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

Martyna Z Wróbel; Andrzej Chodkowski; Franciszek Herold; Anna Gomółka; Jerzy Kleps; Aleksander P Mazurek; Franciszek Pluciński; Andrzej Mazurek; Gabriel Nowak; Agata Siwek; Katarzyna Stachowicz; Anna Sławińska; Małgorzata Wolak; Bernadeta Szewczyk; Grzegorz Satała; Andrzej J Bojarski; Jadwiga Turło

doi:10.1016/j.ejmech.2013.02.033

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

Eur J Med Chem. 2013 May:63:484-500. doi: 10.1016/j.ejmech.2013.02.033. Epub 2013 Mar 5.

Authors

Martyna Z Wróbel¹, Andrzej Chodkowski, Franciszek Herold, Anna Gomółka, Jerzy Kleps, Aleksander P Mazurek, Franciszek Pluciński, Andrzej Mazurek, Gabriel Nowak, Agata Siwek, Katarzyna Stachowicz, Anna Sławińska, Małgorzata Wolak, Bernadeta Szewczyk, Grzegorz Satała, Andrzej J Bojarski, Jadwiga Turło

Affiliation

¹ Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097 Warszawa, Poland.

PMID: 23524160
DOI: 10.1016/j.ejmech.2013.02.033

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antidepressive Agents / chemical synthesis*
Antidepressive Agents / chemistry
Antidepressive Agents / pharmacology
Binding, Competitive
Body Temperature / drug effects
Brain / drug effects
Brain / metabolism
HEK293 Cells
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology
Ligands
Magnetic Resonance Spectroscopy
Male
Mice
Models, Chemical
Models, Molecular
Molecular Structure
Motor Activity / drug effects
Motor Activity / physiology
Protein Structure, Tertiary
Pyrrolidines / chemical synthesis*
Pyrrolidines / chemistry
Pyrrolidines / pharmacology
Pyrrolidinones / chemical synthesis
Pyrrolidinones / chemistry
Pyrrolidinones / pharmacology
Radioligand Assay
Rats
Receptor, Serotonin, 5-HT1A / chemistry
Receptor, Serotonin, 5-HT1A / metabolism
Receptor, Serotonin, 5-HT2A / chemistry
Receptor, Serotonin, 5-HT2A / metabolism
Serotonin Agents / chemical synthesis*
Serotonin Agents / chemistry
Serotonin Agents / pharmacology
Serotonin Plasma Membrane Transport Proteins / chemistry
Serotonin Plasma Membrane Transport Proteins / metabolism
Spectrometry, Mass, Electrospray Ionization
Swimming / physiology

Substances

3-(1H-indol-3-yl)pyrrolidine-2,5-dione
Antidepressive Agents
Indoles
Ligands
Pyrrolidines
Pyrrolidinones
Receptor, Serotonin, 5-HT2A
Serotonin Agents
Serotonin Plasma Membrane Transport Proteins
Receptor, Serotonin, 5-HT1A
pyrrolidine