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Identification of neuropeptide S antagonists: structure-activity relationship studies, X-ray crystallography, and in vivo evaluation.

Abstract：

: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.

journal_name

ACS Chem Neurosci

journal_title

ACS chemical neuroscience

authors

Hassler C,Zhang Y,Gilmour B,Graf T,Fennell T,Snyder R,Deschamps JR,Reinscheid RK,Garau C,Runyon SP

doi

10.1021/cn500113c

subject

Has Abstract

pub_date

2014-08-20 00:00:00

pages

731-44

issue

8

issn

1948-7193

journal_volume

5

pub_type

杂志文章

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