Synthesis and biological evaluation of novel 3-(5-substituted-1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with a dual affinity for serotonin 5-HT1A receptor and SERT

[Display omitted] •Novel 3-(1H-indol-3-yl)pyrrolidine-2,5-dione ligands of aminergic GPCRs.•Compounds with high, dual affinities for 5-HT1AR and SERT.•4f shows favourable receptor binding profile Ki(5-HT1A) = 10.0 nM; Ki(SERT) = 2.8 nM and 5-HT1AR agonistic activity. The serotonin 1A (5-HT1A) recept...

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Published in:Bioorganic chemistry 2023-12, Vol.141, p.106903-106903, Article 106903
Main Authors: Wróbel, Martyna Z., Chodkowski, Andrzej, Dawidowski, Maciej, Siwek, Agata, Stachowicz, Katarzyna, Szewczyk, Bernadeta, Nowak, Gabriel, Satała, Grzegorz, Bojarski, Andrzej J., Turło, Jadwiga
Format: Article
Language:English
Subjects:
5-HT1A agonists
5-HT1A/SERT dual activity
Antidepressants
D2 receptor ligands
Multitarget directed ligand
Serotonin reuptake inhibitors
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Summary:[Display omitted] •Novel 3-(1H-indol-3-yl)pyrrolidine-2,5-dione ligands of aminergic GPCRs.•Compounds with high, dual affinities for 5-HT1AR and SERT.•4f shows favourable receptor binding profile Ki(5-HT1A) = 10.0 nM; Ki(SERT) = 2.8 nM and 5-HT1AR agonistic activity. The serotonin 1A (5-HT1A) receptors and serotonin transporter (SERT) are important biological targets in the treatment of diseases of the central nervous system, especially for depression. In this study, new 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives linked with the 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole moiety were synthesised and evaluated for their affinity for 5-HT1A receptor and serotonin reuptake inhibition. Selected compounds were then tested for their affinity for D2, 5-HT2A, 5-HT6 and 5-HT7 receptors, and also in in vitro metabolic stability assays in human microsomes. Finally, in vivo assays allowed us to evaluate the agonist–antagonist properties of pre- and postsynaptic 5-HT1A receptors. 3-(1-(4-(3-(5-methoxy-1H-indol-3-yl)-2,5-dioxopyrrolidin-1-yl)butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carbonitrile (4f) emerged as the most promising compound from the series, due to its favourable receptor binding profile (Ki(5-HT1A) = 10.0 nM; Ki(SERT) = 2.8 nM), good microsomal stability and 5-HT1A receptor agonistic activity.
ISSN:0045-2068
1090-2120
DOI:10.1016/j.bioorg.2023.106903