Electron ionization mass spectrometry of the ryanodine receptor-based Ca(2+)-channel stabilizer S-107 and its implementation into routine doping control.

Abstract

New insights into the biochemistry of cardiac arrhythmia and skeletal muscle fatigue have yielded new drug candidates to counteract these phenomena. Major biological targets have become ryanodine receptor (RyR)-based Ca(2+)-release channels, which tend to 'leak' under various circumstances including strenuous exercise and, thus, cause aberrant calcium sparks that entail impaired muscle function. Therapeutics, which are referred to as rycals, are currently being developed to treat cardiac arrhythmia via enhancement of calstabin-ryanodine affinities that causes a stabilization of the RyR. These therapeutics possess potential for misuse in sports, and an early implementation of target analytes such as the benzothiazepine derivatives S-107 and JTV-519 or putative metabolites into doping control screening procedures is recommended. Reference compounds, deuterated analogues, and a putative metabolic product were synthesized, and electron ionization mass spectra of these products were studied and dissociation pathways elucidated by means of tandem mass spectrometry (MS/MS) and accurate mass measurements. The characterized analytes were incorporated into existing sports drug testing assays based on liquid-liquid extraction and subsequent gas chromatography/mass spectrometry (GC/MS) analysis, and specificity, lower limit of detection (4-6 ng/mL), intraday and interday precision (1.5-17.2%), as well as recovery (63-66%) were determined. The established procedure proved suitable for routine doping control analysis to detect a potential misuse of the drug candidate S-107 in elite sport.

• Authors: Mario Thevis, Simon Beuck, Andreas Thomas, Gregor Fusshöller, Gerg Sigmund, Nils Schlörer, Grigory Rodchenkov, Mathias Schäfer, Wilhelm Schänzer
• Journal: Rapid communications in mass spectrometry : RCM (Rapid Commun Mass Spectrom) Vol. 23 Issue 15 Pg. 2363-70 (Aug 2009) ISSN: 1097-0231 [Electronic] England
• PMID: 19575395 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Validation Study)
• Copyright: Copyright (c) 2009 John Wiley & Sons, Ltd.

Chemical References

• S-107 compound
• Thiazepines

Topics

• Female
• Gas Chromatography-Mass Spectrometry (methods)
• Humans
• Male
• Molecular Structure
• Sensitivity and Specificity
• Spectrometry, Mass, Electrospray Ionization (methods)
• Substance Abuse Detection (methods)
• Thiazepines (chemical synthesis, metabolism, urine)