title: Reversal of Ethanol-induced Intoxication by a Novel Modulator of Gβγ Protein Potentiation of the Glycine Receptor.
abstract: 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.
authors.affiliation: From the Laboratories of Molecular Neurobiology and.
authors.forename: Loreto
authors.initials: L
authors.lastname: San Martin
authors.affiliation: From the Laboratories of Molecular Neurobiology and.
authors.forename: Fabian
authors.initials: F
authors.lastname: Cerda
authors.affiliation: the Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, North Carolina 27709, and.
authors.forename: Chunyang
authors.initials: C
authors.lastname: Jin
authors.affiliation: the Departamento de Ciencias Químicas, Facultad de Ciencias Exactas, Universidad Andres Bello, 403901 Concepción, Chile.
authors.forename: Veronica
authors.initials: V
authors.lastname: Jimenez
authors.affiliation: From the Laboratories of Molecular Neurobiology and.
authors.forename: Gonzalo E
authors.initials: GE
authors.lastname: Yevenes
authors.affiliation: From the Laboratories of Molecular Neurobiology and.
authors.forename: Tania
authors.initials: T
authors.lastname: Hernandez
authors.affiliation: From the Laboratories of Molecular Neurobiology and.
authors.forename: Daniela
authors.initials: D
authors.lastname: Nova
authors.affiliation: From the Laboratories of Molecular Neurobiology and.
authors.forename: Jorge
authors.initials: J
authors.lastname: Fuentealba
authors.affiliation: Neurophysiology, Department of Physiology, University of Concepción, 403901 Concepción, Chile.
authors.forename: Luis G
authors.initials: LG
authors.lastname: Aguayo
authors.affiliation: From the Laboratories of Molecular Neurobiology and joleguzman@gmail.com.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Guzman
mesh_terms: D000435:Alcoholic Intoxication / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000431:Ethanol / Q000009:adverse effects* / Q000494:pharmacology; D044387:GTP-Binding Protein beta Subunits / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D010455:Peptides; D018009:Receptors, Glycine; D000431:Ethanol
keywords: G protein; Gβγ; alcohol; glycine receptor; molecular pharmacology; small molecule