51. Computer-aided insights into receptor-ligand interaction for novel 5-arylhydantoin derivatives as serotonin $5-HT_7$ receptor agents with antidepressant activity
- Author
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Anna Partyka, Katarzyna Kucwaj-Brysz, Ewa Żesławska, Agnieszka Jankowska, Katarzyna Kieć-Kononowicz, Anna Wesołowska, Wojciech Nitek, Jadwiga Handzlik, Rafał Kurczab, Grzegorz Satała, Agata Siwek, and Magdalena Jastrzębska-Więsek
- Subjects
0301 basic medicine ,Pharmacology ,Molecular model ,010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,Hydantoin ,General Medicine ,01 natural sciences ,0104 chemical sciences ,5-HT7 receptor ,03 medical and health sciences ,Piperazine ,chemistry.chemical_compound ,030104 developmental biology ,chemistry ,Docking (molecular) ,Dopamine receptor D2 ,Drug Discovery ,Pharmacophore ,5-HT receptor - Abstract
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-HT7 receptor (5-HT7R) 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-HT7R and selectivity over 5-HT1AR, dopamine D2R and α1-, α2-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-HT7R in RBA, in particular seven compounds (4, 5, 7, 8 and 10-12, Ki ≤ 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-HT7R affinity than the di-phenyl ones.
- Published
- 2018