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

Laszlo Prokai, Alevtina Zharikova, Tams Janky, Xiaoxu Li, April C. Braddy, Pl Perjsi, Lidia Matveeva, David H. Powell, Katalin Prokai-Tatrai

Research output: Contribution to journalArticle

15 Scopus citations

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.

Original languageEnglish
Pages (from-to)1211-1219
Number of pages9
JournalJournal of Mass Spectrometry
Volume36
Issue number11
DOIs
Publication statusPublished - 13 Dec 2001

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Keywords

  • Atmosphric pressure ionization
  • Combinatorial mixtures
  • Immobilized artificial membrane chromatography
  • In vivo microdialysis
  • Metabolism

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