title: Novel mannich bases, 5-arylimidazolidine-2,4-dione derivatives with dual 5-HT(1A) receptor and serotonin transporter affinity.
abstract: A computer aided ligand design study of imidazolidine-2,4-dione derivatives was conducted in order to obtain compounds with dual 5-HT(1A)  receptor and serotonin transporter (SERT) affinity. According to molecular modeling results, series of Mannich bases were chosen and synthesized. Investigated compounds were tested for 5-HT(1A) , 5-HT(2A) , α(1)  and SERT affinity. Two selected compounds (5, 9) were characterized in functional experiments and possessed a pharmacological profile which may enhance SERT blocking efficacy - 5-HT(1A)  partial agonism and 5-HT(2A)  antagonism in one molecule. Furthermore these compounds displayed satisfactory selectivity over adrenergic α(1)  receptors. The most promising compounds, 5-arylimidazolidine-2,4-dione derivatives with 4-(3-chlorophenyl)piperazinylmethyl moiety were tested for antidepressant and anxiolytic activity. In particular, compound 5 (5-(2-methoxyphenyl)-3-{1-[4-(3-chlorophenyl)piperazin-1-yl]methyl}-imidazolidine-2,4-dione), tested in the forced swim test in mice, exhibited a favorable antidepressant-like profile without affecting spontaneous locomotor activity.
authors.affiliation: Department of Pharmaceutical Chemistry, Jagiellonian University Medical College, Kraków, Poland. aczopek@cm-uj.krakow.pl
authors.forename: Anna
authors.initials: A
authors.lastname: Czopek
authors.forename: Marcin
authors.initials: M
authors.lastname: Kołaczkowski
authors.forename: Adam
authors.initials: A
authors.lastname: Bucki
authors.forename: Hanna
authors.initials: H
authors.lastname: Byrtus
authors.forename: Maciej
authors.initials: M
authors.lastname: Pawłowski
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.forename: Marek
authors.initials: M
authors.lastname: Bednarski
authors.forename: Dagmara
authors.initials: D
authors.lastname: Wróbel
authors.forename: Anna
authors.initials: A
authors.lastname: Wesołowska
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D017076:Computer-Aided Design; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008352:Mannich Bases / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013550:Swimming
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D006827:Hydantoins; D008024:Ligands; D008352:Mannich Bases; D044402:Receptor, Serotonin, 5-HT2A; D050486:Serotonin Plasma Membrane Transport Proteins; D044282:Receptor, Serotonin, 5-HT1A