Synthesis and evaluation of a new series of Neuropeptide S receptor antagonists

Medicinal chemistry efforts have identified a quinolinone class of potent NPSR antagonists that readily cross the blood–brain barrier. Optimization efforts resulted in the identification of a potent NPSR antagonist which dose-dependently and specifically inhibited 125I-NPS binding in the CNS when administered to rats. Administration of Neuropeptide S (NPS) has been shown to produce arousal, that is, independent of novelty and to induce wakefulness by suppressing all stages of sleep, as demonstrated by EEG recordings in rat. Medicinal chemistry efforts have identified a quinolinone class of potent NPSR antagonists that readily cross the blood–brain barrier. We detail here optimization efforts resulting in the identification of a potent NPSR antagonist which dose-dependently and specifically inhibited 125I-NPS binding in the CNS when administered to rats.