title: Synthesis and pharmacological evaluation of new arylpiperazines. 3-[4-[4-(3-chlorophenyl)-1-piperazinyl]butyl]-quinazolidin-4-one - a dual serotonin 5-HT(1A)/5-HT(2A) receptor ligand with an anxiolytic-like activity.
abstract: On the basis of systematic studies on the structure-activity relationships in arylpiperazine group of serotonin ligands, 12 new derivatives containing quinazolidin-4(3H)-one (1-4), 2-phenyl-2,3-dihydrophthalazine-1,4-dione (5-8) or 1-phenyl-1,2-dihydropyridazine-3,6-dione (9-12) fragments were synthesized. The majority of the tested compounds (2, 4, 7, 8 and 10-12) showed a high affinity for 5-HT(1A) receptors (K(i)=11-54 nM) and two (1, 2) were found active at 5-HT(2A) sites (16 and 68 nM, respectively). All the new 5-HT(1A) ligands tested in vivo revealed an antagonistic activity at postsynaptic 5-HT(1A) receptors, and three of them behaved as agonists at presynaptic ones. Additionally, both the meta-chlorophenylpiperazine derivatives containing quinazolidin-4-one fragment showed features of 5-HT(2A) receptor antagonists. The dual 5-HT(1A)/5-HT(2A) receptor ligand (2) was further tested for its potential psychotropic activity. It showed a distinct anxiolytic-like activity in a conflict drinking test in rats and the observed effect was more potent in terms of the active dose, than that produced by diazepam (used as a reference drug).
authors.affiliation: Department of Medicinal Chemistry Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Kraków, Poland. bojarski@if-pan.krakow.pl
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.forename: Piotr
authors.initials: P
authors.lastname: Kowalski
authors.forename: Teresa
authors.initials: T
authors.lastname: Kowalska
authors.forename: Beata
authors.initials: B
authors.lastname: Duszyńska
authors.forename: Sijka
authors.initials: S
authors.lastname: Charakchieva-Minol
authors.forename: Ewa
authors.initials: E
authors.lastname: Tatarczyńska
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Kłodzińska
authors.forename: Ewa
authors.initials: E
authors.lastname: Chojnacka-Wójcik
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D008024:Ligands; D008297:Male; D008606:Mental Processes / Q000187:drug effects; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000737:chemistry*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D014151:Anti-Anxiety Agents; D008024:Ligands; D010879:Piperazines; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists