Abstract
SR9009 and SR9011 are attractive as performance-enhancing substances due to their REV-ERB agonist effects and thus circadian rhythm modulation activity. Although no pharmaceutical preparations are available yet, illicit use of SR9009 and SR9011 for doping purposes can be anticipated, especially since SR9009 is marketed in illicit products. Therefore, the aim was to identify potential diagnostic metabolites via in vitro metabolic studies to ensure effective (doping) control. The presence of SR9009 could be demonstrated in a black market product purchased over the Internet. Via human liver microsomal metabolic assays, eight metabolites were detected for SR9009 and fourteen metabolites for SR9011 by liquid chromatography–high resolution mass spectrometry (LC–HRMS). Structure elucidation was performed for all metabolites by LC–HRMS product ion scans in both positive and negative ionization mode. Retrospective data analysis was applied to 1511 doping control samples previously analyzed by a full-scan LC–HRMS screening method to verify the presence of SR9009, SR9011 and their metabolites. So far, the presence of neither the parent compound nor the metabolites could be detected in routine urine samples. However, to further discourage use of these potentially harmful compounds, incorporation of SR9009 and SR9011 into screening methods is highly recommended.
Highlights
Physiological processes involving metabolism and behavior, e.g., activity/rest, are generally organized on a cycle of approximately 24 h driven by a circadian rhythm [1,2,3]
Pooled hn whuitmh balnanlikve(wr imthiocurot sHoLmMe)s (HLM) from 20–30 donors, the nicotinamide adenine dinucleotide phosphate (NADPH) regenerating system Solutions A and B and phosphate buffer pH 7.4 all from Gentest were purchased from Corning (Amsterdam, The Netherlands). β-Glucuronidase/arylsulfatase from Helix pomatia was from Roche Diagnostics (Mannheim, Germany)
The presence of SR9009 was demonstrated in a black market product obtained via the Internet
Summary
Physiological processes involving metabolism and behavior, e.g., activity/rest, are generally organized on a cycle of approximately 24 h driven by a circadian rhythm [1,2,3]. The nuclear receptors reversed-viral erythroblastosis α and β (REV-ERB α and β) regulate the expression of core clock proteins and help to modulate the circadian rhythm [1,2,4,5]. Modulation of the REV-ERB activity by synthetic agonists, e.g., SR9009 and SR9011 (Figure 1), alters the expression of genes involved in lipid and glucose metabolism and, plays an important role in maintaining the energy homeostasis [1,4,6].
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