title: Synthesis and separation of the enantiomers of the neuropeptide S receptor antagonist (9R/S)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (SHA 68).
abstract: This study reports the synthesis, chromatographic separation, and pharmacological evaluation of the two enantiomers of the neuropeptide S receptor (NPSR) antagonist (9R/S)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (SHA 68). The (9R)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (compound 10) and (9S)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (compound 10a) were synthesized and their purity assessed by chiral chromatography. The absolute configuration of the enantiomer 10 has been assigned from the crystal structure of the corresponding (S)-phenyl ethyl amine derivative 8. Calcium mobilization studies performed on cells expressing the recombinant NPSR demonstrated that compound 10 is the active enantiomer while the contribution of 10a to the NPSR antagonist properties of the racemic mixture is negligible.
authors.affiliation: Department of Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Trapella
authors.forename: Michela
authors.initials: M
authors.lastname: Pela
authors.forename: Luisa
authors.initials: L
authors.lastname: Del Zoppo
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calo
authors.forename: Valeria
authors.initials: V
authors.lastname: Camarda
authors.forename: Chiara
authors.initials: C
authors.lastname: Ruzza
authors.forename: Alberto
authors.initials: A
authors.lastname: Cavazzini
authors.forename: Valentina
authors.initials: V
authors.lastname: Costa
authors.forename: Valerio
authors.initials: V
authors.lastname: Bertolasi
authors.forename: Rainer K
authors.initials: RK
authors.lastname: Reinscheid
authors.forename: Severo
authors.initials: S
authors.lastname: Salvadori
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
mesh_terms: D018360:Crystallography, X-Ray; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D023303:Oxazolidinones / Q000138:chemical synthesis* / Q000302:isolation & purification* / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000302:isolation & purification* / Q000494:pharmacology; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism
chemical_list: C529493:3-oxo-1,1-diphenyltetrahydrooxazolo(3,4-a)pyrazine-7-carboxylic acid 4-fluorobenzylamide; D023303:Oxazolidinones; D011719:Pyrazines; D018013:Receptors, Neuropeptide