Synthesis and biological evaluation of new multi-target 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with potential antidepressant effect

• Published in: European journal of medicinal chemistry Vol. 183; p. 111736
• Main Authors: Wróbel, Martyna Z., Chodkowski, Andrzej, Herold, Franciszek, Marciniak, Monika, Dawidowski, Maciej, Siwek, Agata, Starowicz, Gabriela, Stachowicz, Katarzyna, Szewczyk, Bernadeta, Nowak, Gabriel, Belka, Mariusz, Bączek, Tomasz, Satała, Grzegorz, Bojarski, Andrzej J., Turło, Jadwiga
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.12.2019; Elsevier
• Subjects: 5-HT1A agonists; 5-HT1A/SERT dual activity; Animals; Antidepressants; Antidepressive Agents - chemical synthesis; Antidepressive Agents - pharmacology; Chemistry, Medicinal; CHO Cells; Cricetulus; D2 receptor ligands; HEK293 Cells; Humans; Indoles - chemical synthesis; Indoles - pharmacology; Life Sciences & Biomedicine; Male; Mice; Multitarget directed ligand; Pharmacology & Pharmacy; Pyrrolidinones - chemical synthesis; Pyrrolidinones - pharmacology; Receptors, Serotonin - metabolism; Science & Technology; Serotonin reuptake inhibitors; Serotonin Uptake Inhibitors - chemical synthesis; Serotonin Uptake Inhibitors - metabolism; Serotonin Uptake Inhibitors - pharmacology; PBS; 5-HT1A/SERT dual activity; hERG; P-gp; SSRIs; SAR; FST; Multitarget directed ligand; Serotonin reuptake inhibitors; 8-OH-DPAT; HEK293; Antidepressants; D2 receptor ligands; 5-HT1A agonists; Ki; SYSTEM; NEUROTRANSMISSION; D-2 receptor ligands; SCHIZOPHRENIA; AGONISTS; PATHOPHYSIOLOGY; 5-HT1A RECEPTOR LIGANDS; METABOLISM; DOPAMINE; BREXPIPRAZOLE; SEROTONIN; 5-HT(1A)/SERT dual activity; D receptor ligands; 5-HT(1A) agonists
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111736

A series of novel 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were synthesised and evaluated for their 5-HT1A/D2/5-HT2A/5-HT6/5-HT7 receptor affinity and serotonin reuptake inhibition. Most of the evaluated compounds displayed high affinities for 5-HT1A receptors (e.g., 4cKi = 2.3 nM, 4lKi = 3.2 nM). The antidepressant activity of the selected compounds was screened in vivo using the forced swim test (FST). The results indicate that compound MW005 (agonist of the pre- and postsynaptic 5-HT1A receptor) exhibited promising affinities for the 5-HT1A/SERT/D2/5-HT6/5-HT7 receptors and showed an antidepressant-like activity in the FST model. [Display omitted] •3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were designed and synthesised.•Synthesised compounds display high affinity for 5-HT1A receptor.•MW005 and 4j show polypharmacological profiles potentially beneficial for the treatment of depression.•MW005 combines 5-HT1AR agonism, good metabolic stability and dose-dependent reduction of the immobility time in the FST.