Identification of neuropeptide S antagonists: structure-activity relationship studies, X-ray crystallography, and in vivo evaluation.
ACS Chem Neurosci
; 5(8): 731-44, 2014 Aug 20.
Article
en En
| MEDLINE
| ID: mdl-24964000
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.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Neuropéptidos
/
Receptores de Neuropéptido
/
Neurotransmisores
Tipo de estudio:
Diagnostic_studies
Idioma:
En
Revista:
ACS Chem Neurosci
Año:
2014
Tipo del documento:
Article