title: Long Residence Time at the Neurosteroidogenic 18 kDa Translocator Protein Characterizes the Anxiolytic Ligand XBD173.
abstract: Recent data have demonstrated a positive correlation between the residence time (RT) and neurosteroidogenic efficacy of a ligand at the translocator protein (TSPO), an attractive anxyolitic target. To explore the potential impact of RT on TSPO ligand anxiolytic activity, the RT and the steroidogenic activity of XBD173, a ligand exerting anxiolytic activity in humans, were retrospectively evaluated. To this aim, XBD173 association and dissociation rate constants were measured (1.23 × 10(7) M(-1) min(-1) and 0.0079 min(-1), respectively). XBD173 resulted to have a long RT (127 min) and to stimulate efficaciously neurosteroidogenesis, in terms of pregnenolone production. The present findings corroborate the importance of TSPO ligand RT to predict their effective neurosteroidogenic activity and promising anxiolytic action. These positive results prompted us to set up a fast and high-throughput kinetic method to improve the efficiency of RT-based TSPO drug-discovery process.
authors.affiliation: Department of Pharmacy, University of Pisa , via Bonanno, 6-56126 Pisa, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Costa
authors.affiliation: Department of Pharmacy, University of Pisa , via Bonanno, 6-56126 Pisa, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Da Pozzo
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: 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.initials: C
authors.lastname: Martini
mesh_terms: D000311:Adrenal Glands / Q000166:cytology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002352:Carrier Proteins; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000473:pathology; D007546:Isoquinolines / Q000493:pharmacokinetics; D007668:Kidney / Q000166:cytology; D008024:Ligands; D011284:Pregnenolone / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011687:Purines / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D014151:Anti-Anxiety Agents; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D007546:Isoquinolines; D008024:Ligands; C502525:N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide; D011687:Purines; D011963:Receptors, GABA-A; D014316:Tritium; C069997:Tspo protein, rat; D011284:Pregnenolone; C037850:PK 11195
keywords: 18 kDa translocator protein; TSPO ligands; anxiolytic activity; kinetic binding assay; neurosteroids; residence time