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

The early-phase discovery and development of useful central nervous system (CNS) agents present ample opportunities to exploit mass spectrometry and p rovide detailed compound/mixture characterization, or to make the process f aster and/or more economic. Neuropeptide FF antagonists and centrally activ e thyrotropin-releasing hormone analogues were used as specific examples in this work. We evaluated the characterization of focused libraries of pepti de derivatives by electrospray ionization, tandem mass spectrometry and liq uid chromatography/tandem mass spectrometry on a quadrupole ion trap and na noelectrospray on a Fourier transform ion cyclotron resonance mass spectrom eter. Immobilized artificial-membrane chromatography was employed as a mode l 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 administrat ion of test compounds was used as an in vivo approach, and we took advantag e of microdialysis sampling that furnished samples without interfering tiss ue matrix and afforded the estimation of extracellular concentrations in a localized part of the brain. Overall, making atmospheric-pressure ionizatio n mass spectrometry an integral part of the process has played a major role in increasing throughput, selectivity, specificity and detection sensitivi ty and thereby providing useful information about the extent or mechanism o f transport and metabolic activation/inactivation in early-phase discovery and development of CNS agents. Copyright (C) 2001 John Wiley & Sons, Ltd.