Bulletin of the Korean Chemical Society

Korean Chemical Society (대한화학회)
권호 표지
DOI QR코드

DOI QR Code

The Design and Synthesis of 1,4-Substituted Piperazine Derivatives as Triple Reuptake Inhibitors

  • Han, Min-Soo (Organic Chemistry Laboratory, Korea Institute of Science and Technology) ;
  • Han, Young-Hue (Organic Chemistry Laboratory, Korea Institute of Science and Technology) ;
  • Song, Chi-Man (Organic Chemistry Laboratory, Korea Institute of Science and Technology) ;
  • Hahn, Hoh-Gyu (Organic Chemistry Laboratory, Korea Institute of Science and Technology)
  • Received : 2012.04.12
  • Accepted : 2012.05.07
  • Published : 2012.08.20
Download PDF
⟨ Previous Next ⟩

Abstract

Novel 1,4-substituted piperazine derivatives 5, Series A and B were designed by fragment analysis and molecular modification of 4 selected piperazine-containing compounds which possess antidepressant activity. We synthesized new 39 analogues of Series A and 10 compounds of Series B, respectively. The antidepressant screening against DA, NE, and serotonin neurotransmitter uptake inhibition was carried out using the Neurotransmitter Transporter Uptake Assay Kit. The compounds in Series B showed relatively higher reuptake inhibitory activity for SERT, NET, and DAT than those in Series A. The length of spacer between the central piperazine core and the terminal phenyl ring substituted at the piperazine ring in Series B seems to exert an important role in the activity.

Keywords

References

  1. Prins, J.; Olivier B.; Korte, S. M. Expert Opin. Investig. Drugs 2011, 20(8), 1107. https://doi.org/10.1517/13543784.2011.594039
  2. Kulkarni, S. K.; Dhir, A. Expert Opin. Investig. Drugs 2009, 18(6), 767. https://doi.org/10.1517/13543780902880850
  3. Millan, M. J. Neurotherapeutics 2009, 6, 53. https://doi.org/10.1016/j.nurt.2008.10.039
  4. Skolnick, P.; Basile, A. S. Drug Discov. Today: Ther. Strat. 2006, 3(4), 489. https://doi.org/10.1016/j.ddstr.2006.10.010
  5. Holtzheimer, P. E., III.; Nemeroff, C. B. Neurotherapeutics 2006, 3, 42. https://doi.org/10.1016/j.nurx.2005.12.007
  6. Zisook, S.; Rush, A. J.; Haight, B. R.; Clines, D. C.; Rockett, C. B. Biol. Psychiatry 2006, 59, 203. https://doi.org/10.1016/j.biopsych.2005.06.027
  7. Papakostas, G. I.; Worthington, J. J., III.; Iosifescu, D. V.; Kinrys, G.; Burns, A. M.; Fisher, L. B.; Homberger, C. H.; Mischoulon, D.; Fava, M. Depress. Anxiety 2006, 23, 178. https://doi.org/10.1002/da.20181
  8. Fava, M. J. Clin. Psychiatry 2001, 62(18), 4.
  9. Prica, C.; Hascoet, M.; Bourin, M. Behav. Brain. Res. 2008, 194, 92. https://doi.org/10.1016/j.bbr.2008.06.028
  10. Beer, B.; Stark, J.; Krieter, P.; Czobor, P.; Beer, G.; Lippa, A.; Skolnick, P. J. Clin. Pharmacol 2004, 44(12), 1360. https://doi.org/10.1177/0091270004269560
  11. Skolnick, P.; Popik, P.; Janowsky, A.; Beer, B.; Lippa, A. S. Life Sciences 2003, 73, 3175. https://doi.org/10.1016/j.lfs.2003.06.007
  12. Chen, Z.; Skolnick, P. Expert Opin. Investig. Drugs 2007, 16(9), 1365. https://doi.org/10.1517/13543784.16.9.1365
  13. Domling, A.; Huang, Y. Synthesis 2010, 17, 2859.
  14. Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14, 347. https://doi.org/10.1016/j.cbpa.2010.02.018
  15. Gray, D. L.; Xu, W.; Campbell, B. M.; Dounay, A. B.; Barta, N.; Boroski, S.; Denny, L.; Evans, L.; Stratman, N.; Probert, A. Bioorg. Med. Chem. Lett. 2009, 19, 6604. https://doi.org/10.1016/j.bmcl.2009.10.014
  16. Carter, D. S.; Cai, H.-Y.; Lee, E. K.; Iyer, P. S.; Lucas, M. C.; Roetz, R.; Schoenfeld, R. C.; Weikert, R. J. Bioorg. Med. Chem. Lett. 2010, 20, 3941. https://doi.org/10.1016/j.bmcl.2010.05.008
  17. Glowa, J. R.; Wojnicki, F. H. E.; Matecka, D.; Bacher, J. D.; Mansbach, R. S.; Balster, R. L.; Rice, K. C. Exp. Clin. Psychopharmacol. 1995, 3, 219. https://doi.org/10.1037/1064-1297.3.3.219
  18. Prisinzano, T.; Rice, K. C.; Baumann, M. H.; Rothman, R. B. Curr. Med. Chem.:Central Nervous Syst. Agents 2004, 4, 47. https://doi.org/10.2174/1568015043477630
  19. Khan, A. Expert Opin. Investig. Drugs 2009, 18(11), 1753. https://doi.org/10.1517/13543780903286396
  20. Kim, J. Y.; Kim, D.; Kang, S. Y.; Park, W.-K.; Kim, H. J.; Jung, M. E.; Son, E.-J.; Pae, A. N.; Kim, J.; Lee, J. Bioorg. Med. Chem. Lett. 2010, 20, 6439. https://doi.org/10.1016/j.bmcl.2010.09.081
  21. Kerns, E.; Di, L. Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization; Elsevier: Amsterdam, 2008; p 122.
  22. Pardridge, W. M. J. Neurochem. 1998, 70, 1781.
  23. Pajouhesh, H.; Lenz, G. R. Neurotherapeutics 2005, 2, 541. https://doi.org/10.1602/neurorx.2.4.541
  24. Sonda, S.; Kawahara, T.; Murozono, T.; Sato, N.; Asano, K.; Haga, K. Bioorg. Med. Chem. 2003, 11, 4225. https://doi.org/10.1016/S0968-0896(03)00412-7
  25. Jorgensen, S.; Nielsen, E. O.; Peters, D.; Dyhring, T. Journal of Neuroscience Methods 2008, 169, 168. https://doi.org/10.1016/j.jneumeth.2007.12.004

Cited by

  1. Direct and two-step bioorthogonal probes for Bruton's tyrosine kinase based on ibrutinib: a comparative study vol.13, pp.18, 2015, https://doi.org/10.1039/C5OB00474H
  2. Synthesis, characterization, X-ray diffraction studies and biological evaluation of tert-butyl 4-(2-ethoxy-2-oxoethyl)-piperazine-1-carboxylate and tert-butyl 4-(2-hydrazino-2-oxoethyl)piperazine-1-carboxylate vol.42, pp.10, 2016, https://doi.org/10.1007/s11164-016-2542-7
  3. Synthesis and Structure-Activity Relationship of 1-(2-Furoyl)Piperazine Bearing Benzamides as Butyrylcholinesterase Inhibitors vol.54, pp.6, 2012, https://doi.org/10.1007/s11094-020-02247-2
  4. SYNTHESIS, CRYSTAL STRUCTURE, AND BIOLOGICAL EVALUATION OF (E)-1-(4-(4-BROMOBENZYL)PIPERAZIN-1-YL)- 3-(4-CHLOROPHENYL)PROP-2-EN-1-ONE vol.62, pp.3, 2012, https://doi.org/10.1134/s002247662103015x
  5. Piperazine, a Key Substructure for Antidepressants: Its Role in Developments and Structure‐Activity Relationships vol.16, pp.12, 2021, https://doi.org/10.1002/cmdc.202100045