title: TSPO ligand residence time: a new parameter to predict compound neurosteroidogenic efficacy.
abstract: The pharmacological activation of the cholesterol-binding Translocator Protein (TSPO) leads to an increase of endogenous steroids and neurosteroids determining benefic pleiotropic effects in several pathological conditions, including anxiety disorders. The relatively poor relationship between TSPO ligand binding affinities and steroidogenic efficacies prompted us to investigate the time (Residence Time, RT) that a number of compounds with phenylindolylglyoxylamide structure (PIGAs) spends in contact with the target. Here, given the poor availability of TSPO ligand kinetic parameters, a kinetic radioligand binding assay was set up and validated for RT determination using a theoretical mathematical model successfully applied to other ligand-target systems. TSPO ligand RT was quantified and the obtained results showed a positive correlation between the period for which a drug interacts with TSPO and the compound ability to stimulate steroidogenesis. Specifically, the TSPO ligand RT significantly fitted both with steroidogenic efficacy (Emax) and with area under the dose-response curve, a parameter combining drug potency and efficacy. A positive relation between RT and anxiolytic activity of three compounds was evidenced. In conclusion, RT could be a relevant parameter to predict the steroidogenic efficacy and the in vivo anxiolytic action of new TSPO ligands.
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: Giacomelli
authors.affiliation: Department of Pharmacy, University of Pisa, via Bonanno, 6-56126 Pisa, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barresi
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: D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology*; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D018755:GABA Agonists / Q000494:pharmacology*; D015870:Gene Expression; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D007700:Kinetics; D008024:Ligands; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011284:Pregnenolone / Q000096:biosynthesis / Q000378:metabolism; D011485:Protein Binding; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism*; D013816:Thermodynamics; D013997:Time Factors; D014316:Tritium / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D001570:Benzodiazepinones; D018755:GABA Agonists; D007211:Indoles; D007546:Isoquinolines; D008024:Ligands; C503726:N,N-Di-n-butyl-5-chloro-2-(4-chlorophenyl)indol-3-ylglyoxylamide; D018079:Receptors, GABA; C499229:TSPO protein, human; D014316:Tritium; C028513:4'-chlorodiazepam; D011284:Pregnenolone; C037850:PK 11195