Synthesis and biological evaluation of novel pyrrolidine-2,5-dione derivatives as potential antidepressant agents. Part 1

• DOI: 10.1016/j.ejmech.2013.02.033
• Publication Date: 2013-03-05T10:18:30Z
• Authors: Martyna Z. Wróbel; Andrzej Chodkowski; Franciszek Herold; Anna Gomółka; Jerzy Kleps; Aleksander P. Maz...; Franciszek Pluciński; Andrzej Mazurek; Gabriel Nowak; Agata Siwek; Katarzyna Stachowicz; Anna Sławińska; Małgorzata Wolak; Bernadeta Szewczyk; Grzegorz Satała; Andrzej J. Bojarski; Jadwiga Turło
• Keywords: Pyrrolidine; 5-HT1A receptor; Docking (animal); Proton NMR

A series of 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives was synthesized and their biological activity was evaluated. The chemical structures of the newly prepared compounds were confirmed by (1)H NMR, (13)C NMR and ESI-HRMS spectra data. All tested compounds proved to be potent 5-HT1A receptor and serotonin transporter protein (SERT) ligands. Among them, compounds 15, 18, 19 and 30 showed significant affinity for 5-HT1A and SERT. Computer docking simulations carried out for compounds 15, 31 and 32 to models of 5-HT1A receptor and SERT confirm the results of biological tests. Due to high affinity for the 5-HT1A receptor and moderate affinity for SERT, compounds 31, 32, 35, and 37 were evaluated for their affinity for D2L, 5-HT6, 5-HT7 and 5-HT2A receptors. In vivo tests, in turn, resulted in determining the functional activity of compounds 15, 18, 19 and 30 to the 5-HT1A receptor. The results of these tests indicate that all of the ligands possess properties characteristic of 5-HT1A receptor agonists.