title: Novel routes to either racemic or enantiopure α-amino-(4-hydroxy-pyrrolidin-3-yl)acetic acid derivatives and biological evaluation of a new promising pharmacological scaffold.
abstract: Cycloaddition between (+) or (-)-menthone-derived nitrones and N-benzyl-3-pyrroline afforded enantiopure spiro-fused heterocycles. The reaction occurred enantio- and diastereo-selectively on the less hindered side of the nitrone, the 3-pyrroline N-benzyl group being oriented outwards, thus controlling the configurations of three simultaneously created chiral centers. From either (+) or (-)-menthone, both enantiomeric cycloadducts were synthesized in excellent yield. Removing the chiral auxiliary and the N-benzyl group delivered a series of enantiopure 4-hydroxy-3-glycinyl-pyrrolidine derivatives in 3-5 steps and 36 to 81 overall yields. Using two other achiral nitrones, shorter routes to racemic analogues were developed. Two of the synthesized compounds markedly lowered extracellular glutamate level and modestly interacted with cannabinoid type-1 receptors. As these two neuroactive compounds were devoid of in vitro toxicity and did not cross the blood brain interface, they might represent potential pharmacological agents to target peripheral organs.
authors.affiliation: CNRS UMR 5246, Université Lyon1, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), F-69622 Villeurbanne, France.
authors.forename: Samy
authors.initials: S
authors.lastname: Cecioni
authors.affiliation: CNRS UMR 5246, Université Lyon1, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), F-69622 Villeurbanne, France.
authors.forename: Kaïss
authors.initials: K
authors.lastname: Aouadi
authors.affiliation: CNRS UMR 5246, Université Lyon1, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), F-69622 Villeurbanne, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Guiard
authors.affiliation: INSERM U1028, CNRS UMR5292, Université Lyon 1, Lyon Neuroscience Research Center, NeuroDialyTics Unit, Lyon F-69000, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Parrot
authors.affiliation: INSERM U1028, CNRS UMR5292, Université Lyon 1, Lyon Neuroscience Research Center, Blood Brain Interfaces Exploratory Platform BIP, Lyon F-69000, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Strazielle
authors.affiliation: INSERM U1028, CNRS UMR5292, Université Lyon 1, Lyon Neuroscience Research Center, Blood Brain Interfaces Exploratory Platform BIP, Lyon F-69000, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Blondel
authors.affiliation: INSERM U1028, CNRS UMR5292, Université Lyon 1, Lyon Neuroscience Research Center, Blood Brain Interfaces Exploratory Platform BIP, Lyon F-69000, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Ghersi-Egea
authors.affiliation: Université de Lyon, Pulsalys, F-69000 Lyon, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Chapelle
authors.affiliation: INSERM U1028, CNRS UMR5292, Université Lyon 1, Lyon Neuroscience Research Center, NeuroDialyTics Unit, Lyon F-69000, France; INSERM U1028, CNRS UMR5292, Université Lyon 1, Lyon Neuroscience Research Center, BioRaN, Lyon F-69000, France. Electronic address: luc.denoroy@univ-lyon1.fr.
authors.forename: Luc
authors.initials: L
authors.lastname: Denoroy
authors.affiliation: CNRS UMR 5246, Université Lyon1, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), F-69622 Villeurbanne, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Praly
mesh_terms: D000085:Acetates / Q000737:chemistry; D000818:Animals; D004353:Drug Evaluation, Preclinical; D008297:Male; D008958:Models, Molecular; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
chemical_list: D000085:Acetates; D011759:Pyrrolidines
keywords: Blood brain barrier; CNS receptors; Chiral nitrone; Cycloaddition; Isoxazolidine; Neuroactive analogs; Pyrrolidine