Long Residence Time at the Neurosteroidogenic 18 kDa Translocator Protein Characterizes the Anxiolytic Ligand XBD173

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• 作者：Barbara Costa ; Eleonora Da Pozzo ; Chiara Cavallini ; Sabrina Taliani ; Federico Da Settimo ; Claudia Martini
• 刊名：ACS Chemical Neuroscience
• 出版年：2016
• 出版时间：August 17, 2016
• 年：2016
• 卷：7
• 期：8
• 页码：1041-1046
• 全文大小：337K
• 年卷期：0
• ISSN：1948-7193

文摘

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 × 10⁷ 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.