The cognition-enhancing activity of E1R, a novel positive allosteric modulator of sigma-1 receptors

L. Zvejniece, E. Vavers, B. Svalbe, R. Vilskersts, I. Domracheva, M. Vorona, G. Veinberg, I. Misane, I. Stonans, I. Kalvinsh, M. Dambrova

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

Background and Purpose Here, we describe the in vitro and in vivo effects of (4R,5S)-2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide (E1R), a novel positive allosteric modulator of sigma-1 receptors. Experimental Approach E1R was tested for sigma receptor binding activity in a [3H](+)- pentazocine assay, in bradykinin (BK)-induced intracellular Ca2+ concentration ([Ca2+]i) assays and in an electrically stimulated rat vas deferens model. E1R's effects on cognitive function were tested using passive avoidance (PA) and Y-maze tests in mice. A selective sigma-1 receptor antagonist (NE-100), was used to study the involvement of the sigma-1 receptor in the effects of E1R. The open-field test was used to detect the effects of E1R on locomotion. Key Results Pretreatment with E1R enhanced the selective sigma-1 receptor agonist PRE-084's stimulating effect during a model study employing electrically stimulated rat vasa deferentia and an assay measuring the BK-induced [Ca2+]i increase. Pretreatment with E1R facilitated PA retention in a dose-related manner. Furthermore, E1R alleviated the scopolamine-induced cognitive impairment during the PA and Y-maze tests in mice. The in vivo and in vitro effects of E1R were blocked by treatment with the selective sigma-1 receptor antagonist NE-100. E1R did not affect locomotor activity. Conclusion and Implications E1R is a novel 4,5-disubstituted derivative of piracetam that enhances cognition and demonstrates efficacy against scopolamine-induced cholinergic dysfunction in mice. These effects are attributed to its positive modulatory action on the sigma-1 receptor and this activity may be relevant when developing new drugs for treating cognitive symptoms related to neurodegenerative diseases.

Original languageEnglish
Pages (from-to)761-771
Number of pages11
JournalBritish Journal of Pharmacology
Volume171
Issue number3
DOIs
Publication statusPublished - Feb 2014

Keywords

  • behaviour
  • CNS drugs
  • cognition
  • E1R
  • neurodegenerative diseases
  • racetam
  • receptor binding
  • scopolamine
  • sigma-1 receptor

Field of Science

  • 3.1 Basic medicine

Publication Type

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

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