Skip to main content

Advertisement

SpringerLink
Log in

Determination of benzimidazole- and bicyclic hydantoin-derived selective androgen receptor antagonists and agonists in human urine using LC–MS/MS

  • Original Paper
  • Published:
Analytical and Bioanalytical Chemistry Aims and scope Submit manuscript

Abstract

Selective androgen receptor modulators (SARMs) represent a novel class of drugs with tissue-specific agonistic and antagonistic properties, which are prohibited in sports from January 2008 according to the World Anti-Doping Agency. Preventive approaches to restrict the use of SARMs include early implementation of target analytes into doping control screening assays. Five model SARMs were synthesized, four of which are analogs to prostate-specific androgen receptor antagonists with a 5,6-dichloro-benzimidazole nucleus. The fifth SARM is a muscle-tissue specific agonist with a bicyclic hydantoin structure (BMS-564929). Dissociation pathways after negative electrospray ionization were studied using an LTQ-Orbitrap mass analyzer, and diagnostic product ions and common fragmentation patterns were employed to establish a screening procedure that target the intact SARMs as well as putative metabolic products. Sample preparation based on solid-phase extraction and subsequent LC–MS/MS measurement allowed for detection limits of 1–20 ng/mL, intra- and interday precisions of between 2.4 and 13.2% and between 6.5 and 24.2%, respectively. Recoveries varied from 89 to 106%, and tests for ion suppression or enhancement effects were negative for all analytes.

Precursor ion scanning as a tool to screen for the common nucleus of benzimidazole-derived SARMs

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Fig. 1
Scheme 2
Fig. 2

Similar content being viewed by others

References

  1. Bhasin S, Calof OM, Storer TW, Lee ML, Mazer NA, Jasuja R, Montori VM, Gao W, Dalton JT (2006) Nat Clin Pract Endocrinol Metab 2:146–159

    Article  CAS  Google Scholar 

  2. Hengge UR (2003) AIDS Read 13:S15–S21

    Google Scholar 

  3. Moretti C, Frajese GV, Guccione L, Wannenes F, De Martino MU, Fabbri A, Frajese G (2005) J Endocrinol Invest 28:56–64

    CAS  Google Scholar 

  4. Gooren LJ, Bunck MC (2004) Drugs 64:1861–1891

    Article  CAS  Google Scholar 

  5. Dalton JT, Mukherjee A, Zhu Z, Kirkovsky L, Miller DD (1998) Biochem Biophys Res Commun 244:1–4

    Article  CAS  Google Scholar 

  6. Mohler ML, Nair VA, Hwang DJ, Rakov IM, Patil R, Miller DD (2005) Exp Opin Ther Patents 15:1565–1585

    Article  CAS  Google Scholar 

  7. Chen J, Kim J, Dalton JT (2005) Mol Interv 5:173–188

    Article  CAS  Google Scholar 

  8. Negro-Vilar A (1999) J Clin Endocrinol Metab 84:3459–3462

    Article  CAS  Google Scholar 

  9. Gao W, Dalton JT (2007) Drug Discov Today 12:241–248

    Article  CAS  Google Scholar 

  10. Thevis M, Schänzer W (2007) Mini-Rev Med Chem 7:533–539

    Article  Google Scholar 

  11. Omwancha J, Brown TR (2006) Curr Opin Investig Drugs 7:873–881

    CAS  Google Scholar 

  12. World Anti-Doping Agency (2008) The 2008 Prohibited List. http://www.wada-ama.org/rtecontent/document/2008_List_En.pdf. Accessed 28 Nov 2007

  13. Thevis M, Kohler M, Maurer J, Schlörer N, Kamber M, Schänzer W (2007) Rapid Commun Mass Spectom 21:3477–3486

    Article  CAS  Google Scholar 

  14. Thevis M, Kamber M, Schänzer W (2006) Rapid Commun Mass Spectrom 20:870–876

    Article  CAS  Google Scholar 

  15. Thevis M, Kohler M, Schänzer W (2007) Mass spectrometry of new growth promoting drugs: hydantoin-derived selective androgen receptor modulators and growth hormone secretagogues. In: Schänzer W, Geyer H, Gotzmann A, Mareck U (eds) Recent advances in doping analysis. Sport und Buch Strauß, Cologne (in press)

  16. Ng RA, Guan J, Alford VC, Jr., Lanter JC, Allan GF, Sbriscia T, Lundeen SG, Sui Z (2007) Bioorg Med Chem Lett 17:955–958

    Article  CAS  Google Scholar 

  17. Ng RA, Guan J, Alford VC Jr, Lanter JC, Allan GF, Sbriscia T, Linton O, Lundeen SG, Sui Z (2007) Bioorg Med Chem Lett 17:784–788

    Google Scholar 

  18. Ostrowski J, Kuhns JE, Lupisella JA, Manfredi MC, Beehler BC, Krystek SR, Jr., Bi Y, Sun C, Seethala R, Golla R, Sleph PG, Fura A, An Y, Kish KF, Sack JS, Mookhtiar KA, Grover GJ, Hamann LG (2006) Endocrinology 48:4–12

    Article  Google Scholar 

  19. Sun C, Robl JA, Wang TC, Huang Y, Kuhns JE, Lupisella JA, Beehler BC, Golla R, Sleph PG, Seethala R, Fura A, Krystek SR, Jr., An Y, Malley MF, Sack JS, Salvati ME, Grover GJ, Ostrowski J, Hamann LG (2006) J Med Chem 49:7596–7599

    Article  CAS  Google Scholar 

  20. Ng RA, Lanter JC, Alford VC, Allan GF, Sbriscia T, Lundeen SG, Sui Z (2007) Bioorg Med Chem Lett 17:1784–1787

    Article  CAS  Google Scholar 

  21. Handelsman DJ (2004) Sci STKE 244:pe41

    Article  Google Scholar 

  22. Catlin DH, Ahrens BD, Kucherova Y (2002) Rapid Commun Mass Spectrom 16:1273–1275

    Article  CAS  Google Scholar 

  23. Catlin DH, Sekera MH, Ahrens BD, Starcevic B, Chang Y-C, Hatton CK (2004) Rapid Commun Mass Spectrom 18:1245–1249

    Article  CAS  Google Scholar 

  24. Sekera MH, Ahrens BD, Chang YC, Starcevic B, Georgakopoulos C, Catlin DH (2005) Rapid Commun Mass Spectrom 19:781–784

    Article  CAS  Google Scholar 

  25. Thevis M, Schänzer W (2005) J Chromatogr Sci 43:22–31

    CAS  Google Scholar 

  26. ICH (2005) Validation of analytical procedures: text and methodology. http://www.ich.org/LOB/media/MEDIA417.pdf. Accessed 28 Jan 2008

  27. Kromidas A (1999) Validierung in der Analytik. Wiley-VCH, Weinheim

  28. Dams R, Huestis MA, Lambert WE, Murphy CM (2003) J Am Soc Mass Spectrom 14:1290–1294

    Article  CAS  Google Scholar 

  29. Matuszewski BK, Constanzer ML, Chavez-Eng CM (2003) Anal Chem 75:3019–3030

    Article  CAS  Google Scholar 

  30. Thevis M, Geyer H, Mareck U, Schänzer W (2005) J Mass Spectrom 40:955–962

    Article  CAS  Google Scholar 

  31. Mazzarino M, Botre F (2006) Rapid Comm Mass Spectrom 20:3465–3476

    Article  CAS  Google Scholar 

  32. Kolmonen M, Leinonen A, Pelander A, Ojanpera I (2007) Anal Chim Acta 585:94–102

    Article  CAS  Google Scholar 

  33. Georgakopoulos CG, Vonaparti A, Stamou M, Kiousi P, Lyris E, Angelis YS, Tsoupras G, Wuest B, Nielen MW, Panderi I, Koupparis M (2007) Rapid Commun Mass Spectrom 21:2439–2446

    Article  CAS  Google Scholar 

  34. Nielen MW, Bovee TF, van Engelen MC, Rutgers P, Hamers AR, van Rhijn JH, Hoogenboom LR (2006) Anal Chem 78:424–431

    Article  CAS  Google Scholar 

  35. Jemal M, Ouyang Z, Zhao W, Zhu M, Wu WW (2003) Rapid Commun Mass Spectrom 17:2732–2740

    Article  CAS  Google Scholar 

  36. Hakala KS, Kostiainen R, Ketola RA (2006) Rapid Commun Mass Spectrom 20:2081–2090

    Article  CAS  Google Scholar 

  37. Li AC, Gohdes MA, Shou WZ (2007) Rapid Commun Mass Spectrom 21:1421–1430

    Article  CAS  Google Scholar 

  38. Xia YQ, Miller JD, Bakhtiar R, Franklin RB, Liu DQ (2003) Rapid Commun Mass Spectrom 17:1137–1145

    Article  CAS  Google Scholar 

  39. Thevis M, Kohler M, Schlörer N, Kamber M, Kuhn A, Linscheid MW, Schänzer W (2007) J Mass Spectrom. DOI 10.1002/jms.1364

Download references

Acknowledgments

The study was carried out with the support of the Federal Office of Sports, Magglingen, Switzerland, and the Manfred Donike Institute for Doping Analysis, Cologne, Germany.

Author information

Authors and Affiliations

  1. Center for Preventive Doping Research, Institute of Biochemistry, German Sport University Cologne, Carl-Diem-Weg 6, 50933, Cologne, Germany

    Mario Thevis, Maxie Kohler, Andreas Thomas, Joachim Maurer & Wilhelm Schänzer

  2. Institute of Organic Chemistry, University of Cologne, Greinstraße 4, 50939, Cologne, Germany

    Nils Schlörer

  3. Department of Doping Prevention, Federal Office of Sports, 2532, Magglingen, Switzerland

    Matthias Kamber

Authors
  1. Mario Thevis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maxie Kohler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andreas Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joachim Maurer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nils Schlörer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Matthias Kamber
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wilhelm Schänzer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mario Thevis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thevis, M., Kohler, M., Thomas, A. et al. Determination of benzimidazole- and bicyclic hydantoin-derived selective androgen receptor antagonists and agonists in human urine using LC–MS/MS. Anal Bioanal Chem 391, 251–261 (2008). https://doi.org/10.1007/s00216-008-1882-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00216-008-1882-6

Keywords

Search

Navigation