Structural Characterization of In Vitro Rat Liver Microsomal Metabolites of a Selective Muscarinic M_(2) Receptor Antagonist Using LTQ-Orbitrap Mass Spectrometer

摘要

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment and personality changes. One of findings in brains of AD patients is the loss of cholinergic markers, including levels of acetylcholine and choline acetyltransferase. The cholinergic therapy for the treatment of AD includes counteracting this loss in cholinergic activity by pharmacologic intervention to increase cholinergic transmission. One of alternative approaches involves inhibition of central presynaptic M_(2) receptors, resulting in an increase in acetylcholine release. SCH 57790 is a selective muscarinic M_(2) receptor antagonist 4-cyclohexyl-alpha-[4 [[4-methoxyphenyl] sulphinyl]-phenyl]- piperazine-acetonitrile and has been shown to produce robust increases in acetylcholine release in the CNS and lead to consistent improvements in cognitive performance in animal models. In this presentation, we explore the use of LTQ-Orbitrap mass spectrometer in conjunction with on-line H/D exchange HR-LC/MS for rapid identification of drug metabolites from in vitro incubation of SCH 57790 in rat liver microsomes.