Reversal of ethanol-induced intoxication by a novel modulator of Gβγ protein potentiation of the glycine receptor

Loreto San Martin, Fabian Cerda, Chunyang Jin, Veronica Jimenez, Gonzalo E. Yevenes, Tania Hernandez, Daniela Nova, Jorge Fuentealba, Luis G. Aguayo, Leonardo Guzman

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8 Citations (Scopus)


The acute intoxicating effects of ethanol in the central nervous system result from the modulation of several molecular targets. It is widely accepted that ethanol enhances the activity of the glycine receptor (GlyR), thus enhancing inhibitory neurotransmission, leading to motor effects, sedation, and respiratory depression. We previously reported that small peptides interfered with the binding of Gβγ to the GlyR and consequently inhibited the ethanol-induced potentiation of the receptor. Now, using virtual screening, we identified a subset of small molecules capable of interacting with the binding site of Gβγ. One of these compounds, M554, inhibited the ethanol potentiation of the GlyR in both evoked currents and synaptic transmission in vitro. When this compound was tested in vivo in mice treated with ethanol (1-3.5 g/kg), it was found to induce a faster recovery of motor incoordination in rotarod experiments and a shorter sedative effect in loss of righting reflex assays. This study describes a novel molecule that might be relevant for the design of useful therapeutic compounds in the treatment of acute alcohol intoxication.

Original languageEnglish
Pages (from-to)18791-18798
Number of pages8
JournalJournal of Biological Chemistry
Issue number36
Publication statusPublished - 2 Sept 2016

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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