期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 23, 期 13, 页码 3436-3447出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.04.026
关键词
Antidepressant activity; Antipsychotic activity; Imidazolidine-2,4-dione spirohydantoins; D-2/5-HT2A antagonist; 5-HT(1)A partial agonist
资金
- National Science Center [UMO-2011/01/B/NZ4/00695, UMO-2012/07/B/NZ7/01173]
- European Regional Development Fund of the Polish Innovation Economy Operational Program [POIG.02.01.00-12-023/08]
A series of novel spirohydantoin derivatives with arylpiperazinylbutyl moiety were synthesized and evaluated for serotonin 5-HT1A, 5-HT2A, 5-HT7 and dopamine D-2 receptors. Based on these data, four compounds were selected for further binding affinity assays on dopamine D-1, D-3, D-4, and 5-HT2C, 5-HT6 as well as adrenergic alpha 1 and alpha(2C) receptors, which are involved in various CNS diseases such as schizophrenia, anxiety and/or depression. The compound 14, 1-{4-[4-(2-metoxyphe-nyl) piperazin-1-yl] butyl}-3',4'-dihydro-2H, 2'H, 5H-spiro[imidazolidine-4,1'-naphthalene]-2,5-dione, with the most promising functional profile, mixed 5-HT2A/D-2 antagonist and 5-HT1A partial agonist, was selected. In the mouse D-amphetamine-induced locomotor hyperactivity model, compound 14 produced antipsychotic-like activity, which is devoid of cataleptogenic effects and in the forced swim test in mice, it showed a significant antidepressant-like effect unlike the reference drug aripiprazole. (C) 2015 Elsevier Ltd. All rights reserved.
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