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

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

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2764-2771
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number10
DOIs
Publication statusPublished - 15 May 2013
Externally publishedYes

Keywords

  • 2-(5-Methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide
  • Agonist
  • Enantiomers
  • Modulation
  • Sigma-1 receptor

Field of Science

  • 3.1 Basic medicine
  • 1.6 Biological sciences
  • 1.4 Chemical sciences

Publication Type

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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