Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 45, Issue 4, Pages 1295-1303Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2009.11.053
Keywords
Pre- and postsynaptic 5-HT1A receptor agonists; Imidazolidine-2,4-diones; Anxiolytics; Antidepressants
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Funding
- Polish Ministry of Science and Higher Education [2P05F04329]
- European Social Fund
- The Integrated Regional Operational Programme
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The synthesis of 5-(cyclo)alky1-5-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-HT1A (13-22) and 5-HT2A (18, 20, 21, 23) receptors and diversified pharmacological profile. Compounds 17, 20 and 22 showed antagonistic, partial agonistic and agonistic activity, respectively, toward 5-HT1A 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-HT1A 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-HT1A 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. (C) 2009 Elsevier Masson SAS. All rights reserved.
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