Novel spirohydantoin derivative as a potent multireceptor-active antipsychotic and antidepressant agent

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.