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 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.
Prokai
L
L
Center for Drug Discovery, College of Pharmacy, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32610-0497, USA. lprokai@grove.ufl.edu
Zharikova
A
A
Janáky
T
T
Li
X
X
Braddy
A C
AC
Perjési
P
P
Matveeva
L
L
Powell
D H
DH
Prokai-Tatrai
K
K
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D002491:Central Nervous System Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D002853:Chromatography, Liquid; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D005110:Extracellular Space / Q000378:metabolism; D007202:Indicators and Reagents; D008297:Male; D013058:Mass Spectrometry; D017551:Microdialysis; D009479:Neuropeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D002491:Central Nervous System Agents; D007202:Indicators and Reagents; D009479:Neuropeptides