Doping control analysis of tricyclic tetrahydroquinoline-derived selective androgen receptor modulators using liquid chromatography/electrospray ionization tandem mass spectrometry.
Selective androgen receptor modulators represent an emerging class of therapeutics to counteract various diseases such as osteoporosis and muscle wasting. Numerous drug candidates have been developed and investigated including a group that comprises a tricyclic tetrahydroquinoline nucleus such as 2-methyl-2-(8-nitro-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]chinolin-4-yl)propan-1-ol. Due to their novelty and medicinal purpose, these compounds also possess great potential for misuse in sports, and studies on the mass spectrometric behavior of three synthesized model substances and drug candidates were conducted to provide information on typical dissociation pathways following electrospray ionization and collision-induced dissociation. Product ion mass spectra derived from protonated molecules were studied using high resolution/high accuracy orbitrap mass spectrometry, and characteristic fragmentation routes and product ions were elucidated. Major and general findings include the elimination of a hydroxyl radical from [M+H](+), the elimination of the 2-substituted side chain, and the gas-phase rearrangement of the investigated tricyclic tetrahydroquinolines to 6-nitroquinoline yielding a common product ion at m/z 175. Knowledge of these dissociation pathways supports the identification of related substances as well as metabolic products, which is of utmost importance to drug testing laboratories. The compounds were implemented into existing screening procedures, and detection limits (0.2-0.6 ng/mL), recoveries (92-97%), and intraday and interday precision (<22%) were evaluated.
Thevis
Mario
M
Center for Preventive Doping Research - Institute of Biochemistry, German Sport University Cologne, Carl-Diem Weg 6, 50933 Cologne, Germany. m.thevis@biochem.dshs-koeln.de
Kohler
Maxie
M
Thomas
Andreas
A
Schlörer
Nils
N
Schänzer
Wilhelm
W
D045930:Anabolic Agents / Q000138:chemical synthesis / Q000652:urine*; D000726:Androgen Antagonists / Q000138:chemical synthesis / Q000652:urine*; D059002:Androgen Receptor Antagonists; D002851:Chromatography, High Pressure Liquid; D004300:Doping in Sports / Q000517:prevention & control*; D006801:Humans; D011944:Receptors, Androgen; D015203:Reproducibility of Results; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D015813:Substance Abuse Detection / Q000379:methods*; D053719:Tandem Mass Spectrometry / Q000379:methods
C410798:AR protein, human; D045930:Anabolic Agents; D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D011944:Receptors, Androgen