Journal of Integrative Natural Science (통합자연과학논문집)

The Basic Science Institute Chosun University (조선대학교 기초과학연구원)
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3D QSAR Study of 2-Methoxyphenylpiperazinylakanamides as 5-Hydroxytryptamine (Serotonin) Receptor 7 Antagonists

  • Received : 2016.05.30
  • Accepted : 2016.06.25
  • Published : 2016.06.30
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Abstract

5-hydroxytryptamine (serotonin) receptor ($5-HT_7R$) 7 is one of G-Protein coupled receptors, which is activated by the neurotransmitter Serotonin. After activation by serotonin, $5-HT_7$ activates the production of the intracellular signaling molecule cyclic AMP. $5-HT_7$ receptor has been found to be involved in the pathophysiology of various disorders. It is reported that $5-HT_7$ receptor antagonists can be used as antidepressant agents. In this study, we report the important structural and chemical parameters for 2-methoxyphenylpiperazinylakanamides as $5-HT_7R$ inhibitors. A 3D QSAR study based on comparative molecular field analysis (CoMFA) was performed. The best predictions were obtained for the best CoMFA model with $q^2$ of 0.594 with 6 components, $r^2$ of 0.986, Fisher value as 60.607, and an estimated standard error of 0.043. The predictive ability of the test set was 0.602. Results obtained the CoMFA models suggest that the data are well fitted and have high predictive ability. The contour maps are generated and studied. The contour analyses may serve as tool in the future for designing of novel and more potent $5-HT_7R$ derivatives.

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References

  1. P. Vanhoenacker, G. Haegeman, and J. E. Leysen, "5-HT7 receptors: current knowledge and future prospects", Trends Pharmacol. Sci., Vol. 21, pp. 70-77, 2000. https://doi.org/10.1016/S0165-6147(99)01432-7
  2. M. Ruat, E. Traiffort, R. Leurs, J. Tardivel-Lacombe, J. Diaz, J. M. Arrang, and J. C. Schwartz, "Molecular cloning, characterization, and localization of a high-affinity serotonin receptor (5-HT7) activating cAMP formation", P. Natl. Acad. Sci. U.S.A., Vol. 90, pp. 8547-8551, 1993. https://doi.org/10.1073/pnas.90.18.8547
  3. J. A. Bard, J. Zgombick, N. Adham, P. Vaysse, T. A. Branchek, and R. L. Weinshank, "Cloning of a novel human serotonin receptor (5-HT7) positively linked to adenylate cyclase", J. Biol. Chem., Vol. 268, pp. 23422-23426, 1993.
  4. D. Hoyer, D. E. Clarke, J. R. Fozard, P. R. Hartig, G. R. Martin, E. J. Mylecharane, P. R. Saxena, and P. P. Humphrey, "International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin)", Pharmacol Rev., Vol. 46, pp. 157-203, 1994.
  5. J. P. P. Foong and J. C. Bornstein, "5-HT antagonists NAN-190 and SB 269970 block alpha2-adrenoceptors in the guinea pig", Neuroreport, Vol. 20, pp. 325-330, 2009. https://doi.org/10.1097/WNR.0b013e3283232caa
  6. G. Sarkisyan, A. J. Roberts, and P. B. Hedlund, "The 5-HT(7) receptor as a mediator and modulator of antidepressant-like behavior", Behav. Brain Res., Vol. 209, pp. 99-108, 2010. https://doi.org/10.1016/j.bbr.2010.01.022
  7. O. Mnie-Filali, C. Faure, L. Lambas-Senas, E. M. Mansari, H. Belblidia, E. Gondard, A. Etievant, H. Scarna, A. Didier, A. Berod, P. Blier, and N, Haddjeri, "Pharmacological blockade of 5-HT7 receptors as a putative fast acting antidepressant strategy", Neuropsychopharmacol., Vol. 36, pp. 1275-1288, 2011. https://doi.org/10.1038/npp.2011.13
  8. G. S. Perez-García and A. Meneses, "Effects of the potential 5-HT7 receptor agonist AS 19 in an autoshaping learning task", Behav. Brain Res., Vol. 163, pp. 136-140, 2005. https://doi.org/10.1016/j.bbr.2005.04.014
  9. V. S. Naumenko, N. K. Popova, E. Lacivita, M. Leopoldo, and E. G. Ponimaskin, "Interplay between serotonin 5-HT1A and 5-HT7 receptors in depressive disorders". CNS Neurosci. Ther., Vol 20 pp. 582-590, 2014. https://doi.org/10.1111/cns.12247
  10. K. A. Krobert and F. O. Levy, "The human 5-HT7 serotonin receptor splice variants: constitutive activity and inverse agonist effects", Brit. J. Pharmacol., Vol 135, pp. 1563-1571, 2002. https://doi.org/10.1038/sj.bjp.0704588
  11. Y. Kim, J. Tae, K. Lee, H. Rhim, I. H. Choo, H. Cho, W.-K. Park, G. Keum, and H. Choo, "Novel N-biphenyl-2-ylmethyl 2-methoxyphenylpiperazinylalkanamides as 5-HT7R antagonists for the treatment of depression", Bioorgan. Med. Chem., Vol. 22, pp. 4587-4596, 2014. https://doi.org/10.1016/j.bmc.2014.07.026
  12. S. J. Cho and A. Tropsha, "Cross-validated R2-guided region selection for comparative molecular field analysis: A simple method to achieve consistent results", J. Med. Chem., Vol. 38, pp. 1060-1066, 1995. https://doi.org/10.1021/jm00007a003
  13. S. Wold, M. Sjostrom, and L. Eriksson, "PLS-regression: a basic tool of chemometrics", Chemometr. intell. lab., Vol. 58, pp. 109-130, 2001. https://doi.org/10.1016/S0169-7439(01)00155-1
  14. U. Debnath, S. Verma, S. Jain, S. B. Katti, and Y. S. Prabhakar, "Pyridones as NNRTIs against HIV-1 mutants: 3D-QSAR and protein informatics" J. Comput. Aid. Mol. Des., Vol. 27, pp. 637-654, 2013. https://doi.org/10.1007/s10822-013-9667-1
  15. D. Fernandez, J. Ortega-Castro, and J. Frau, "Human farnesyl pyrophosphate synthase inhibition by nitrogen bisphosphonates: A 3D-QSAR study" J. Comput. Aid. Mol. Des., Vol. 27, pp. 739-754, 2013. https://doi.org/10.1007/s10822-013-9674-2