Computer-aided insights into receptor-ligand interaction for novel 5-arylhydantoin derivatives as serotonin 5-HT7 receptor agents with antidepressant activity.

This paper presents a computer-aided insight into the receptor-ligand interaction for novel analogs of the lead structure 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione ( 1, MF-8), as part of the search for potent and selective serotonin 5-HT 7 receptor (5-HT 7 R) agents. New hydantoin derivatives ( 4 - 19 ) were designed and synthesized. For 5-phenyl-3-(2-hydroxy-3-(4-(2-ethoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione ( 4 ), its crystal structure was determined experimentally. Molecular modeling studies were performed, including both pharmacophore and structure-based approaches. New compounds were investigated in radioligand binding assays (RBA) for their affinity toward 5-HT 7 R and selectivity over 5-HT 1A R, dopamine D 2 R and α 1 -, α 2 -and β-adrenoceptors. Selected compounds ( 5 - 8 ) were assessed for their antidepressant and anxiolytic effects in vivo in mice. Most of the tested compounds displayed potent affinity and selectivity for 5-HT 7 R in RBA, in particular seven compounds ( 4, 5, 7, 8 and 10-12, K i  ≤ 10 nM). Antidepressant-like activity in vivo for all tested compounds ( 5 - 8 ) was confirmed. SAR analysis based on both crystallography-supported molecular modeling and RBA results indicated that mono -phenyl substituents at both hydantoin and piperazine are more favorable for 5-HT 7 R affinity than the di -phenyl ones. [ABSTRACT FROM AUTHOR]