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  3. 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

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

  • Bioorg Med Chem. 2013 May 15;21(10):2764-71. doi: 10.1016/j.bmc.2013.03.016.
Grigory Veinberg 1,  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
Affiliations

Affiliation

  • 1 Latvian Institute of Organic Synthesis, 21 Aizkraukles Str., Riga LV 1006, Latvia. veinberg@osi.lv
PMID: 23582449 DOI: 10.1016/j.bmc.2013.03.016
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.

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