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 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.
Department of Pharmaceutical Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. Electronic address: anna.czopek@uj.edu.pl.
Anna
A
Czopek
Department of Pharmaceutical Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
Marcin
M
Kołaczkowski
Department of Pharmaceutical Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
Adam
A
Bucki
Department of Pharmaceutical Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
Hanna
H
Byrtus
Department of Pharmaceutical Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
Maciej
M
Pawłowski
Department of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
Grzegorz
G
Kazek
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.
Andrzej J
AJ
Bojarski
Faculty of Chemistry, Jagiellonian University, 3 Ingardena Street, 30-060 Kraków, Poland.
Agata
A
Piaskowska
Faculty of Chemistry, Jagiellonian University, 3 Ingardena Street, 30-060 Kraków, Poland.
Justyna
J
Kalinowska-Tłuścik
Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
Anna
A
Partyka
Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
Anna
A
Wesołowska
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy / Q000503:physiopathology; D000068180:Aripiprazole / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy / Q000503:physiopathology; D003913:Dextroamphetamine; D006827:Hydantoins / Q000138:chemical synthesis / Q000494:pharmacology*; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D048289:Imidazolidines / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology*; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000378:metabolism; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013550:Swimming
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D006827:Hydantoins; D048289:Imidazolidines; D010879:Piperazines; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor; D044282:Receptor, Serotonin, 5-HT1A; D000068180:Aripiprazole; D003913:Dextroamphetamine
5-HT(1A) partial agonist; Antidepressant activity; Antipsychotic activity; D(2)/5-HT(2A) antagonist; Imidazolidine-2,4-dione spirohydantoins