1st International Conference on Chemo and BioInformatics, ICCBIKG  2021, (355-358)

AUTHOR(S) / AUTOR(I): Deana B. Andrić, Slađana Dukić-Stefanovic, Jelena Z. Penjišević, Ivana I. Jevtić, Vladimir B. Šukalović, Relja Suručić, Slađana Kostić-Rajačić


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DOI: 10.46793/ICCBI21.355A


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.


5HT1A, aripiprazole, arylpiperazines, molecular docking, binding assay


  • Wang, Y. Zhang, X. Dud, T. Ding, W.Gong, F. Liu., Review of antidepressants in clinic and active ingredients of traditional Chinese medicine targeting 5-HT1A receptors pharmacological, Biomedicine and Pharmacotherapy, 120 (2019) 109408.
  • Z. Wróbel, A. Chodkowski, M. Marciniak, M. Dawidowski, A. Maksymiuk, A. Siwek, G. Nowak, J. Turło., Synthesis of new 4-butyl-arylpiperazine-3-(1H-indol-3- yl)pyrrolidine-2,5-dione derivatives and evaluation for their 5-HT1A and D2 receptor affinity and serotonin transporter inhibition, Bioorganic Chemistry, 97 (2020) 103662 .
  • Takahashi, O. Nakagawasai, W. Nemoto, T. Odaira, W. Sakuma, K. Tan-No., Antidepressant- like effect of aripiprazole via 5-HT1A, D1, and D2 receptors in the prefrontal cortex of olfactory bulbectomized mice, Journal of Pharmacological Sciences, 137 (2019) 241-247.
  • Xu, S. Huang, H. Zhang, C. Mao, X.E. Zhou, X. Cheng, I.A. Simon, D.-D. Shen, H.-Y. Yen, C.V. Robinson, K. Harpsøe, B. Svensson, J. Guo, H. Jiang, D.E. Gloriam, K. Melcher, Y. Jiang, Y. Zhang, H.E. Xu., Structural insights into the lipid and ligand regulation of serotonin receptors, Nature, 592 (2021) 469-473.
  • Sukalovic, A.E. Bogdan, G. Tovilovic, Dj. Ignjatovic, D. Andric, S. Kostic-Rajacic, V. Soskic., N-{[2-(4-Phenyl-piperazin-1-yl)-ethyl]-phenyl}-arylamides with       dopamine       D2                                          and 5-hydroxytryptamine 5HT1A activity:synthesis, testing, and molecular modeling, Archiv Der Pharmazie, 346 (2013) 708-717.
  • Sukalovic, Dj. Ignjatovic, G. Tovilovic, D. Andric, K. Shakib, S. Kostic-Rajacic, V. Soskic., Interactions of N-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-2-aryl-2-yl-acetamides and 1-{[2- (4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-3-aryl-2-yl-ureas with dopamine D2 and 5- hydroxytryptamine 5HT1A receptors, Bioorganic and Medicinal Chemistry Letters, 22 (2012) 3967-3972.
  • Sherman, T. Day, M.P. Jacobson, R.A. Friesner, R. Farid, Novel Procedure for Modeling Ligand/Receptor Induced Fit Effects, Journal of Medicinal Chemistry, 49 (2006) 534-553.
  • Sherman, H.S. Beard, R. Farid, Use of an Induced Fit Receptor Structure in Virtual Screening, Chemical Biology & Drug Design, 67 (2006) 83-84.
  • A. Shapiro, S. Renock, E. Arrington, L.A. Chiodo, L.X. Liu , D.R. Sibley, B.L. Roth, R. Mailman., Aripiprazole, A Novel Atypical Antipsychotic Drug with a Unique and Robust Pharmacology, Neuropsychopharmacology, 28 (2003) 1400-1411.