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

Matthias J Richter,Simon D Brandt,Lea Wagmann,Tanja M Gampfer,Markus R Meyer

doi:10.3390/metabo11080509

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), 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.

Highlights

Synthetic cannabinoids, known as synthetic cannabinoid receptor agonists (SCRAs), 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]
Even though the number of new SCRAs detected annually in the EU decreased in recent years, they continue to represent an important group of newly occurring NPSs alongside cathinones and opioids [2]
High-resolution full scan data were examined for these masses and the corresponding MS spectra were interpreted

Summary

Introduction

Known as synthetic cannabinoid receptor agonists (SCRAs), 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]. Even though the number of new SCRAs detected annually in the EU decreased in recent years, they continue to represent an important group of newly occurring NPSs alongside cathinones and opioids [2]. In 2007, quinolin-8-yl 4-methyl-3-(piperidine-1-sulfonyl)benzoate (QMPSB) was identified as a potent SCRA as a result of a high-throughput screening [4]. QMPSB was the template for a new group of SCRAs based on a sulfamoyl benzoate structure

Methods

Results

Conclusion