Discovery of anxiolytic 2-ferrocenyl-1,3-thiazolidin-4-ones exerting GABAA receptor interaction via the benzodiazepine-binding site

• Design and synthesis of a library of novel GABAA benzodiazepine-binding site ligands.
• Potent novel N-substituted 2-ferrocenyl-1,3-thiazolidin-4-one-based anxiolytics.
• Library compounds compete with known GABAA-targeting agents in vivo.
• Ligand docking demonstrated favorable interactions with the GABAA receptor complex.
• Incorporation of a ferrocene core was crucial for the observed anxiolytic effect.

Herein, we report on the synthesis, spectral, crystallographic and electrochemical properties of a small library of N-substituted 2-ferrocenyl-1,3-thiazolidin-4-ones, designed as novel GABAA benzodiazepine-binding site ligands. The anxiolytic properties of the title compounds were evaluated in several different in vivo models, whereas the involvement of the GABAA receptor complex in the activity of the most potent compound, 2-ferrocenyl-3-(4-methoxyphenylethyl)-1,3-thiazolidin-4-one, was inferred from experiments with known GABAA-targeting agents. Ligand docking experiments revealed that the high, dose-dependent, anxiolytic activity of the new compounds might be due to their favorable interactions with the benzodiazepine-binding site of the GABAA receptor complex. The incorporation of the ferrocene core and fine tuning of the distance between the thiazolidinone core and an additional aromatic ring were judged to be crucial structural requirements for the observed anxiolytic effect.

Figure optionsDownload as PowerPoint slide