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

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In Vitro Metabolic Fate of the Synthetic Cannabinoid Receptor Agonists QMPSB and QMPCB (SGT-11) Including Isozyme Mapping and Esterase Activity H OH metabolites OH Article In Vitro Metabolic Fate of the Synthetic Cannabinoid Receptor Agonists QMPSB and QMPCB (SGT-11) Including Isozyme Mapping and Esterase Activity Matthias J. Richter 1 , Lea Wagmann 1 , Tanja M. Gampfer 1, Simon D. Brandt 2 and Markus R. Meyer 1,* 1 Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacologyand Toxicology, Center for Molecular Signaling (PZMS), Saarland University, 66421 Homburg, Germany; [email protected] (M.J.R.); [email protected] (L.W.); [email protected] (T.M.G.) 2 School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, UK; [email protected] * Correspondence: [email protected]; Tel.: +49-6841-16-26438 Abstract: 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), re- combinant human monooxygenases, three recombinant human carboxylesterases, and pooled human liver microsomes. Analyses were carried out by liquid chromatography high-resolution tandem mass Citation: Richter, M.J.; Wagmann, L.; spectrometry. QMPSB and QMPCB showed ester hydrolysis, and hydroxy and carboxylic acid prod- Gampfer, T.M.; Brandt, S.D.; Meyer, M.R. In Vitro Metabolic Fate of the ucts were detected in both cases. Mono/dihydroxy metabolites were formed, as were corresponding Synthetic Cannabinoid Receptor glucuronides and sulfates. Most of the metabolites could be detected in positive ionization mode with Agonists QMPSB and QMPCB the exception of some QMPSB metabolites, which could only be found in negative mode. Monooxy- (SGT-11) Including Isozyme Mapping genase activity screening revealed that CYP2B6/CYP2C8/CYP2C9/CYP2C19/CYP3A4/CYP3A5 and Esterase Activity. Metabolites were involved in hydroxylations. Esterase screening showed the involvement of all investigated 2021, 11, 509. https://doi.org/ isoforms. Additionally, extensive non-enzymatic ester hydrolysis was observed. Considering the 10.3390/metabo11080509 results of the in vitro experiments, inclusion of the ester hydrolysis products and their glucuronides and monohydroxy metabolites into toxicological screening procedures is recommended. Academic Editor: Cornelius Hess Keywords: QMPSB; QMPCB; synthetic cannabinoid receptor agonists; SCRA; NPS; metabolism; Received: 25 June 2021 LC-HRMS/MS Accepted: 29 July 2021 Published: 3 August 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in published maps and institutional affil- Synthetic cannabinoids, also known as synthetic cannabinoid receptor agonists (SCRAs), iations. represent one of the largest groups of the so-called new psychoactive substances (NPSs) [1,2]. SCRAs are often sold on the drug market after being sprayed on plant material [3]. Contin- uous changes in the chemical structures lead to a continuous introduction of new SCRAs in an attempt to circumvent legislation [3]. Even though the number of new SCRAs detected annually in the EU decreased in recent years, they continue to represent an important Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. group of newly occurring NPSs alongside cathinones and opioids [2]. This article is an open access article In 2007, quinolin-8-yl 4-methyl-3-(piperidine-1-sulfonyl)benzoate (QMPSB) was identi- distributed under the terms and fied as a potent SCRA as a result of a high-throughput screening [4]. Further investigations conditions of the Creative Commons revealed that QMPSB is a potent full agonist at the CB1 and CB2 receptors with moderate Attribution (CC BY) license (https:// selectivity for the CB2 receptor [4,5]. In Queensland (Australia), QMPSB was found in a creativecommons.org/licenses/by/ large number of plant materials seized in 2011 and 2012 and published in 2016 [6]. QMPSB 4.0/). was also the template for a new group of SCRAs based on a sulfamoyl benzoate structure Metabolites 2021, 11, 509. https://doi.org/10.3390/metabo11080509 https://www.mdpi.com/journal/metabolites Metabolites 2021, 11, x FOR PEER REVIEW 2 of 15 Metabolites 2021, 11, 509 moderate selectivity for the CB2 receptor [4,5]. In Queensland (Australia), QMPSB2 ofwas 14 found in a large number of plant materials seized in 2011 and 2012 and published in 2016 [6]. QMPSB was also the template for a new group of SCRAs based on a sulfamoyl ben- and/orzoate structure a quinolin-8-yl and/or a ester quinolin head-8 group.-yl ester In head 2012, group. the company In 2012, Stargatethe company International Stargate startedInternational research started on this research new SCRA on this group new SCRA which group included which the included amide analog the amide of QMPSB, analog quinolin-8-ylof QMPSB, quinolin 4-methyl-3-(piperidine-1-carbonyl)benzoate-8-yl 4-methyl-3-(piperidine-1-carbonyl)benzoate (QMPCB, SGT-11). (QMPCB, Chemical SGT-11). structuresChemical ofstructures QMPSB of and QMPSB QMPCB and can QMPCB be found can in be Figure found1. in By Figure replacing 1. By the replacing sulfamoyl the tailsulfamoyl group linkertail group with linker a carbonyl with a carbonyl linker, the linker, influence the influence of the linker of the group linker ongroup the on phar- the macologicalpharmacological properties properties was furtherwas further investigated. investigated. However, However, tests tests on human on human volunteers volun- showedteers showed that the that amide the amide analog analog QMPCB QMPCB had had a lower a lower potency potency than than QMPSB QMPSB [7 [7]].. Further Further structuralstructural modificationsmodifications ledled toto aa combinationcombination ofof thethe quinolin-8-ylquinolin-8-yl esterester headhead groupgroup withwith anan NN-alkyl-1-alkyl-1HH-indole-indole core,core, whichwhich resultedresulted inin thethe developmentdevelopment andand appearanceappearance ofof PB-22PB-22 (QUPIC),(QUPIC), andand BB-22BB-22 (QUCHIC)(QUCHIC) amongstamongst othersothers [7[7,8],8].. FigureFigure 1.1. ChemicalChemical structuresstructures ofof thethe studiedstudied compounds.compounds. InIn thethe contextcontext ofof clinicalclinical andand forensicforensic toxicology,toxicology, data data on on thethe metabolismmetabolism ofof emergingemerging NPSsNPSs areare important,important, particularlyparticularly forfor developingdeveloping analyticalanalytical screeningscreening proceduresprocedures inin urine.urine. ToTo ourour knowledge,knowledge, no data data on on the the metabolism metabolism of of QMPSB QMPSB and and QMPCB QMPCB are are available available in the in theliterature. literature. Therefore, Therefore, the the aim aim of ofthe the study study was was to to identify identify the the metabolites metabolites of of these sub-sub- stancesstances asas potentialpotential targetstargets forfor toxicologicaltoxicological screeningsscreenings byby liquidliquid chromatographychromatography coupledcoupled toto high-resolutionhigh-resolution tandem tandem mass mass spectrometry spectrometry (LC-HRMS/MS). (LC-HRMS/MS). InIn vitrovitroincubations incubations usingusing pooledpooled humanhuman liver liver S9 S9 fraction fraction (pHLS9) (pHLS9) were were performed performed to to identify identify phase phase I andI and II II metabo- metab- lites.olites. Incubations Incubations with with pHLS9 pHLS9 have have been been shown shown to to generate generate the the main main human human metabolites metabolites comparedcompared toto humanhuman primaryprimary hepatocyteshepatocytes andand areare thereforetherefore appropriateappropriate alternativesalternatives toto incubationsincubations withwith humanhuman primaryprimary hepatocyteshepatocytes [[9]9].. AnAnin in vitrovitromonooxygenase monooxygenase activity activity assay assay should should clarify clarify the the involvement involvement of individualof individ- monooxygenasesual monooxygenases in the in the initial initial metabolic metabolic steps. steps. Due Due to to the the instability instability of of the the ester ester bond bond alreadyalready describeddescribed inin thethe literatureliterature [[5,6]5,6],, thethe additionaladditional influenceinfluence ofof humanhuman esterasesesterases onon esterester hydrolysishydrolysis waswas investigated.investigated. 2. Results and Discussion 2. Results and Discussion 2.1. Identification of In Vitro Phase I and II Metabolites of QMPSB 2.1. Identification of In Vitro Phase I and II Metabolites of QMPSB For metabolite identification, exact protonated or deprotonated precursor ion (PI) massesFor of metabolite expected phase identification, I and II metabolites exact protonated were calculated. or deprotonated High-resolution precursor full ion scan (PI) datamasses were of examinedexpected forphase these I and masses II metabolites and the corresponding were calculated. MS2 Highspectra-resolution were interpreted. full scan 2 Deviationsdata were examined between measured for these masses and calculated and the PIcorresponding mass were only MS accepted spectra were up to interpreted. 5 ppm. All metabolitesDeviations werebetween tentatively measured identified and calculated since no PI reference mass were material
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