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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
Authors:Grigory Veinberg  Maxim Vorona  Liga Zvejniece  Reinis Vilskersts  Edijs Vavers  Edvards Liepinsh  Helena Kazoka  Sergey Belyakov  Anatoly Mishnev  Jevgenijs Kuznecovs  Sergejs Vikainis  Natalja Orlova  Anton Lebedev  Yuri Ponomaryov  Maija Dambrova
Institution:Latvian Institute of Organic Synthesis, 21 Aizkraukles Str., Riga LV 1006, Latvia
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.
Keywords:2-(5-Methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide  Enantiomers  Sigma-1 receptor  Agonist  Modulation
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