Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Structural Requirements for Modulating 4-Benzylpiperidine Carboxamides from Serotonin/Norepinephrine Reuptake Inhibitors to Triple Reuptake Inhibitors

  • Paudel, Suresh (College of Pharmacy, Chonnam National University) ;
  • Kim, Eunae (College of Pharmacy, Chosun University) ;
  • Zhu, Anlin (College of Pharmacy, Chonnam National University) ;
  • Acharya, Srijan (College of Pharmacy, Chonnam National University) ;
  • Min, Xiao (College of Pharmacy, Chonnam National University) ;
  • Cheon, Seung Hoon (College of Pharmacy, Chonnam National University) ;
  • Kim, Kyeong-Man (College of Pharmacy, Chonnam National University)
  • Received : 2020.12.28
  • Accepted : 2021.04.02
  • Published : 2021.07.01
Download PDF
⟨ Previous Next ⟩

Abstract

In this study, we determined the effect of 24 different synthetic 4-benzylpiperidine carboxamides on the reuptake of serotonin, norepinephrine, and dopamine (DA), and characterized their structure-activity relationship. The compounds with a two-carbon linker inhibited DA reuptake with much higher potency than those with a three-carbon linker. Among the aromatic ring substituents, biphenyl and diphenyl groups played a critical role in determining the selectivity of the 4-benzylpiperidine carboxamides toward the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. Compounds with a 2-naphthyl ring were found to exhibit a higher degree of inhibition on the norepinephrine transporter (NET) and SERT than those with a 1-naphthyl ring. A docking simulation using a triple reuptake inhibitor 8k and a serotonin/norepinephrine reuptake inhibitor 7j showed that the regions spanning transmembrane domain (TM)1, TM3, and TM6 form the ligand binding pocket. The compound 8k bound tightly to the binding pocket of all three monoamine reuptake transporters; however, 7j showed poor docking with DAT. Co-expression of DAT with the dopamine D2 receptor (D2R) significantly inhibited DA-induced endocytosis of D2R probably by reuptaking DA into the cells. Pretreatment of the cells with 8f, which is one of the compounds with good inhibitory activity on DAT, blocked DAT-induced inhibition of D2R endocytosis. In summary, this study identified critical structural features contributing to the selectivity of a molecule for each of the monoamine transporters, critical residues on the compounds that bound to the transporters, and the functional role of a DA reuptake inhibitor in regulating D2R function.

Keywords

Acknowledgement

This study was financially supported by Chonnam National University (Grant number: 2020-1874).

References

  1. Belmaker, R. H. and Agam, G. (2008) Major depressive disorder. N. Engl. J. Med. 358, 55-68. https://doi.org/10.1056/NEJMra073096
  2. ChemAxon (2014) MarvinSketch (version 6.2.2). Calculation module developed by ChemAxon. Available from: http://www.chemaxon.com/products/marvin/marvinsketch/.
  3. Cho, D., Zheng, M., Min, C., Ma, L., Kurose, H., Park, J. H. and Kim, K. M. (2010) Agonist-induced endocytosis and receptor phosphorylation mediate resensitization of dopamine D(2) receptors. Mol. Endocrinol. 24, 574-86. https://doi.org/10.1210/me.2009-0369
  4. Cipriani, A., Furukawa, T. A., Salanti, G., Chaimani, A., Atkinson, L. Z., Ogawa, Y., Leucht, S., Ruhe, H. G., Turner, E. H., Higgins, J. P. T., Egger, M., Takeshima, N., Hayasaka, Y., Imai, H., Shinohara, K., Tajika, A., Ioannidis, J. P. A. and Geddes, J. R. (2018) Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 391, 1357-1366. https://doi.org/10.1016/S0140-6736(17)32802-7
  5. Coleman, J. A., Green, E. M. and Gouaux, E. (2016) X-ray structures and mechanism of the human serotonin transporter. Nature 532, 334-339. https://doi.org/10.1038/nature17629
  6. Culpepper, L., Muskin, P. R. and Stahl, S. M. (2015) Major depressive disorder: understanding the significance of residual symptoms and balancing efficacy with tolerability. Am. J. Med. 128, S1-S15. https://doi.org/10.1016/j.amjmed.2014.10.001
  7. Furukawa, T. A., Salanti, G., Atkinson, L. Z., Leucht, S., Ruhe, H. G., Turner, E. H., Chaimani, A., Ogawa, Y., Takeshima, N., Hayasaka, Y., Imai, H., Shinohara, K., Suganuma, A., Watanabe, N., Stockton, S., Geddes, J. R. and Cipriani, A. (2016) Comparative efficacy and acceptability of first-generation and second-generation antidepressants in the acute treatment of major depression: protocol for a network meta-analysis. BMJ Open 6, e010919. https://doi.org/10.1136/bmjopen-2015-010919
  8. Goodwin, G. M. (2015) The overlap between anxiety, depression, and obsessive-compulsive disorder. Dialogues Clin. Neurosci. 17, 249-60. https://doi.org/10.31887/DCNS.2015.17.3/ggoodwin
  9. Hepler, J. R. and Gilman, A. G. (1992) G proteins. Trends Biochem. Sci. 17, 383-387. https://doi.org/10.1016/0968-0004(92)90005-T
  10. Hirschfeld, R. M. (2000) History and evolution of the monoamine hypothesis of depression. J. Clin. Psychiatry 61 Suppl 6, 4-6.
  11. Jakubovski, E., Varigonda, A. L., Freemantle, N., Taylor, M. J. and Bloch, M. H. (2016) Systematic review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder. Am. J. Psychiatry 173, 174-183. https://doi.org/10.1176/appi.ajp.2015.15030331
  12. Kim, K. M., Valenzano, K. J., Robinson, S. R., Yao, W. D., Barak, L. S. and Caron, M. G. (2001) Differential regulation of the dopamine D2 and D3 receptors by G protein-coupled receptor kinases and beta-arrestins. J. Biol. Chem. 276, 37409-37414. https://doi.org/10.1074/jbc.M106728200
  13. Koyuncu, A., Ertekin, E., Yuksel, C., Aslantas Ertekin, B., Celebi, F., Binbay, Z. and Tukel, R. (2015) Predominantly inattentive type of ADHD is associated with social anxiety disorder. J. Atten. Disord. 19, 856-864. https://doi.org/10.1177/1087054714533193
  14. Maier, J. A., Martinez, C., Kasavajhala, K., Wickstrom, L., Hauser, K. E. and Simmerling, C. (2015) ff14SB: improving the accuracy of protein side chain and backbone parameters from ff99SB. J. Chem. Theory Comput. 11, 3696-3713. https://doi.org/10.1021/acs.jctc.5b00255
  15. Masson, J., Sagne, C., Hamon, M. and El Mestikawy, S. (1999) Neurotransmitter transporters in the central nervous system. Pharmacol. Rev. 51, 439-464.
  16. Millan, M. J. (2006) Multi-target strategies for the improved treatment of depressive states: conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol. Ther. 110, 135-370. https://doi.org/10.1016/j.pharmthera.2005.11.006
  17. Nestler, E. J. and Carlezon, W. A., Jr. (2006) The mesolimbic dopamine reward circuit in depression. Biol. Psychiatry 59, 1151-1159. https://doi.org/10.1016/j.biopsych.2005.09.018
  18. Paudel, S., Acharya, S., Yoon, G., Kim, K. M. and Cheon, S. H. (2017a) Design, synthesis and in vitro activity of 1,4-disubstituted piperazines and piperidines as triple reuptake inhibitors. Bioorg. Med. Chem. 25, 2266-2276. https://doi.org/10.1016/j.bmc.2017.02.051
  19. Paudel, S., Cao, Y., Guo, S., An, B., Kim, K. M. and Cheon, S. H. (2015) Design and synthesis of 4-benzylpiperidine carboxamides as dual serotonin and norepinephrine reuptake inhibitors. Bioorg. Med. Chem. 23, 6418-6426. https://doi.org/10.1016/j.bmc.2015.08.022
  20. Paudel, S., Min, X., Acharya, S., Khadka, D. B., Yoon, G., Kim, K. M. and Cheon, S. H. (2017b) Triple reuptake inhibitors: design, synthesis and structure-activity relationship of benzylpiperidinetetrazoles. Bioorg. Med. Chem. 25, 5278-5289. https://doi.org/10.1016/j.bmc.2017.07.046
  21. Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C. and Ferrin, T. E. (2004) UCSF Chimera--a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605-1612. https://doi.org/10.1002/jcc.20084
  22. Prins, J., Olivier, B. and Korte, S. M. (2011) Triple reuptake inhibitors for treating subtypes of major depressive disorder: the monoamine hypothesis revisited. Expert Opin. Investig. Drugs 20, 1107-1130. https://doi.org/10.1517/13543784.2011.594039
  23. Ramsay, R. R., Popovic-Nikolic, M. R., Nikolic, K., Uliassi, E. and Bolognesi, M. L. (2018) A perspective on multi-target drug discovery and design for complex diseases. Clin. Transl. Med. 7, 3. https://doi.org/10.1186/s40169-017-0181-2
  24. Sharma, H., Santra, S. and Dutta, A. (2015) Triple reuptake inhibitors as potential next-generation antidepressants: a new hope? Future Med. Chem. 7, 2385-2406. https://doi.org/10.4155/fmc.15.134
  25. Talevi, A. (2015) Multi-target pharmacology: possibilities and limitations of the "skeleton key approach" from a medicinal chemist perspective. Front. Pharmacol. 6, 205. https://doi.org/10.3389/fphar.2015.00205
  26. Torres, G. E., Yao, W. D., Mohn, A. R., Quan, H., Kim, K. M., Levey, A. I., Staudinger, J. and Caron, M. G. (2001) Functional interaction between monoamine plasma membrane transporters and the synaptic PDZ domain-containing protein PICK1. Neuron 30, 121-134. https://doi.org/10.1016/S0896-6273(01)00267-7
  27. Trivedi, M. H. (2006) Major depressive disorder: remission of associated symptoms. J. Clin. Psychiatry 67 Suppl 6, 27-32.
  28. Trott, O. and Olson, A. J. (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31, 455-461. https://doi.org/10.1002/jcc.21334
  29. Wang, K. H., Penmatsa, A. and Gouaux, E. (2015) Neurotransmitter and psychostimulant recognition by the dopamine transporter. Nature 521, 322-327. https://doi.org/10.1038/nature14431
  30. Waterhouse, A., Bertoni, M., Bienert, S., Studer, G., Tauriello, G., Gumienny, R., Heer, F. T., de Beer, T. A. P., Rempfer, C., Bordoli, L., Lepore, R. and Schwede, T. (2018) SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 46, W296-W303. https://doi.org/10.1093/nar/gky427
  31. Zhang, X. and Kim, K. M. (2017) Multifactorial regulation of G protein-coupled receptor endocytosis. Biomol. Ther. (Seoul) 25, 26-43. https://doi.org/10.4062/biomolther.2016.186
  32. Zheng, Y. Y., Guo, L., Zhen, X. C. and Li, J. Q. (2012) Synthesis and antidepressant activity of arylalkanol-piperidine derivatives as triple reuptake inhibitors. Eur. J. Med. Chem. 54, 123-136. https://doi.org/10.1016/j.ejmech.2012.04.030