Archiv der Pharmazie (Weinheim) 2013-02-01

Novel mannich bases, 5-arylimidazolidine-2,4-dione derivatives with dual 5-HT(1A) receptor and serotonin transporter affinity.

Anna Czopek, Marcin Kołaczkowski, Adam Bucki, Hanna Byrtus, Maciej Pawłowski, Agata Siwek, Andrzej J Bojarski, Marek Bednarski, Dagmara Wróbel, Anna Wesołowska

文献索引：Arch. Pharm. (Weinheim) 346(2) , 98-109, (2013)

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摘要

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.Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.