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Comprehensive Physico-Chemical Characterization of a Serotonin Inclusion Complex with 2-Hydroxypropyl-β-Cyclodextrin

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Abstract

The main objective of this study is to encapsulate the serotonin hydrochloride (SER) molecule, as an important neurotransmitter, into the 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) binding cavity. The results indicate the formation of the photo-stable 2-HP-β-CD:SER inclusion complex with the stoichiometry ratio of 1:1 (AL type) as an enthalpy-driven process. The complex was extensively characterized by using various spectroscopic techniques (FT-IR, 1H-NMR, XRD and ICD), scanning electron microscopy (FE-SEM), and thermal methods (TGA, DTG and DTA). Besides, molecular docking and molecular dynamics simulations were applied. In those simulations, explicit solvation models, emphasizing the role of the van der Waals forces and H-bonds in the complex formation were applied. Furthermore, the hydroxyl group of SER was found to be localized at the vicinity of the 2-HP-β-CD secondary rim. The study confirmed the possibility of utilizing this formulation as a CNS-active compound with improved solubility and stability to treat some behavioral dysfunctions and mental disorders.

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Abbreviations

2-HP-β-CD:

2-Hydroxypropyl-β-cyclodextrin

DTG:

Differential thermal gravimetric

DTA:

Differential thermal analysis

EE:

Efficiency of encapsulation

FE-SEM:

Field emission scanning electron microscopy

FT-IR:

Fourier-transform infrared spectroscopy

GAFF:

General amber force field

ICD:

Induced circular dichroism

IC:

Inclusion complex

MD:

Molecular dynamics

MM-GBSA:

Molecular mechanics generalized Born surface area

MM-PBSA:

Molecular mechanics Poisson–Boltzmann surface area

XRD:

X-ray diffraction

RMSD:

Root-mean-square deviation

RMSF:

Root-mean-square fluctuation

RDF:

Radial distribution function

1H-NMR:

Hydrogen nuclear magnetic resonance spectroscopy

SASA:

Solvent accessible surface area

SER:

Serotonin hydrochloride

TGA:

Thermal gravimetric analysis

References

  1. Pradhan, T., Jung, H.S., Jang, J.H., Kim, T.W., Kang, C., Kim, J.S.: Chemical sensing of neurotransmitters. Chem. Soc. Rev. 43, 4684–4713 (2014)

    CAS  PubMed  Google Scholar 

  2. Chaudhuri, S., Chakraborty, S., Sengupta, P.K.: Encapsulation of serotonin in β-cyclodextrin nano-cavities: fluorescence spectroscopic and molecular modeling studies. J. Mol. Struct. 975, 160–165 (2010)

    CAS  Google Scholar 

  3. Valenzuela, C.F., Puglia, M.P., Zucca, S.: Focus on: neurotransmitter systems. Alcohol Res. Health 34, 106–120 (2011)

    PubMed  PubMed Central  Google Scholar 

  4. Berger, M., Gray, J.A., Roth, B.L.: The expanded biology of serotonin. Annu. Rev. Med. 60, 355–366 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Jian, B., Xu, J., Connolly, J., Savani, R.C., Narula, N., Liang, B., Levy, R.J.: Serotonin mechanisms in heart valve disease I: Serotonin-Induced up-regulation of transforming growth factor-beta1 via G-protein signal transduction in aortic valve interstitial cells. Am. J. Pathol. 161, 2111–2121 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Whitford, G.M.: Alzheimer’s disease and serotonin : a review. Neuropsychobiol. 142, 133–142 (1986)

    Google Scholar 

  7. Si, B., Song, E.: Recent advances in the detection of neurotransmitters. Chemosensors 6, 1–24 (2018)

    Google Scholar 

  8. Sarnyai, Z., Sibille, E.L., Pavlides, C., Fenster, R.J., McEwen, B.S., Toth, M.: Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin(1A) receptors. Proc. Natl. Acad. Sci. USA 97, 14731–14736 (2000)

    CAS  PubMed  Google Scholar 

  9. Heisler, L.K., Chu, H.-M., Brennan, T.J., Danao, J.A., Bajwa, P., Parsons, L.H., Tecott, L.H.: Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc. Natl. Acad. Sci. USA 95, 15049–15054 (1998)

    CAS  PubMed  Google Scholar 

  10. Ramboz, S., Oosting, R., Amara, D.A., Kung, H.F., Blier, P., Mendelsohn, M., Mann, J.J., Brunner, D., Hen, R.: Serotonin receptor 1A knockout: an animal model of anxiety-related disorder. Proc. Natl. Acad. Sci. USA 95, 14476–14481 (1998)

    CAS  PubMed  Google Scholar 

  11. Azmitia, E.C.: Serotonin and brain: evolution, neuroplasticity, and homeostasis. Int. Rev. Neurobiol. 77, 31–56 (2006)

    Google Scholar 

  12. Del Valle, E.M.M.: Cyclodextrins and their uses: a review. Process Biochem. 39, 1033–1046 (2004)

    Google Scholar 

  13. Astray, G., Gonzalez-Barreiro, C., Mejuto, J.C., Rial-Otero, R., Simal-Gándara, J.: A review on the use of cyclodextrins in foods. Food Hydrocoll. 23, 1631–1640 (2009)

    CAS  Google Scholar 

  14. Gidwani, B., Vyas, A.: A comprehensive review on cyclodextrin-based carriers for delivery of chemotherapeutic cytotoxic anticancer drugs. Biomed Res. Int. 2015, 15 (2015)

    Google Scholar 

  15. Crini, G.: Review: a history of cyclodextrins. Chem. Rev. 114, 10940–10975 (2014)

    CAS  PubMed  Google Scholar 

  16. Loftsson, T., Duchêne, D.: Cyclodextrins and their pharmaceutical applications. Int. J. Pharm. 329, 1–11 (2007)

    CAS  PubMed  Google Scholar 

  17. Radu, C.D., Parteni, O., Ochiuz, L.: Applications of cyclodextrins in medical textiles: review. J. Control. Release 224, 146–157 (2016)

    CAS  PubMed  Google Scholar 

  18. Loftsson, T., Brewster, M.E.: Pharmaceutical applications of cyclodextrins: basic science and product development. J. Pharm. Pharmacol. 62, 1607–1621 (2010)

    CAS  PubMed  Google Scholar 

  19. Li, S., William, C.P.: Cyodextrins and their applications in analytical chemistry. Chem. Rev. 92, 1457–1470 (1992)

    CAS  Google Scholar 

  20. Xu, J.: Applications in the textile industry. Cyclodextrins Preparation and Application in Industry Physical, pp. 209–230. World Scientific, Singapore (2018)

    Google Scholar 

  21. Hedges, A.R.: Industrial applications of cyclodextrins. Chem. Rev. 98, 2035–2044 (1998)

    CAS  PubMed  Google Scholar 

  22. Dufour, G., Evrard, B., De Tullio, P.: Rapid quantification of 2-hydroxypropyl-β-cyclodextrin in liquid pharmaceutical formulations by1H nuclear magnetic resonance spectroscopy. Eur. J. Pharm. Sci. 73, 20–28 (2015)

    CAS  PubMed  Google Scholar 

  23. Yao, Y., Xie, Y., Hong, C., Li, G., Shen, H., Ji, G.: Development of a myricetin/hydroxypropyl-β-cyclodextrin inclusion complex: preparation, characterization, and evaluation. Carbohydr. Polym. 110, 329–337 (2014)

    CAS  PubMed  Google Scholar 

  24. Kurkov, S.V., Loftsson, T.: Cyclodextrins. Int. J. Pharmaceut. 453, 167–180 (2013)

    CAS  Google Scholar 

  25. Huang, Y., Zu, Y., Zhao, X., Wu, M., Feng, Z., Deng, Y., Zu, C., Wang, L.: Preparation of inclusion complex of apigenin-hydroxypropyl-β-cyclodextrin by using supercritical antisolvent process for dissolution and bioavailability enhancement. Int. J. Pharm. 511, 921–930 (2016)

    CAS  PubMed  Google Scholar 

  26. Bisby, R.H., Botchway, S.W., Dad, S., Parker, A.W.: Single- and multi-photon excited fluorescence from serotonin complexed with β-cyclodextrin. Photochem. Photobiol. Sci. 5, 122–125 (2007)

    Google Scholar 

  27. Abbaspour, A., Noori, A.: A cyclodextrin host–guest recognition approach to an electrochemical sensor for simultaneous quantification of serotonin and dopamine. Biosens. Bioelectron. 26, 4674–4680 (2011)

    CAS  PubMed  Google Scholar 

  28. Higuchi, T., Connors, K.A.: Phase-solubility techniques. Adv. Anal. Chem. Instrum. 4, 212–217 (1965)

    Google Scholar 

  29. Higuchi, T.C.K.A.: Phase solubility diagram. Adv. Anal. Chem. Instrum. 4, 117–212 (1965)

    CAS  Google Scholar 

  30. Kfoury, M., Lounès-Hadj Sahraoui, A., Bourdon, N., Laruelle, F., Fontaine, J., Auezova, L., Greige-Gerges, H., Fourmentin, S.: Solubility, photostability and antifungal activity of phenylpropanoids encapsulated in cyclodextrins. Food Chem. 196, 518–525 (2016)

    CAS  PubMed  Google Scholar 

  31. Kfoury, M., Auezova, L., Greige-Gerges, H., Ruellan, S., Fourmentin, S.: Cyclodextrin, an efficient tool for trans-anethole encapsulation: chromatographic, spectroscopic, thermal and structural studies. Food Chem. 164, 454–461 (2014)

    CAS  PubMed  Google Scholar 

  32. Morris, G.M., Goodsell, D.S., Halliday, R.S., Huey, R., Hart, W.E., Belew, R.K., Olson, A.J.: AutoDock-related material automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J. Comput. Chem. 19, 1639–1662 (1998)

    CAS  Google Scholar 

  33. Cézard, C., Trivelli, X., Aubry, F., Djedaïni Pilard, F., Dupradeau, F.Y.: Molecular dynamics studies of native and substituted cyclodextrins in different media: 1. Charge derivation and force field performances. Phys. Chem. Chem. Phys. 13, 15103–15121 (2011)

    PubMed  Google Scholar 

  34. Hratchian, H.P., Keith, T.A., Millam, J.: Gaussian 05 User’s Reference. (2009)

  35. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Mennucci, B., Petersson, G.A., Nakatsuji, H., Caricato, M., Li, X., Hratchian, H.P., Izmaylov, A.F., Bloino, J., Zheng, G., Sonnenberg, J.L., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Vreven, T., Montgomery, J.A., Peralta, J.E., Ogliaro, F., Bearpark, M., Heyd, J.J., Brothers, E., Kudin, K.N., Staroverov, V.N., Kobayashi, R., Normand, J., Raghavachari, K., Rendell, A., Burant, J.C., Iyengar, S.S., Tomasi, J., Cossi, M., rega, N., Millam, J.M., Klene, M., Knox, J.E., Cross, J.B., Bakken, V., Adamo, C., Jaramillo, J., Gomperts, R., Stratmann, R. E., Yazyev, O., Austin, A.J., Cammi, R., Pomelli, C., Ochterski, J.W., Martin, E.L., Morokuma, K., Zakrzewski, V.G., Voth, G.A., Salvador, P., Dannenberg, J.J., Dapprich, S., Daniels, A.D., Farkas, O., Foresman, J.B., Ortiz, J.V., Cioslowski, J., Fox, D.J., Gaussian 09 ed., Gaussian, Inc.: Wallingford CT (2009)

  36. Case, D.A., Darden, T., Cheatham, T.E., Simmerling, C., Wang, J., Duke, R.E., Luo, R., Walker, R.C., Zhang, W., Merz, K.M., Roberts, B.P., Hayik, S., Roitberg, A., Seabra, G., Swails, J., Götz, A.W., Kolossváry, I., Wong, K.F., Paesani, F., Vanicek, J., Wolf, R.M., Liu, J., Wu, X., Brozell, S.R., Steinbrecher, T., Gohlke, H., Cai, Q., Ye, X., Wang, J., Hsieh, M.-J., Cui, G., Roe, D.R., Mathews, D.H., Seetin, M.G., Salomon-Ferrer, R., Sagui, C., Babin, V., Luchko, T., Gusarov, S., Kovalenko, A., Kollman, P.A.: Amber 12 Reference Manual Principal Contributors to the Current Codes (2012)

  37. Wang, J., Wolf, R.M., Caldwell, J.W., Kollman, P.A., Case, D.A.: Development and testing of a general Amber force field. J. Comput. Chem. 25, 1157–1174 (2004)

    CAS  PubMed  Google Scholar 

  38. Price, D.J., Brooks, C.L., Price, D.J., Brooks, C.L.: A modified TIP3P water potential for simulation with Ewald summation. J. Chem. Phys. 121, 10096–10103 (2004)

    CAS  PubMed  Google Scholar 

  39. Kollman, P.A., Massova, I., Reyes, C., Kuhn, B., Huo, S., Chong, L., Lee, M., Lee, T., Donini, O., Cieplak, P., Case, D.A., Cheatham, T.E.: Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc. Chem. Res. 33, 889–897 (2000)

    CAS  PubMed  Google Scholar 

  40. Loftsson, T., Brewster, M.E.: Pharmaceutical applications of cyclodextrins: drug solubilisation and stabilization. J. Pharm. Sci. 85, 1017–1025 (1996)

    CAS  PubMed  Google Scholar 

  41. Mourtzinos, I., Kalogeropoulos, N., Papadakis, S.E., Konstantinou, K., Karathanos, V.T.: Encapsulation of nutraceutical monoterpenes in β-cyclodextrin and modified starch. J. Food Sci. 73, 89–94 (2008)

    Google Scholar 

  42. Iacovino, R., Rapuano, F., Caso, J.V., Russo, A., Lavorgna, M., Russo, C., Isidori, M., Russo, L., Malgieri, G., Isernia, C.: β-Cyclodextrin inclusion complex to improve physicochemical properties of pipemidic acid: characterization and bioactivity evaluation. Int. J. Mol. Sci. 14, 13022–13041 (2013)

    PubMed  PubMed Central  Google Scholar 

  43. Ashwaq, A.A.S., Rasedee, A., Abdul, A.B., Taufiq-Yap, Y.H., Al-Qubaisi, M.S., Eid, E.E.M.: Characterization, drug release profile and cytotoxicity of dentatin-hydroxypropyl-β-cyclodextrin complex. J. Incl. Phenom. Macrocycl. Chem. 87, 167–178 (2017)

    CAS  Google Scholar 

  44. Williams, R.O., Mahaguna, V., Sriwongjanya, M.: Characterization of an inclusion complex of cholesterol and hydroxypropyl-β-cyclodextrin. Eur. J. Pharm. Biopharm. 46, 355–360 (1998)

    CAS  PubMed  Google Scholar 

  45. Fateminasab, F., Bordbar, A.K., Shityakov, S.: Detailed chemical characterization and molecular modeling of serotonin inclusion complex with unmodified β-cyclodextrin. Heliyon. 5, e01405 (2019)

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Liu, Y., Han, B.-H., Zhang, H.-Y.: Molecular recognition studies on modified cyclodextrins. Curr. Org. Chem. 8, 35–46 (2004)

    CAS  Google Scholar 

  47. Harata, K., Uedaira, H.: The circular dichroism spectra of the β-cyclodextrin complex with naphthalene derivatives. Bull. Chem. Soc. Jpn. 48, 375–378 (1975)

    CAS  Google Scholar 

  48. Bani-Yaseen, A.D., Al-Rawashdeh, N.F., Al-Momani, I.: Influence of inclusion complexation with β-cyclodextrin on the photostability of selected imidazoline-derived drugs. J. Incl. Phenom. Macrocycl. Chem. 63, 109–115 (2009)

    CAS  Google Scholar 

  49. Guedes, I.A., de Magalhães, C.S., Dardenne, L.E.: Receptor–ligand molecular docking. Biophys. Rev. 6, 75–87 (2014)

    CAS  PubMed  Google Scholar 

  50. Cai, W., Sun, T., Chipot, C.: Can the anomalous aqueous solubility of β-cyclodextrin be explained by its hydration free energy alone? Phys. Chem. Chem. Phys. 10, 3236–3243 (2008)

    CAS  PubMed  Google Scholar 

  51. Zhang, H., Tan, T., Feng, W., Spoel, D.V.: Molecular recognition in different environments: β-cyclodextrin dimer formation in organic solvents. J. Phys. Chem. B 116, 12684–12693 (2012)

    CAS  PubMed  Google Scholar 

  52. Nutho, B., Khuntawee, W., Rungnim, C., Pongsawasdi, P., Wolschann, P., Karpfen, A., Kungwan, N., Rungrotmongkol, T.: Binding mode and free energy prediction of fisetin/β-cyclodextrin inclusion complexes. Beilstein J. Org. Chem. 10, 2789–2799 (2014)

    PubMed  PubMed Central  Google Scholar 

  53. Huang, C., Li, C., Choi, P.Y.K., Nandakumar, K., Kostiuk, L.W.: Effect of cut-off distance used in molecular dynamics simulations on fluid properties. Mol. Simul. 36, 856–864 (2010)

    CAS  Google Scholar 

  54. Figueiras, A., Sarraguc, J.M.G., Carvalho, R.A., Pais, A.A.C.C., Veiga, F.J.B.: Interaction of omeprazole with a methylated derivative of β-cyclodextrin: phase solubility, NMR spectroscopy and molecular simulation. Pharm. Res. 24, 377–389 (2007)

    CAS  PubMed  Google Scholar 

  55. Lee, B., Richards, F.M.: The interpretation of protein structures: estimation of static accessibility. J. Mol. Biol. 55, 379–400 (1971)

    CAS  Google Scholar 

  56. Durham, E., Dorr, B., Woetzel, N., Staritzbichler, R., Meiler, J.: Solvent accessible surface area approximations for rapid and accurate protein structure prediction. J. Mol. Model. 15, 1093–1108 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Yao, X.X.: Molecular dynamics simulation on beta-cyclodextrin and steroids. Acta Chim. Sin. 67, 1318–1324 (2009)

    CAS  Google Scholar 

  58. Nair, P.C., Miners, J.O.: Molecular dynamics simulations: from structure function relationships to drug discovery. Silico Pharmacol. 2, 4 (2014)

    Google Scholar 

  59. Khuntawee, W., Karttunen, M., Wong-Ekkabut, J.: A molecular dynamics study of conformations of beta-cyclodextrin and its eight derivatives in four different solvents. Phys. Chem. Chem. Phys. 19, 24219–24229 (2017)

    CAS  PubMed  Google Scholar 

  60. Köhler, J.E.H., Grczelschak-mick, N., Erika, J., Köhler, H., Grczelschak-mick, N.: The β-cyclodextrin/benzene complex and its hydrogen bonds: a theoretical study using molecular dynamics, quantum mechanics and COSMO-RS. Beilstein J. Org. Chem. 9, 118–134 (2013)

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors gratefully acknowledge the Research Council of Isfahan University for financial support.

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Authors and Affiliations

  1. Department of Chemistry, University of Isfahan, 8174673441, Isfahan, Iran

    F. Fateminasab & A. K. Bordbar

  2. Department of Anesthesia and Critical Care, University of Würzburg, 97080, Würzburg, Germany

    S. Shityakov

  3. Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran

    A. A. Saboury

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  1. F. Fateminasab
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Fateminasab, F., Bordbar, A.K., Shityakov, S. et al. Comprehensive Physico-Chemical Characterization of a Serotonin Inclusion Complex with 2-Hydroxypropyl-β-Cyclodextrin. J Solution Chem 49, 915–944 (2020). https://doi.org/10.1007/s10953-020-00997-x

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