Research Article

Integration of mass spectrometry into early-phase discovery and development of central nervous system agents†

  1. Laszlo Prokai1,*,
  2. Alevtina Zharikova1,
  3. Tamás Janáky1,‡,
  4. Xiaoxu Li1,
  5. April C. Braddy1,
  6. Pál Perjési1,§,
  7. Lidia Matveeva2,
  8. David H. Powell2,
  9. Katalin Prokai-Tatrai3

Article first published online: 11 OCT 2001

DOI: 10.1002/jms.227

Issue

Journal of Mass Spectrometry

Journal of Mass Spectrometry

Volume 36, Issue 11, pages 1211–1219, November 2001

Additional Information

How to Cite

Prokai, L., Zharikova, A., Janáky, T., Li, X., Braddy, A. C., Perjési, P., Matveeva, L., Powell, D. H. and Prokai-Tatrai, K. (2001), Integration of mass spectrometry into early-phase discovery and development of central nervous system agents. J. Mass Spectrom., 36: 1211–1219. doi: 10.1002/jms.227

Author Information

  1. 1

    Center for Drug Discovery, College of Pharmacy, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32610-0497, USA

  2. 2

    Department of Chemistry, University of Florida, Gainesville, Florida 32611, USA

  3. 3

    Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, Florida 32610, USA

  1. ‡

    On leave from the Department of Medical Chemistry, University of Szeged, Szeged, Hungary.

  2. §

    On leave from the Department of Medical Chemistry, University of Pécs, Pécs, Hungary.

*Center for Drug Discovery, College of Pharmacy, University of Florida, P.O. Box 100497, Health Science Center, Gainesville, Florida 32610-0497, USA

  1. †

    Paper presented at the 19th Informal Meeting on Mass Spectrometry, Noszvaj, Hungary, 29 April – 3 May 2001.

  2. ‡

    On leave from the Department of Medical Chemistry, University of Szeged, Szeged, Hungary.

  3. §

    On leave from the Department of Medical Chemistry, University of Pécs, Pécs, Hungary.

Publication History

  1. Issue published online: 12 NOV 2001
  2. Article first published online: 11 OCT 2001
  3. Manuscript Accepted: 16 AUG 2001
  4. Manuscript Received: 8 MAY 2001

Funded by

  • National Institutes of Health. Grant Numbers: DA10543, MH59360, RR12023

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Keywords:

  • atmospheric pressure ionization;
  • combinatorial mixtures;
  • immobilized artificial membrane chromatography;
  • in vivo microdialysis;
  • metabolism

Abstract

The early-phase discovery and development of useful central nervous system (CNS) agents present ample opportunities to exploit mass spectrometry and provide detailed compound/mixture characterization, or to make the process faster and/or more economic. Neuropeptide FF antagonists and centrally active thyrotropin-releasing hormone analogues were used as specific examples in this work. We evaluated the characterization of focused libraries of peptide derivatives by electrospray ionization, tandem mass spectrometry and liquid chromatography/tandem mass spectrometry on a quadrupole ion trap and nanoelectrospray on a Fourier transform ion cyclotron resonance mass spectrometer. Immobilized artificial-membrane chromatography was employed as a model to predict/rank new agents against lead compounds for their potential to reach the central nervous system in pharmacologically significant amounts. Measuring brain concentrations in rodents after the intravenous administration of test compounds was used as an in vivo approach, and we took advantage of microdialysis sampling that furnished samples without interfering tissue matrix and afforded the estimation of extracellular concentrations in a localized part of the brain. Overall, making atmospheric-pressure ionization mass spectrometry an integral part of the process has played a major role in increasing throughput, selectivity, specificity and detection sensitivity and thereby providing useful information about the extent or mechanism of transport and metabolic activation/inactivation in early-phase discovery and development of CNS agents. Copyright © 2001 John Wiley & Sons, Ltd.

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