Novel Spirohydantoin Derivative as a Potent Multireceptor-Active Antipsychotic and Antidepressant Agent

Authors
Czopek A, Ko?aczkowski M, Bucki A, Byrtus H et al.

Lab
Department of Pharmaceutical Chemistry, Jagiellonian University Medical College, Kraków, Poland

Journal
Bioorg Med Chem.

Abstract
A series of novel spirohydantoin derivatives with arylpiperazinylbutyl moiety were synthesized and evaluated for serotonin 5-HT1A, 5-HT2A, 5-HT7 and dopamine D2 receptors. Based on these data, four compounds were selected for further binding affinity assays on dopamine D1, D3, D4, and 5-HT2C, 5-HT6 as well as adrenergic ?1 and ?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,2H,5H-spiro[imidazolidine-4,1-naphthalene]-2,5-dione, with the most promising functional profile, mixed 5-HT2A/D2 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.

BIOSEB Instruments Used:
Forced Swimming Test: New FST DUAL SENSOR (BIO-FST-DSM)