title: Synthesis and biological evaluation of 2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide stereoisomers as novel positive allosteric modulators of sigma-1 receptor.
abstract: Novel positive allosteric modulators of sigma-1 receptor represented by 2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide enantiomers were synthesised using an asymmetric Michael addition of 2-nitroprop-1-enylbenzene to diethyl malonate. Following the chromatographic separation of the methyl erythro- and threo-4-nitro-3R- and 3S-phenylpentanoate diastereoisomers, target compounds were obtained by their reductive cyclisation into 5-methyl-4-phenylpyrrolidin-2-one enantiomers and the attachment of the acetamide group to the heterocyclic nitrogen. Experiments with electrically stimulated rat vas deference contractions induced by the PRE-084, an agonist of sigma-1 receptor, showed that (4R,5S)- and (4R,5R)-2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamides with an R-configuration at the C-4 chiral centre in the 2-pyrrolidone ring were more effective positive allosteric modulators of sigma-1 receptor than were their optical antipodes.
authors.affiliation: Latvian Institute of Organic Synthesis, 21 Aizkraukles Str., Riga LV 1006, Latvia. veinberg@osi.lv
authors.forename: Grigory
authors.initials: G
authors.lastname: Veinberg
authors.forename: Maxim
authors.initials: M
authors.lastname: Vorona
authors.forename: Liga
authors.initials: L
authors.lastname: Zvejniece
authors.forename: Reinis
authors.initials: R
authors.lastname: Vilskersts
authors.forename: Edijs
authors.initials: E
authors.lastname: Vavers
authors.forename: Edvards
authors.initials: E
authors.lastname: Liepinsh
authors.forename: Helena
authors.initials: H
authors.lastname: Kazoka
authors.forename: Sergey
authors.initials: S
authors.lastname: Belyakov
authors.forename: Anatoly
authors.initials: A
authors.lastname: Mishnev
authors.forename: Jevgenijs
authors.initials: J
authors.lastname: Kuznecovs
authors.forename: Sergejs
authors.initials: S
authors.lastname: Vikainis
authors.forename: Natalja
authors.initials: N
authors.lastname: Orlova
authors.forename: Anton
authors.initials: A
authors.lastname: Lebedev
authors.forename: Yuri
authors.initials: Y
authors.lastname: Ponomaryov
authors.forename: Maija
authors.initials: M
authors.lastname: Dambrova
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000494:Allosteric Regulation; D000818:Animals; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000097605:Sigma-1 Receptor
chemical_list: D000081:Acetamides; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor