title: 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.
authors: Research Triangle Institute , Post Office Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors: Carla
authors: C
authors: Hassler
authors: Yanan
authors: Y
authors: Zhang
authors: Brian
authors: B
authors: Gilmour
authors: Tyler
authors: T
authors: Graf
authors: Timothy
authors: T
authors: Fennell
authors: Rodney
authors: R
authors: Snyder
authors: Jeffrey R
authors: JR
authors: Deschamps
authors: Rainer K
authors: RK
authors: Reinscheid
authors: Celia
authors: C
authors: Garau
authors: Scott P
authors: SP
authors: Runyon
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007536:Isomerism; D008297:Male; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D023303:Oxazolidinones / Q000737:chemistry / Q000494:pharmacology; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: C529493:3-oxo-1,1-diphenyltetrahydrooxazolo(3,4-a)pyrazine-7-carboxylic acid 4-fluorobenzylamide; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D023303:Oxazolidinones; D011719:Pyrazines; D018013:Receptors, Neuropeptide; C539972:neuropeptide S, mouse; D014867:Water