title: 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.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, Jagiellonian University Medical College, 9 Medyczna Str, 30-688 Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Czopek
authors.forename: Hanna
authors.initials: H
authors.lastname: Byrtus
authors.forename: Marcin
authors.initials: M
authors.lastname: Kołaczkowski
authors.forename: Maciej
authors.initials: M
authors.lastname: Pawłowski
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Dybała
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nowak
authors.forename: Ewa
authors.initials: E
authors.lastname: Tatarczyńska
authors.forename: Anna
authors.initials: A
authors.lastname: Wesołowska
authors.forename: Ewa
authors.initials: E
authors.lastname: Chojnacka-Wójcik
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D048289:Imidazolidines; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists