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

Anna Czopek; Marcin Kołaczkowski; Adam Bucki; Hanna Byrtus; Maciej Pawłowski; Grzegorz Kazek; Andrzej J Bojarski; Agata Piaskowska; Justyna Kalinowska-Tłuścik; Anna Partyka; Anna Wesołowska

doi:10.1016/j.bmc.2015.04.026

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

Bioorg Med Chem. 2015 Jul 1;23(13):3436-47. doi: 10.1016/j.bmc.2015.04.026. Epub 2015 Apr 16.

Affiliations

¹ Department of Pharmaceutical Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. Electronic address: anna.czopek@uj.edu.pl.
² Department of Pharmaceutical Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
³ Department of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
⁴ Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.
⁵ Faculty of Chemistry, Jagiellonian University, 3 Ingardena Street, 30-060 Kraków, Poland.
⁶ Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.

PMID: 25936259
DOI: 10.1016/j.bmc.2015.04.026

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 α1 and α2C 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/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.

Keywords: 5-HT(1A) partial agonist; Antidepressant activity; Antipsychotic activity; D(2)/5-HT(2A) antagonist; Imidazolidine-2,4-dione spirohydantoins.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Anxiety Agents / chemical synthesis
Anti-Anxiety Agents / pharmacology*
Antidepressive Agents / chemical synthesis
Antidepressive Agents / pharmacology*
Antipsychotic Agents / chemical synthesis
Antipsychotic Agents / pharmacology*
Anxiety / drug therapy
Anxiety / physiopathology
Aripiprazole / pharmacology
Depression / drug therapy
Depression / physiopathology
Dextroamphetamine
Hydantoins / chemical synthesis
Hydantoins / pharmacology*
Hyperkinesis / chemically induced
Hyperkinesis / drug therapy
Hyperkinesis / physiopathology
Imidazolidines / chemical synthesis
Imidazolidines / pharmacology*
Male
Mice
Piperazines / chemical synthesis
Piperazines / pharmacology*
Receptor, Serotonin, 5-HT1A / chemistry
Receptor, Serotonin, 5-HT1A / metabolism
Receptor, Serotonin, 5-HT2A / chemistry
Receptor, Serotonin, 5-HT2A / metabolism
Receptors, Dopamine D2 / chemistry
Receptors, Dopamine D2 / metabolism
Receptors, Serotonin / chemistry
Receptors, Serotonin / metabolism
Structure-Activity Relationship
Swimming

Substances

Anti-Anxiety Agents
Antidepressive Agents
Antipsychotic Agents
Hydantoins
Imidazolidines
Piperazines
Receptor, Serotonin, 5-HT2A
Receptors, Dopamine D2
Receptors, Serotonin
serotonin 7 receptor
Receptor, Serotonin, 5-HT1A
Aripiprazole
Dextroamphetamine