title: Synthesis and biological evaluation of novel pyrrolidine-2,5-dione derivatives as potential antidepressant agents. Part 1.
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.
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097 Warszawa, Poland.
authors.forename: Martyna Z
authors.initials: MZ
authors.lastname: Wróbel
authors.forename: Andrzej
authors.initials: A
authors.lastname: Chodkowski
authors.forename: Franciszek
authors.initials: F
authors.lastname: Herold
authors.forename: Anna
authors.initials: A
authors.lastname: Gomółka
authors.forename: Jerzy
authors.initials: J
authors.lastname: Kleps
authors.forename: Aleksander P
authors.initials: AP
authors.lastname: Mazurek
authors.forename: Franciszek
authors.initials: F
authors.lastname: Pluciński
authors.forename: Andrzej
authors.initials: A
authors.lastname: Mazurek
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nowak
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Stachowicz
authors.forename: Anna
authors.initials: A
authors.lastname: Sławińska
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Wolak
authors.forename: Bernadeta
authors.initials: B
authors.lastname: Szewczyk
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Satała
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Turło
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D017434:Protein Structure, Tertiary; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry / Q000378:metabolism; D018490:Serotonin Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013550:Swimming / Q000502:physiology
chemical_list: C584485:3-(1H-indol-3-yl)pyrrolidine-2,5-dione; D000928:Antidepressive Agents; D007211:Indoles; D008024:Ligands; D011759:Pyrrolidines; D011760:Pyrrolidinones; D044402:Receptor, Serotonin, 5-HT2A; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D044282:Receptor, Serotonin, 5-HT1A; C032519:pyrrolidine