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Molecular dynamics of 5-HT1A and 5-HT2A serotonin receptors with methylated buspirone analogues

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Abstract

In the present study experimentally determined ligand selectivity of three methylated buspirone analogues (denoted as MM2, MM5 and P55) towards 5-HT1A and 5-HT2A serotonin receptors was theoretically investigated on a molecular level. The relationships between the ligand structure and 5-HT1A and 5-HT2A receptor affinities were studied and the results were found to be in agreement with the available site-directed mutagenesis and binding affinity data. Molecular dynamics (MD) simulations of ligand-receptor complexes were performed for each investigated analogue, docked twice into the central cavity of 5-HT1A/5-HT2A, each time in a different orientation. Present results were compared with our previous theoretical results, obtained for buspirone and its non-methylated analogues. It was found that due to the presence of the methyl group in the piperazine ring the ligand position alters and the structure of the ligand-receptor complex is modified. Further, the positions of derivatives with pyrimidinyl aromatic moiety and quinolinyl moiety are significantly different at the 5-HT2A receptor. Thus, methylation of such derivatives alters the 3D structures of ligand-receptor complexes in different ways. The ligand-induced changes of the receptor structures were also analysed. The obtained results suggest, that helical domains of both receptors have different dynamical behaviour. Moreover, both location and topography of putative binding sites for buspirone analogues are different at 5-HT1A and 5-HT2A receptors.

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References

  1. Westenberg, H.G., J. Clin. Psychiatry, 60 (1999) 4. Discussion 46.

    Google Scholar 

  2. Cohen, M.L., Schenck, K.W., Colbert, W. and Wittenauer, L., J. Pharmacol. Exp. Ther., 232 (1985) 770.

    Google Scholar 

  3. Stockmeier, C.A., Shapiro, L.A., Dilley, G.E., Kolli, T.N., Friedman, L. and Rajkowska, G., J. Neurosci., 18 (1998) 7394.

    Google Scholar 

  4. Cusack, B., Nielson, A. and Richelson, E., Psychopharmacology (Berl), 114 (1994) 559.

    Google Scholar 

  5. Matsuoka, H., Ishii, M., Goto, A. and Sugimoto, T., Am. J. Physiol., 249 (1985) Pt 1.

  6. Schotte, A., Janssen, P.F., Gommeren, W., Luyten, W.H., Van Gompel, P., Lessage, A.S., De Loore, K. and Leysen, J.E., Psychopharmacology (Berl), 124 (1996) 57.

    Google Scholar 

  7. Peroutka, S.J., CNS Drugs, 4 (1995) 18.

    Google Scholar 

  8. Kennett, G.A., Wood, M.D., Bright, F., Cilia, J., Piper, D.C., Gager, T., Thomas, D., Baxter, G.S., Forbes, I.T., Ham, P. and Blackburn, T.P., Br. J. Pharmacol., 117 (1996) 427.

    Google Scholar 

  9. Bromidge, S.M.. Dabbs, S., Davies, D.T., Duckworth, D.M., Forbes, I.T., Ham, P., Jones, G.E., King, F.D., Saunders, D.V., Starr, S., Thewlis, K.M., Wyman, P.A., Blaney, F.E., Naylor, C.B., Bailey, F., Blackbourn, T.P., Holland, V., Kennett, G.A., Riley, G.J. and Wood, M.D., J. Med. Chem., 7, 41 (1998) 1598.

    Google Scholar 

  10. Bakish, D., Habin, R. and Hooper, C.L., CNS Drugs, 9 (1998) 271.

    Google Scholar 

  11. Gammans, R.E., Stringfellow, J.C., Hvizdos, A.J., Seidehamel, R.J., Cohn, J.B., Wilcox, C.S., Fabre, L.F., Pecknold, J.C., Smith, W.T. and Rickels, K., Neuropsychobiology, 25 (1992) 193.

    Google Scholar 

  12. Goa, K.L. and Ward A., Drugs, 32 (1986) 114.

    Google Scholar 

  13. Delle Chiaie, R., Pancheri, P., Casacchia, M., Stratta, P., Kotzalidis and G.D., Zibellini, M., J. Clin. Psychopharmacol., 15 (1995) 12.

    Google Scholar 

  14. Cottraux, J., Note, I.D., Cungi, C., Legeron, P., Heim, F., Chneiweiss, L., Bernard, G. and Bouvard, M., Br. J. Psychiatry, 167 (1995) 635.

    Google Scholar 

  15. Sramek, J.J., Tansman, M., Suri, A., Hornig-Rohan, M., Amsterdam, J.D., Stahl, S.M., Weisler, R.H. and Cutler, N.R., J. Clin. Psychiatry, 57 (1996) 287.

    Google Scholar 

  16. Robinson, D.S., Rickels, K., Feighner, J., Fabre, L.F. Jr., Gammans, R.E., Schrotiya, R.C., Alms, D.R., Andary, J.J. and Messina, M.E., J. Clin. Psychopharmacol., 10 (1990) Suppl. 67S.

  17. Rickels, K., Amsterdam, J.D., Clary, C., Puzzuoli, G. and Schweizer, E., J. Clin. Psychiatry, 52 (1991) 34.

    Google Scholar 

  18. Aceto, M.D. and Bowman, E.R., Arzneimittelforschung, 43 (1993) 942.

    Google Scholar 

  19. Giannini, A.J., Loiselle, R.H., Graham, B.H. and Folts, D.J., J. Subst. Abuse Treat., 10 (1993) 523.

    Google Scholar 

  20. Hedlund, L. and Wahlstroem, G., Alcohol. Alcohol., 31 (1996) 149.

    Google Scholar 

  21. Hedlund, L. and Wahlstroem, G., Alcohol. Clin. Exp. Res., 23 (1999) 822.

    Google Scholar 

  22. Farid, P. and Abate, M.A., Ann. Pharmacother., 32 (1998) 1362.

    Google Scholar 

  23. Realmuto, G.M., August, G.J. and Garfinkel, B.D., J. Clin. Psychopharmacol., 9 (1989) 122.

    Google Scholar 

  24. McCormick, L.H., Arch. Farm. Med., 6 (1997) 368.

    Google Scholar 

  25. Millan, M.J., Hjorth, S., Samanin, R., Schreiber, R., Jaffard, R., De Ladonchamps, B., Veiga, S., Goument, B., Peglion, J.L., Spedding, M. and Brocco, M., J. Pharmacol. Exp. Ther., 282 (1997) 148.

    Google Scholar 

  26. Matheson, G.K., Pfeifer, D.M., Weiberg, M.B. and Michel, C., Gen. Pharmacol., 25 (1994) 675–83.

    Google Scholar 

  27. Traber, J. and Glaser, T., Trends Pharmacol. Sci., 8 (1987) 432.

    Google Scholar 

  28. Balster, R.L., J. Clin. Psychopharmacol., 10 (1990) 31S.

    Google Scholar 

  29. Kleven, M.S. and Koek, W., J. Pharmacol. Exp. Ther., 276 (1996) 388.

    Google Scholar 

  30. Bronowska, A., Leś A., Chilmonczyk Z., Filipek S., Edvardsen Ø., Østensen R., Sylte I., Bioorg. Med. Chem., 9 (2001) 881.

    Google Scholar 

  31. Chilmonczyk, Z., Leś A., Woźniakowska, A., Cybulski, J., Kozioł, A.E. and Gdaniec, M., J.Med. Chem., 38 (1995) 1701.

    Google Scholar 

  32. Ferrin, T.E., J. Mol. Graphics, 6 (1988) 13.

    Google Scholar 

  33. Pearlman, D.A., Case, D.A., Caldwell, J.W., Ross, W.S., Cheatham, T.E. III, DeBolt, S., Ferguson, D.M., Seibel, G.L. and Kollman, P.A., Comp. Phys. Commun., 91 (1995) 1.

    Google Scholar 

  34. Amber 5, Case, D.A., Pearlman, D.A., Caldwell, J.W., Cheatham, T.E. III, Ross, W.S., Simmerling, C., Darden, T., Merz, K.M., Stanton, R.V., Cheng, A., Vincent, J.J., Crowley, M., Ferguson, D.M., Radmer, R., Seibel, G.L., Chandra Singh, U., Weiner, P. and Kollman, P.A., UCSF, San Francisco, 1997.

  35. Cornell, W.D., Cieplak, P., Bayly, C.I. and Kollman, P.A., J. Am. Chem. Soc., 115 (1993) 9620.

    Google Scholar 

  36. Gaussian 94, Revision D.1, M.J., Frisch, G.W., Trucks, H.B., Schlegel, P.M.W., Gill, B.G., Johnson, M.A., Robb, J.R., Cheeseman, T., Keith, G.A., Petersson, J.A., Montgomery, K., Raghavachari, M.A., Al-Laham, V.G., Zakrzewski, J.V., Ortiz, J.B., Foresman, J., Cioslowski, B.B., Stefanov, A., Nanayakkara, M., Challacombe, C.Y., Peng, P.Y., Ayala, W., Chen, M.W., Wong, J.L., Andres, E.S., Replogle, R., Gomperts, R.L., Martin, D.J., Fox, J.S., Binkley, D., J., Defrees, J., Baker, J.P., Stewart, M., Head-Gordon, C., Gonzalez, and J.A. Pople, Gaussian, Inc., Pittsburgh PA, 1995.

  37. Filipek, S., unpublished data.

  38. Chanda, P.A., Minchin, M.C.W., Davis, A.R., Greenberg, L., Reilly, Y., McGregor, W.H., Bhat, R., Lubeck, M.H., Mizutani, S. and Hung, P.P., Mol. Pharmacol., 43 (1993) 516.

    Google Scholar 

  39. Baldwin, J.M., Schertler, G.F.X. and Unger, V.M., J. Mol. Biol. 272 (1997) 144.

    Google Scholar 

  40. Van Rhee, A.M. and Jacobson, K.A., Drug. Dev. Res., 37 (1996) 1.

    Google Scholar 

  41. Lomize, A.L., Pogozheva, I.D. and Mosberg, H.I., J. Comp. Aid. Mol. Des., 13 (1999) 325.

    Google Scholar 

  42. Sylte, I., Chilmonczyk, Z., Dahl, S.G., Cybulski, J. and Edvardsen, Ø., J. Pharm. Pharmacol., 49 (1997) 698.

    Google Scholar 

  43. Bronowska, A., Molecular modelling of interactions between serotonin receptors and their ligands (doctoral dissertation), University of Warsaw, Warsaw, November 2000.

    Google Scholar 

  44. Cook, E.H., Jr., Fletcher, K.E., Wainwright, M., Marks, N., Yan, S.Y. and Leventhal, B.L., J. Neurochem., 63 (1994) 465.

    Google Scholar 

  45. Farrens, D.L., Altenbach, C., Yang, K., Hubbel, W.L. and Khorana, H.G., Science, 274 (1996) 768.

    Google Scholar 

  46. Liu, J., Blin, N., Conklin, B.R. and Wess, J., J. Biol. Chem., 271 (1996) 6172.

    Google Scholar 

  47. Fannelli, F., Menziani, C.M., Scheer, A., Cotecchia, S. and De Benedetti, P.G., Methods, 14 (1998) 302.

    Google Scholar 

  48. Sylte, I., Bronowska, A., Dahl, S.G., Eur. J. Pharmacol., 416(1–2) (2001), 33.

    Google Scholar 

  49. Ho, B.Y., Karschin, A., Branchek, T., Davidson, N. and Lester, H.A., FEBS Lett., 312 (1992) 259.

    Google Scholar 

  50. Guan, X.-M., Peroutka, S.J. and Kobilka, B.K., Mol. Pharmacol., 41 (1992) 695.

    Google Scholar 

  51. Palczewski, K., Kumasaka, T., Hori, T., Behnke, C.A., Motoshima, H., Fox, B.A., Le Trong, I., Teller, D.C., Okada, T., Stenkamp, R.E., Yamamoto, M. and Miyano, M., Science, 289 (2000) 739.

    Google Scholar 

  52. Sealfon, S.C., Chi, L., Ebersole, B.J., Rodie, V., Zhang, D., Ballesteros, J.A. and Weinstein, H., J. Biol. Chem., 270 (1995) 16683.

    Google Scholar 

  53. Zhou, W., Flanagan, C., Ballesteros, J.A., Konvicka, K., Davidson, J.S., Weinstein, H., Millar, R.P. and Sealfon, S.C., Mol. Pharmacol., 45 (1994) 165.

    Google Scholar 

  54. Gudermann, T., Nuernberg, B. and Schultz, G., Clin. Investig., 73 (1995) 51.

    Google Scholar 

  55. Samama, P., Cotecchia, S., Costa, T. and Lefkowitz, R.J., J. Biol. Chem., 268 (1993) 4625.

    Google Scholar 

  56. Lefkowitz, R.J., Cotecchia, S., Samama, P. and Costa, T., Trends. Pharmacol. Sci., 14 (1993) 303.

    Google Scholar 

  57. Scheer, A., Fanelli, F., Costa, T., De Benedetti, P.G. and Cotecchia, S., EMBO J., 15 (1996) 3566.

    Google Scholar 

  58. Scheer, A., Fanelli, F., Costa, T., De Benedetti, P.G. and Cotecchia, S., Proc. Natl. Acad. Sci. USA, 94 (1997) 808.

    Google Scholar 

  59. Strange, P.G., Trends Pharmacol. Sci., 19 (1998) 85.

    Google Scholar 

  60. Kristiansen, K., Kroeze, W.K., Willins, D.L., Gelber, E.I., Savage, J.E., Glennon, R.A. and Roth, B.L., J. Pharmacol. Exp. Ther., 293 (2000) 735.

    Google Scholar 

  61. Zhukovsky, E.A. and Oprian, D.D., Science, 246 (1989) 401.

    Google Scholar 

  62. Zhukovsky, E.A., Robinson, P.R. and Oprian, D.D., Biochemistry, 27 (1992) 10400.

    Google Scholar 

  63. Roth, B.L., Shokam, M., Choudhary, M.S. and Khan, N., Mol. Pharmacol., 52 (1997) 259.

    Google Scholar 

  64. Choudhary, M.S., Sachs, N., Uluer, A., Glennon, R.A., Westkaemper, R.B. and Roth, B.L., Mol. Pharmacol., 47 (1995) 568.

    Google Scholar 

  65. Wieland, K., Zuurmond, H.M., Krasel, C., Ijerman, A.P. and Lohse, M.J., Proc. Natl. Acad. Sci. USA, 93 (1996) 9276.

    Google Scholar 

  66. Lappalainen, J., Zhang, L., Dean, M., Oz, M., Ozaki, N., Yu, D.H., Virkkunen, M., Wieght, F., Linnoila, M. and Goldman, D., Genomics, 27 (1995) 274.

    Google Scholar 

  67. Ling, K., Wang, P., Zhao, J., Wu, Y.L., Cheng, Z.J., Wu, G.X., Hu, W., Ma, L. and Pei, G., Proc. Natl. Acad. Sci. USA, 96 (1999) 7992.

    Google Scholar 

  68. Chilmonczyk, Z., Cybulski, M., Iskra-Jopa, J., Chojnacka-Wójcik, E., Tatarczynska, E., Kłodzinska, A., Leś A., Bronowska, A. and Sylte, I., Interactions of 1,2,4-substituted piperazines, new serotonin receptor ligands, with 5-HT1A and 5-HT2A receptors., Il Farmaco (in press).

  69. Gether, U., Lin, S., Ghanouni, P., Ballesteros, J.A., Weinstein, H. and Kobilka, B.K., EMBO J., 16 (1997) 6737.

    Google Scholar 

  70. Eason, M.G. and Liggett, S.B., J. Biol. Chem., 270 (1995) 24753.

    Google Scholar 

  71. Buck, F., Meyerhof, W., Werr, H. and Richter, D., Biochem. Biophys. Res. Commun., 178 (1991) 1421.

    Google Scholar 

  72. Hoyer, D. and Schoeffter, P., J. Recept. Res., 11 (1991) 197.

    Google Scholar 

  73. Szelejewska-Woźniakowska, A., Chilmonczyk, Z., Cybulski, J. and Cybulski, M., unpublished data.

  74. Liu, J., Conklin, B.R., Blin, N., Yun, J. and Wess, J., Proc. Natl. Acad. Sci. USA, 92 (1995) 11642.

    Google Scholar 

  75. Titeler, M., Lyon, R.A., Davis, K.H. and Glennon, R.A., Biochem. Pharmacol., 36 (1987) 3265.

    Google Scholar 

  76. Chilmonczyk, Z., Szelejewska-Woźniakowska, A., Cybulski, J., Cybulski, M., Kozioł, A.E. and Gdaniec, M., Arch. Pharm. Pharm. Med. Chem., 330 (1997) 146.

    Google Scholar 

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Authors and Affiliations

  1. Department of Chemistry, University of Warsaw, 1 Pasteura Str., 02-093, Warsaw, Poland

    Agnieszka Bronowska & Andrzej Leś

  2. Drug Institute, 30/34 Chełmska Str., 00-725, Warsaw, Poland

    Zdzisław Chilmonczyk

  3. Pharmaceutical Research Institute, 8 Rydygiera Str., 01-793, Warsaw, Poland

    Andrzej Leś

  4. Department of Pharmacology, Institute of Pharmacy, University of Tromsø, N-9037, Tromsø, Norway

    Øyvind Edvardsen

  5. Department of Physics, University of Tromsø, N-9037, Tromsø, Norway

    Roy Østensen

  6. Department of Pharmacology, Institute of Medical Biology, University of Tromsø, N-9035, Tromsø, Norway

    Ingebrigt Sylte

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  1. Agnieszka Bronowska
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Bronowska, A., Chilmonczyk, Z., Leś, A. et al. Molecular dynamics of 5-HT1A and 5-HT2A serotonin receptors with methylated buspirone analogues. J Comput Aided Mol Des 15, 1005–1023 (2001). https://doi.org/10.1023/A:1014856107486

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