Synthesis and pharmacological evaluation of new 5-(cyclo)alkyl-5-phenyl- and 5-spiroimidazolidine-2,4-dione derivatives. Novel 5-HT1A receptor agonist with potential antidepressant and anxiolytic activity

• Published in: European journal of medicinal chemistry 2010-04, Vol.45 (4), p.1295-1303
• Main Authors: CZOPEK, Anna, BYRTUS, Hanna, KOLACZKOWSKI, Marcin, PAWLOWSKI, Maciej, DYBALA, Małgorzata, NOWAK, Gabriel, TATARCZYNSKA, Ewa, WESOLOWSKA, Anna, CHOJNACKA-WOJCIK, Ewa
• Format: Article
• Language: English
• Subjects: Animals; Anti-Anxiety Agents - chemical synthesis; Anti-Anxiety Agents - chemistry; Anti-Anxiety Agents - pharmacology; Antidepressive Agents - chemical synthesis; Antidepressive Agents - chemistry; Antidepressive Agents - pharmacology; Biological and medical sciences; Imidazolidines - chemical synthesis; Imidazolidines - chemistry; Imidazolidines - pharmacology; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Models, Molecular; Motor Activity - drug effects; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Rats; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists - chemical synthesis; Serotonin Receptor Agonists - chemistry; Serotonin Receptor Agonists - pharmacology; Serotoninergic system
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2009.11.053

The synthesis of 5-(cyclo)alkyl-5-phenyl- and 5-spiroimidazolidine-2,4-dione derivatives with an arylpiperazinylpropyl moiety (12-23) and their in vitro and in vivo pharmacological properties and molecular characteristics were described. The investigated compounds exhibited high affinity for 5-HT(1A) (13-22) and 5-HT(2A) (18, 20, 21, 23) receptors and diversified pharmacological profile. Compounds 17, 20 and 22 showed antagonistic, partial agonistic and agonistic activity, respectively, toward 5-HT(1A) receptor and they were investigated as potential antidepressants and/or anxiolytics. The most interesting compound 22 (1-[3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl]-3',4'-dihydro-2'H-spiro[imidazolidine-4,1'-naphthalene]-2,5-dione), a pre- and postsynaptic 5-HT(1A) receptor agonist produced an antidepressant-like effect, which was more pronounced than that of imipramine in the forced swim test in mice, without affecting locomotor activity. Moreover, compound 22 produced a weak anxiolytic-like effect in the four-plate test in mice. Molecular docking studies of compound 22 to the homology model of the 5-HT(1A) receptor showed that a 3',4'-dihydro-2'H-spiro[imidazolidine-4,1'-naphthalene]-2,5-dione moiety played an important role in stabilizing the ligand-receptor complex.