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.

Synthesis and Pharmacological Activity of a New Series of 1‐(1H‐Indol‐4‐yloxy)‐3‐(2‐(2‐methoxyphenoxy)ethylamino)propan‐2‐ol Analogs

“…Ligand docking to the models of G protein‐coupled receptors involved adrenergic α 1A ‐receptor homology models and β 1 ‐receptor crystal structure. The homology models have been obtained by applying the well‐validated method , which has been used in successful modeling of several receptor models .…”

Mannich bases in medicinal chemistry and drug design

“…In addition, computer-aided design of novel Mannich bases of imidazoline-2,4-diones led to the identification of several compounds with potential dual affinity for 5HT 1A receptors and serotonin transporter, whose synthesis and evaluation finally led to candidates 337 (R ¼ H or F) ( Fig. 64) having the desired pharmacological profile [492].…”

Antidepressant- and anxiolytic-like activity of 7-phenylpiperazinylalkyl-1,3-dimethyl-purine-2,6-dione derivatives with diversified 5-HT1A receptor functional profile

“…18 Purine-2, 6-dione derivatives containing phenylpiperazinalkyl substituent in N7-position were flexibly docked to the binding sites of the receptor model assembly, which mimics conformational flexibility of the protein. Best scored complexes were examined to describe proper binding mode characterized by advantageous ligand-receptor interactions, which would explain considerable affinity for the biological target.…”