Design, synthesis and pharmacological evaluation of N-{4-[2-(4-aryl-piperazin-1-yl)-ethyl]-phenyl}-arylamides

Abstract

5HT1A receptor targeting drugs have been used as the treatment for the many neuropsychiatric disorders, such as schizophrenia and depression. As a part of ongoing research, we designed series of new compounds that share arylpiperazine common structural motif with the 5HT1A receptor ligand aripiprazole. Receptor-ligand interactions were determined by the molecular docking simulations, revealing the positive impact of the phenyl substitution in the arylpiperazine part of the molecules. Nine selected compounds were synthesized in four reaction steps in high overall yields (59-73%). In vitro pharmacological evaluation of the synthesized compounds revealed three compounds (5b, 6b and 6c) with high 5HT1A binding affinity, comparable with aripiprazole (Ki 12.0, 4.8, 12.8, 5.6 nM, respectively). Compounds from b series, 5b and 6b, possess 2-methoxyphenyl substituents, while 6c possess 2,3-dichlorophenyl substituent in the arylpiperazine part of the molecule. The pharmacological results are therefore in accordance with the molecular docking simulations thus proving the rational design. Compounds 5c, 6b and 6c can be considered as the candidates for further evaluation as new, potential antidepressants.