title: Enhancing neurosteroid synthesis--relationship to the pharmacology of translocator protein (18 kDa) (TSPO) ligands and benzodiazepines.
abstract: BACKGROUND
  The treatment of anxiety disorders is still a challenge; novel pharmacological approaches that combine rapid anxiolytic efficacy with fewer side effects are needed. A promising target for such compounds is the mitochondrial translocator protein (18 kDa) (TSPO). TSPO plays an important role for the synthesis of neurosteroids, known to modulate GABAA receptors, thereby exerting anxiolytic effects.
  
  
  METHODS
  We investigated the pharmacological profile of 2 well established TSPO ligands (XBD173 and etifoxine) compared to the benzodiazepine diazepam with regard to TSPO binding affinity, TSPO expression and neurosteroidogenesis.
  
  
  RESULTS
  In BV-2 microglia and C6 glioma cells all compounds significantly enhanced TSPO protein expression. Radioligand binding assays revealed the highest binding affinity to TSPO for XBD173, followed by diazepam and etifoxine. Pregnenolone synthesis was most potently enhanced by etifoxine.
  
  
  CONCLUSIONS
  Etifoxine turned out to be the most potent enhancer of neurosteroidogenesis, although its binding affinity to TSPO was lowest. These results indicate that the efficacy of TSPO ligands to stimulate neurosteroid synthesis, thereby leading to anxiolytic effects cannot be concluded from their binding affinity to TSPO.
authors: Department of Psychiatry and Psychotherapy, University Regensburg, Regensburg, Germany.
authors: L
authors: L
authors: Wolf
authors: Department of Psychiatry and Psychotherapy, University Regensburg, Regensburg, Germany.
authors: A
authors: A
authors: Bauer
authors: Department of Psychiatry and Psychotherapy, University Regensburg, Regensburg, Germany.
authors: D
authors: D
authors: Melchner
authors: Department of Psychiatry and Psychotherapy, University Regensburg, Regensburg, Germany.
authors: H
authors: H
authors: Hallof-Buestrich
authors: Department of Psychiatry and Psychotherapy, University Regensburg, Regensburg, Germany.
authors: P
authors: P
authors: Stoertebecker
authors: Department of Psychiatry and Psychotherapy, University Regensburg, Regensburg, Germany.
authors: E
authors: E
authors: Haen
authors: Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany.
authors: M
authors: M
authors: Kreutz
authors: Department of Psychiatry and Psychotherapy, University Regensburg, Regensburg, Germany.
authors: N
authors: N
authors: Sarubin
authors: Department of Psychiatry and Psychotherapy, University Regensburg, Regensburg, Germany.
authors: V M
authors: VM
authors: Milenkovic
authors: Department of Psychiatry and Psychotherapy, University Regensburg, Regensburg, Germany.
authors: C H
authors: CH
authors: Wetzel
authors: Department of Psychiatry and Psychotherapy, University Regensburg, Regensburg, Germany.
authors: R
authors: R
authors: Rupprecht
authors: Department of Psychiatry and Psychotherapy, University Regensburg, Regensburg, Germany.
authors: C
authors: C
authors: Nothdurfter
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D018377:Neurotransmitter Agents / Q000096:biosynthesis*; D010078:Oxazines / Q000494:pharmacology*; D011284:Pregnenolone / Q000378:metabolism; D011687:Purines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D018079:Receptors, GABA / Q000187:drug effects* / Q000378:metabolism*
chemical_list: C502525:N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide; D018377:Neurotransmitter Agents; D010078:Oxazines; D011687:Purines; D018079:Receptors, GABA; C499229:TSPO protein, human; D011284:Pregnenolone; D003975:Diazepam; C002125:etifoxine