The Anxiolytic Etifoxine Binds to TSPO Ro5-4864 Binding Site with Long Residence Time Showing a High Neurosteroidogenic Activity

被引:36
作者
Costa, Barbara [1 ]
Cavallini, Chiara [1 ]
Da Pozzo, Eleonora [1 ]
Taliani, Sabrina [1 ]
Da Settimo, Federico [1 ]
Martini, Claudia [1 ]
机构
[1] Univ Pisa, Dept Pharm, Via Bonanno 6, I-56126 Pisa, Italy
关键词
Etifoxine; residence time; neurosteroidogenic efficacy; anxiolytic effect; kinetic binding parameters; PERIPHERAL BENZODIAZEPINE-RECEPTOR; PROTEIN; 18; KDA; ANXIETY; BIOSYNTHESIS; INHIBITION; MODULATION; DISORDERS; EFFICACY; LIGANDS; TARGET;
D O I
10.1021/acschemneuro.7b00027
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1448 / 1454
页数:7
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