San Martin Loreto, Cerda Fabian, Jin Chunyang, Jimenez Veronica, Yevenes Gonzalo E, Hernandez Tania, Nova Daniela, Fuentealba Jorge, Aguayo Luis G, Guzman Leonardo
From the Laboratories of Molecular Neurobiology and.
the Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, North Carolina 27709, and.
J Biol Chem. 2016 Sep 2;291(36):18791-8. doi: 10.1074/jbc.M116.740555. Epub 2016 Jul 11.
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.
乙醇在中枢神经系统中的急性中毒作用源于对多个分子靶点的调节。乙醇增强甘氨酸受体（GlyR）的活性，进而增强抑制性神经传递，导致运动效应、镇静和呼吸抑制，这一观点已被广泛接受。我们之前报道过小肽会干扰Gβγ与GlyR的结合，从而抑制乙醇诱导的受体增强作用。现在，通过虚拟筛选，我们鉴定出了一组能够与Gβγ结合位点相互作用的小分子。其中一种化合物M554，在体外诱发电流和突触传递中均能抑制乙醇对GlyR的增强作用。当在乙醇（1 - 3.5 g/kg）处理的小鼠体内测试该化合物时，发现在转棒实验中它能使运动不协调恢复得更快，在翻正反射丧失实验中镇静作用持续时间更短。这项研究描述了一种新型分子，它可能与设计治疗急性酒精中毒的有效治疗化合物相关。
