Open AccessIdentification of Neuropeptide S Antagonists: Structure–Activity Relationship Studies, X-ray Crystallography, and in Vivo Evaluation
Author(s) -
Carla Haßler,
Yanan Zhang,
Brian P. Gilmour,
Tyler N. Graf,
Timothy R. Fennell,
Rodney W. Snyder,
Jeffrey R. Deschamps,
Rainer K. Reinscheid,
Celia Garau,
Scott P. Runyon
Publication year - 2014
Publication title -
acs chemical neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.158
H-Index - 69
ISSN - 1948-7193
DOI - 10.1021/cn500113c
Subject(s) - in vivo , antagonist , neuropeptide , neuropeptide y receptor , chemistry , pharmacology , biological activity , enantiomer , receptor , panic disorder , panic , g protein coupled receptor , pharmacokinetics , stereochemistry , in vitro , biochemistry , medicine , biology , anxiety , microbiology and biotechnology , psychiatry
Modulation of the neuropeptide S (NPS) system has been linked to a variety of CNS disorders such as panic disorder, anxiety, sleeping disorders, asthma, obesity, PTSD, and substance abuse. In this study, a series of diphenyltetrahydro-1H-oxazolo[3,4-α]pyrazin-3(5H)-ones were synthesized and evaluated for antagonist activity at the neuropeptide S receptor. The absolute configuration was determined by chiral resolution of the key synthetic intermediate, followed by analysis of one of the individual enantiomers by X-ray crystallography. The R isomer was then converted to a biologically active compound (34) that had a Ke of 36 nM. The most potent compound displayed enhanced aqueous solubility compared with the prototypical antagonist SHA-68 and demonstrated favorable pharmacokinetic properties for behavioral assessment. In vivo analysis in mice indicated a significant blockade of NPS induced locomotor activity at an ip dose of 50 mg/kg. This suggests that analogs having improved drug-like properties will facilitate more detailed studies of the neuropeptide S receptor system.