Skip to main content
Log in

A pseudoreceptor docking study of 4,5-α-epoxymorphinans with a range of dielectric constants

  • Research Papers
  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Summary

Thirteen 4,5-epoxymorphinan μ agonists with established analgesic action were docked into an Asp-Lys-His-Phe pseudoreceptor complex under a range of distance-dependent dielectric conditions. The number of compounds with potential energies of the docked complexes that agreed in rank order with corresponding analgesic potencies was determined for each condition. Two dielectric conditions, n-decane (1.991) and ethanol (24.3), enabled the greatest number of compounds to relate to their pseudoreceptors with each having 9 and 8 successes respectively. Both of these conditions demonstrated unique influences on the types of structures that were successfully docked. For example, the morphine stereoisomer α-isomorphine, the geometric isomer B/C trans-morphine, and the 8-position-substituted γ-isomorphine were successes in the n-decane condition, whereas the ethanol condition produced the substituted codeine derivatives dihydroco-deinone and dihydroxycodeinone. These findings emphasize the importance of dielectric influence when developing force-field modeled quantitative structure-activity relationships for a closely related homologous series.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Dammkoehler, R.A., Karasek, S.F., Berkley Shands, E.F. and Marshall, G.R., J. Comput.-Aided Mol. Design, 3 (1989) 3.

    Google Scholar 

  2. Havel, T.F., Kuntz, I.D. and Crippen, G.M., Bull. Math. Biol., 45 (1983) 665.

    Google Scholar 

  3. Ghose, A.K., Crippen, G.M., Revankar, G.R., McKernan, P.A., Smee, D.F. and Robins, R.K., J. Med. Chem., 32 (1989) 746.

    Google Scholar 

  4. Pattabiram, N., Levitt, M., Ferrin, T.E. and Langridge, R., J. Comput. Chem., 6 (1985) 432.

    Google Scholar 

  5. Henry, E.R., Levitt, M. and Eaton, W.A., Proc. Natl. Acad. Sci. USA, 82 (1985) 2034.

    Google Scholar 

  6. Ross, W.S., Hardin, C.C., Tinoco, I., Jr., Rao, S.N., Pearlman, D.A. and Kollman, P.A. Biopolymers, 28 (1989) 1939.

    Google Scholar 

  7. Balaji, V.N., Mobasser, A. and Rao, S.N., Biochem. Biophys. Res. Commun., 160 (1989) 109.

    Google Scholar 

  8. Rao, S.N., Lybrand, T., Michaud, D., Jerina, D.M. and Kollman, P.A., Carcinogenesis, 10 (1989) 27.

    Google Scholar 

  9. Belleau, B., Conway, T., Ahmed, F.R. and Hardy, A.D., J. Med. Chem., 17 (1974) 907.

    Google Scholar 

  10. Dimaio, J., Ahmed, F.R., Shiller, P. and Belleau, B., In Gualtieri, F., Gianella, M. and Melchiorre, C. (Eds.), Recent Advances in Receptor Chemistry, Elsevier/North-Holland Biomedical Press, Amsterdam, 1979, pp. 221–234.

    Google Scholar 

  11. Belleau, B. and Morgan, P., J. Med. Chem., 17 (1974) 908.

    Google Scholar 

  12. Kolb, V.M. and Sheiner, S., J. Pharmaceut. Sci., 73 (1984) 719.

    Google Scholar 

  13. Bennett, L.K. and Beamer, R.L., J. Pharmaceut. Sci., 75 (1986) 769.

    Google Scholar 

  14. Bennett, L.K. and Beamer, R.L., J. Pharmaceut. Sci., 77 (1988) 986.

    Google Scholar 

  15. Cheney, B.V., J. Med. Chem., 31 (1988) 521.

    Google Scholar 

  16. Casy, A.F. and Parfitt, R.T., In Opioid Analgesics Chemistry and Receptors, Plenum Press, New York, 1986, p. 27.

    Google Scholar 

  17. Foye, W.O., In Principles of Medicinal Chemistry, Lea and Febiger, Philadelphia, 1974, p. 256.

    Google Scholar 

  18. Carr III, P., In Wolff, M.E. (Ed.), Burger's Medicinal Chemistry (Fourth Edition), John Wiley & Sons, 1981, p. 729.

  19. Pert, C.B. and Snyder, S.H., Mol. Pharmacol., 10 (1974) 868.

    Google Scholar 

  20. Reden, J., Reich, F., Rice, K.C., Jacobson, A.E., Brossi, A., Sreaty, R.A. and Klee, W.A., J. Med. Chem., 22 (1979) 256.

    Google Scholar 

  21. Merz, H.A., Langbein, A., Stockhaus, K., Walther, G. and Wick, H., Adv. Biochem. Psychopharmacol., 8 (1974) 91.

    Google Scholar 

  22. Tseng, L.-F., Loh, H.H. and Li, C.H., Nature, 263 (1976) 239.

    Google Scholar 

  23. Belluzi, J.D., Grant, N., Garsky, V., Sarantakis, D., Wise, C.D. and Stein, L., Nature, 260 (1976) 625.

    Google Scholar 

  24. Cheney, B.V., Lathi, A., Barshun, C. and Gay, D.D., Mol. Pharmacol., 22 (1982) 349.

    Google Scholar 

  25. Gussio, R., Syi, J., Pou, S., Chen, J. and Smythers, G.W., Proc. Am. Chem. Soc., 200 (August, MEDI, 53) 493.

  26. Gussio, R., Syi, J., Pou, S., Chen, J. and Smythers, G.W., Quant. Struct.-Act. Relationsh., in press.

  27. Gylbert, L., Acta Crystallogr., B 29 (1973) 1630.

    Google Scholar 

  28. Hagler, A.T., Lifson, S. and Dauber, P., J. Am. Chem. Soc., 101 (1979) 5122.

    Google Scholar 

  29. INSIGHT II and DISCOVER: Biosym Technologies, Inc., San Diego, CA.

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gussio, R., Pou, S., Chen, JH. et al. A pseudoreceptor docking study of 4,5-α-epoxymorphinans with a range of dielectric constants. J Computer-Aided Mol Des 6, 149–158 (1992). https://doi.org/10.1007/BF00129425

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00129425

Key words

Navigation