | 2021-08-01 |
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| series | Metabolites |
| spelling | doaj.art-9c61ce099ae047d2b94e040c12410fc92023-11-22T08:39:19ZengMDPI AGMetabolites2218-19892021-08-0111850910.3390/metabo11080509In Vitro Metabolic Fate of the Synthetic Cannabinoid Receptor Agonists QMPSB and QMPCB (SGT-11) Including Isozyme Mapping and Esterase ActivityMatthias J. Richter0Lea Wagmann1Tanja M. Gampfer2Simon D. Brandt3Markus R. Meyer4Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacologyand Toxicology, Center for Molecular Signaling (PZMS), Saarland University, 66421 Homburg, GermanyDepartment of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacologyand Toxicology, Center for Molecular Signaling (PZMS), Saarland University, 66421 Homburg, GermanyDepartment of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacologyand Toxicology, Center for Molecular Signaling (PZMS), Saarland University, 66421 Homburg, GermanySchool of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, UKDepartment of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacologyand Toxicology, Center for Molecular Signaling (PZMS), Saarland University, 66421 Homburg, GermanyQuinolin-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.https://www.mdpi.com/2218-1989/11/8/509QMPSBQMPCBsynthetic cannabinoid receptor agonistsSCRANPSmetabolism |
| spellingShingle | Matthias J. Richter Lea Wagmann Tanja M. Gampfer Simon D. Brandt Markus R. Meyer In Vitro Metabolic Fate of the Synthetic Cannabinoid Receptor Agonists QMPSB and QMPCB (SGT-11) Including Isozyme Mapping and Esterase Activity Metabolites QMPSB QMPCB synthetic cannabinoid receptor agonists SCRA NPS metabolism |
| title | In Vitro Metabolic Fate of the Synthetic Cannabinoid Receptor Agonists QMPSB and QMPCB (SGT-11) Including Isozyme Mapping and Esterase Activity |
| title_full | In Vitro Metabolic Fate of the Synthetic Cannabinoid Receptor Agonists QMPSB and QMPCB (SGT-11) Including Isozyme Mapping and Esterase Activity |
| title_fullStr | In Vitro Metabolic Fate of the Synthetic Cannabinoid Receptor Agonists QMPSB and QMPCB (SGT-11) Including Isozyme Mapping and Esterase Activity |
| title_full_unstemmed | In Vitro Metabolic Fate of the Synthetic Cannabinoid Receptor Agonists QMPSB and QMPCB (SGT-11) Including Isozyme Mapping and Esterase Activity |
| title_short | In Vitro Metabolic Fate of the Synthetic Cannabinoid Receptor Agonists QMPSB and QMPCB (SGT-11) Including Isozyme Mapping and Esterase Activity |
| title_sort | in vitro metabolic fate of the synthetic cannabinoid receptor agonists qmpsb and qmpcb sgt 11 including isozyme mapping and esterase activity |
| topic | QMPSB QMPCB synthetic cannabinoid receptor agonists SCRA NPS metabolism |
| url | https://www.mdpi.com/2218-1989/11/8/509 |
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