Synthesis and pharmacological evaluation of new arylpiperazines.: 3-{4-[4-(3-chlorophenyl)-1-piperazinyl]butyl}-quinazolidin-4-one -: A dual serotonin 5-HT1A/5-HT2A receptor ligand with an anxiolytic-like activity

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-phen-1-2,3-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-HT1A receptors (K-i= 11-54 nM) and two (1, 2) were found active at 5-HT2A sites (16 and 68 nM, respectively). All the new 5-HT1A ligands tested in vivo revealed an antagonistic activity at postsynaptic 5-HT1A 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-HT2A receptor antagonists. The dual 5-HT1A/5-HT2A 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). (C) 2002 Published by Elsevier Science Ltd.