The Anxiolytic Etifoxine Binds to TSPO Ro5-4864 Binding Site with Long Residence Time Showing a High Neurosteroidogenic Activity
The Anxiolytic Etifoxine Binds to TSPO Ro5-4864 Binding Site with Long Residence Time Showing a High Neurosteroidogenic Activity
复制标题
DOI：
10.1021/acschemneuro.7b00027
复制
发表时间：
2017-07-01
影响因子：
5
通讯作者：
Martini, Claudia
中科院分区：
文献类型：
--
作者：
Costa, Barbara;Cavallini, Chiara;Martini, Claudia
已批准的抗焦虑药物替福辛(Stresam)与激素性18 kDa转位蛋白(TSPO)的低结合亲和力使人怀疑该蛋白在介导替福辛神经激素性疗效中的特殊作用。经典的TSPO配体PK11195结合部位的停留时间(RT)正逐渐成为一种相关的神经类固醇生成效能的衡量指标，而不是结合亲和力。在这里，我们评价了(I)体外神经类固醇合成活性与神经类固醇合成较差的参考TSPO配体(PK11195和Ro5-4864)的比较，以及(Ii)大鼠肾膜上[H-3]PK1119S和[H-3]Ro5-4864结合位点的亲和力和RT。依替福辛表现出(1)高神经类固醇合成效率和(2)低亲和力/短RT(位于[H-3]PK11195位)和低亲和力/长RT(位于[H-3]Ro5-4864位)，与之竞争性结合。这些发现表明，Ro5-4864结合位点的长RT可能是其高神经类固醇生成效果的原因。
The low binding affinity of the approved anxiolytic drug etifoxine (Stresam) at the steroidogenic 18 kDa translocator protein (TSPO) has questioned the specific contribution of this protein in mediating the etifoxine neurosteroidogenic efficacy. Residence time (RT) at the binding site of the classical TSPO ligand PK11195 is emerging as a relevant neurosteroidogenic efficacy, measure rather than the binding affinity. Here etifoxine was evaluated for (i) the in vitro neurosteroidogenic activity in comparison to poorly neurosteroidogenic reference TSPO ligands (PK11195 and Ro5-4864) and (ii) the affinity and RT at [H-3]PK1119S and [H-3]Ro5-4864 binding sites in rat kidney membranes. Etifoxine shows (i) high neurosteroidogenic efficacy and (ii) low affinity/short RT at the [H-3]PK11195 site and low affinity/long RT at the [H-3]Ro5-4864 site, at which etifoxine competitively bound. These findings suggest that the long RT of etifoxine at the Ro5-4864 binding site could account for its high neurosteroidogenic efficacy.