title: The Anxiolytic Etifoxine Binds to TSPO Ro5-4864 Binding Site with Long Residence Time Showing a High Neurosteroidogenic Activity.
abstract: 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 [3H]PK11195 and [3H]Ro5-4864 binding sites in rat kidney membranes. Etifoxine shows (i) high neurosteroidogenic efficacy and (ii) low affinity/short RT at the [3H]PK11195 site and low affinity/long RT at the [3H]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.
authors.affiliation: Department of Pharmacy, University of Pisa , via Bonanno, 6-56126 Pisa, Italy.
authors.forename: Barbara
authors.identifier: 0000-0002-7598-1275
authors.initials: B
authors.lastname: Costa
authors.affiliation: Department of Pharmacy, University of Pisa , via Bonanno, 6-56126 Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cavallini
authors.affiliation: Department of Pharmacy, University of Pisa , via Bonanno, 6-56126 Pisa, Italy.
authors.forename: Eleonora
authors.identifier: 0000-0003-4762-8949
authors.initials: E
authors.lastname: Da Pozzo
authors.affiliation: Department of Pharmacy, University of Pisa , via Bonanno, 6-56126 Pisa, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.affiliation: Department of Pharmacy, University of Pisa , via Bonanno, 6-56126 Pisa, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.affiliation: Department of Pharmacy, University of Pisa , via Bonanno, 6-56126 Pisa, Italy.
authors.forename: Claudia
authors.identifier: 0000-0001-9379-3027
authors.initials: C
authors.lastname: Martini
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism* / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010078:Oxazines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D011284:Pregnenolone / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D013816:Thermodynamics; D014316:Tritium
chemical_list: D014151:Anti-Anxiety Agents; D001570:Benzodiazepinones; D002352:Carrier Proteins; D018757:GABA Modulators; D000960:Hypolipidemic Agents; D007546:Isoquinolines; D018377:Neurotransmitter Agents; D010078:Oxazines; D011963:Receptors, GABA-A; D014316:Tritium; C069997:Tspo protein, rat; C028513:4'-chlorodiazepam; D005442:Flumazenil; D011284:Pregnenolone; C002125:etifoxine; C037850:PK 11195
keywords: Etifoxine; anxiolytic effect; kinetic binding parameters; neurosteroidogenic efficacy; residence time