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

Authors

  • Laszlo Prokai,

    Corresponding author
    1. Center for Drug Discovery, College of Pharmacy, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32610-0497, USA
    • Center for Drug Discovery, College of Pharmacy, University of Florida, P.O. Box 100497, Health Science Center, Gainesville, Florida 32610-0497, USA
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  • Alevtina Zharikova,

    1. Center for Drug Discovery, College of Pharmacy, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32610-0497, USA
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  • Tamás Janáky,

    1. Center for Drug Discovery, College of Pharmacy, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32610-0497, USA
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    • On leave from the Department of Medical Chemistry, University of Szeged, Szeged, Hungary.

  • Xiaoxu Li,

    1. Center for Drug Discovery, College of Pharmacy, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32610-0497, USA
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  • April C. Braddy,

    1. Center for Drug Discovery, College of Pharmacy, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32610-0497, USA
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  • Pál Perjési,

    1. Center for Drug Discovery, College of Pharmacy, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32610-0497, USA
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    • On leave from the Department of Medical Chemistry, University of Pécs, Pécs, Hungary.

  • Lidia Matveeva,

    1. Department of Chemistry, University of Florida, Gainesville, Florida 32611, USA
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  • David H. Powell,

    1. Department of Chemistry, University of Florida, Gainesville, Florida 32611, USA
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  • Katalin Prokai-Tatrai

    1. Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, Florida 32610, USA
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  • Paper presented at the 19th Informal Meeting on Mass Spectrometry, Noszvaj, Hungary, 29 April – 3 May 2001.

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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