The neuropeptide S receptor (NPSR) is a G-protein coupled receptor, first described by Sato and co-workers in 2004. Further research has detailed the distribution and expression of neuropeptide S (NPS) precursor mRNA and NPSR mRNA in various regions of the brain. Central administration of NPS has been shown to promote hyperlocomotion and wakefulness in various rodent models, implicating the importance of this circuitry in the control of sleep, stress, anxiety and arousal. Also, two polymorphisms of NPSR have been linked to asthma. Recent findings suggest that the receptor might be coupled to signaling through the Gq, Gs and mitogen-activated protein kinase (MAPK) pathways. Although several potent inhibitors on the NPS/NPSR signaling pathway have been found, none of these compounds have as yet demonstrated robust in vivo efficacy in multiple animal models. Thus, there is a clear need to discover novel small molecule antagonists of the NPSR to help probe NPS/NPSR pharmacology, and to validate the importance of this neurocircuitry in animal models. The present report discloses the discovery and characterization of a potent NPSR antagonist having an imidazo-pyridinium molecular core and an unusual, yet stable phosphorothioyl species. The small molecular probe ML154 (CID-46930969) is the most potent in vivo active compound yet reported, and has promising microsomal stability compared to other lead NPSR antagonists disclosed in the literature. The probe completely antagonizes NPS activation of the NPS/NPSR neurocircuitry in a food intake rat model using intracerebroventricular (icv) administration. This potent probe molecule can be used as a tool molecule by biologists interested in understanding NPS/NPSR pharmacology and the role of NPSR antagonism in sleep, anxiety, food intake, and addiction.