Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 7, Pages 4089-4108Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c02223
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Funding
- FAR (Fondo di Ateneo per la Ricerca Scientifica) grants from the University of Ferrara
- FIR (Fondo per l'Incentivazione alla Ricerca) grant from the University of Ferrara
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Neuropeptide S modulates neurobiological functions through interaction with its receptor, with NPSR antagonists showing potential for treating substance abuse disorders. Compound 16, a new NPSR antagonist, demonstrated significantly improved potency in vivo, making it a valuable tool for studying the translational potential of the NPSergic system. Molecular modeling investigation provided insights into structure-activity relationships and ligand/NPSR interactions.
Neuropeptide S modulates important neurobiological functions including locomotion, anxiety, and drug abuse through interaction with its G protein-coupled receptor known as neuropeptide S receptor (NPSR). NPSR antagonists are potentially useful for the treatment of substance abuse disorders against which there is an urgent need for new effective therapeutic approaches. Potent NPSR antagonists in vitro have been discovered which, however, require further optimization of their in vivo pharmacological profile. This work describes a new series of NPSR antagonists of the oxazolo[3,4-a]pyrazine class. The guanidine derivative 16 exhibited nanomolar activity in vitro and 5-fold improved potency in vivo compared to SHA-68, a reference pharmacological tool in this field. Compound 16 can be considered a new tool for research studies on the translational potential of the NPSergic system. An in-depth molecular modeling investigation was also performed to gain new insights into the observed structure-activity relationships and provide an updated model of ligand/NPSR interactions.
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