Costa Barbara, Cavallini Chiara, Da Pozzo Eleonora, Taliani Sabrina, Da Settimo Federico, Martini Claudia
Department of Pharmacy, University of Pisa , via Bonanno, 6-56126 Pisa, Italy.
ACS Chem Neurosci. 2017 Jul 19;8(7):1448-1454. doi: 10.1021/acschemneuro.7b00027. Epub 2017 Apr 4.
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]PK11195 and [H]Ro5-4864 binding sites in rat kidney membranes. Etifoxine shows (i) high neurosteroidogenic efficacy and (ii) low affinity/short RT at the [H]PK11195 site and low affinity/long RT at the [H]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.
已获批的抗焦虑药物依替福辛（Stresam）对类固醇生成性18 kDa转位蛋白（TSPO）的低结合亲和力，引发了人们对该蛋白在介导依替福辛神经甾体生成功效中具体作用的质疑。经典TSPO配体PK11195在结合位点的驻留时间（RT）正成为一种相关的神经甾体生成功效衡量指标，而非结合亲和力。在此，对依替福辛进行了如下评估：（i）与神经甾体生成能力较差的参考TSPO配体（PK11195和Ro5-4864）相比的体外神经甾体生成活性，以及（ii）在大鼠肾膜中[H]PK11195和[H]Ro5-4864结合位点的亲和力和驻留时间。依替福辛表现出：（i）高神经甾体生成功效，以及（ii）在[H]PK11195位点的低亲和力/短驻留时间，和在[H]Ro5-4864位点的低亲和力/长驻留时间，依替福辛在该位点存在竞争性结合。这些发现表明，依替福辛在Ro5-4864结合位点的长驻留时间可能是其高神经甾体生成功效的原因。
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