Novel Mannich Bases, 5-Arylimidazolidine-2,4-dione Derivatives with Dual 5-HT1A Receptor and Serotonin Transporter Affinity

A computer aided ligand design study of imidazolidine-2,4-dione derivatives was conducted in order to obtain compounds with dual 5-HT1A 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-HT1A, 5-HT2A, 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-HT1A partial agonism and 5-HT2A antagonism in one molecule. Furthermore these compounds displayed satisfactory selectivity over adrenergic 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.