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

  • Bioorg Chem. 2023 Dec:141:106903. doi: 10.1016/j.bioorg.2023.106903.
Martyna Z Wróbel  1 ,  Andrzej Chodkowski  2 ,  Maciej Dawidowski  2 ,  Agata Siwek  3 ,  Katarzyna Stachowicz  4 ,  Bernadeta Szewczyk  4 ,  Gabriel Nowak  5 ,  Grzegorz Satała  6 ,  Andrzej J Bojarski  6 ,  Jadwiga Turło  2
Affiliations
  • 1. Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097 Warszawa, Poland. Electronic address: [email protected].
  • 2. Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097 Warszawa, Poland.
  • 3. Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
  • 4. Department of Neurobiology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Kraków, Poland.
  • 5. Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland; Department of Neurobiology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Kraków, Poland.
  • 6. Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Kraków, Poland.
PMID: 37827015 DOI: 10.1016/j.bioorg.2023.106903
Abstract

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.

Keywords
5-HT(1A) agonists; 5-HT(1A)/SERT dual activity; Antidepressants; D(2) receptor ligands; Multitarget directed ligand; Serotonin reuptake inhibitors.
Products