Pharmaceutical Research

, Volume 1, Issue 6, pp 271–274 | Cite as

Phosphorus GABA Analogues as Potential Prodrugs

  • Lindley A. Cates
  • Mohamed S. Rashed


Analogues of γ-aminobutyric acid (GABA), wherein a P=O moiety is separated by three carbon atoms from an amino group, were incorporated into Schiff bases as potential acid-labile carrier molecules. These include 3-aminophenylphosphonic acid, its dimethyl ester and its previously unreported N,N′-diisopropylphosphonodiamide. A benzophenone derivative of GABA was also synthesized.A study of the degrees of in vitro hydrolysis of four Schiff bases indicated that lability of the C=N bond is determined by electronic influences of ring substituents.All new products were tested for abilities to inhibit maximal electroshock- and subcutaneous pentylenetetrazol (Metrazol)-induced seizures in mice.Activity was found only in the former system with moderate inhibition displayed by two dimethyl ester and the GABA Schiff bases.


Ester Hydrolysis Phosphorus Carbon Atom Dimethyl 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. (1).
    Cates, L. A., Li, V.-S., Yakshe, C. S., Fadeyi, M. O., Andree, T. H., Karbon, E. W., Enna, S. J. (1984) J. Med. Chem., 21, 654–659.Google Scholar
  2. (2).
    Cates, L. A., Drug Dev. Res., in press.Google Scholar
  3. (3).
    Billman, J. H., Keehler, F., May, R. (1969) J. Pharm. Sci. 58, 767–769.Google Scholar
  4. (4).
    Popp, F. D., Roth, S., Kirby, J. (1963) J. Med. Chem. 6, 83–85.Google Scholar
  5. (5).
    Hodnett, E. M., Tai, J. (1971) J. Med. Chem. 14, 1115–1116.Google Scholar
  6. (6).
    Santilli, A. A., Kim, D. H., Fieber, R. A., Wanser, S. V. (1974) J. Pharm. Sci. 63, 449–451.Google Scholar
  7. (7).
    Kaplan, J.-P., Raizon, B. M., Desarmenien, M., Feltz, P., Headley, P. M., Worms, P., Lloyd, K. G., Bartholini, G. (1980) J. Med. Chem. 23, 702–704.Google Scholar
  8. (8).
    Bartholini, G., Scatton, B., Zivkovic, B., Lloyd, K. G. (1979) in GABA-Neurotransmitters (Krogsgaard-Larsen, P., Scheel-Kruger, J., eds.) pp. 326–339. Academic Press, N. Y.Google Scholar
  9. (9).
    Chase, T. N., Walters, J. R. (1976) in GABA in Nervous System Function (Roberts, E., Chase, T. N., Tower, D. B., eds.) p. 497. Raven Press, N. Y.Google Scholar
  10. (10).
    Lien, E. J., Tong, G. L. Chou, J. T., Lien, L. L. (1973) J. Pharm. Sci., 62, 246–250.Google Scholar
  11. (11).
    Langman, E. M., Healy, W., Dutt, P. K. (1927) Quart. J. Indian Chem. Soc. 4, 75–79.Google Scholar
  12. (12).
    Reeves, R. L. (1965) J. Org. Chem. 30, 3129–3135.Google Scholar
  13. (13).
    Al-Sayyab, A. F., Lawson, A., Stevens, J. O. (1968) J. Chem. Soc. (C), 411–415.Google Scholar
  14. (14).
    Kosolapoff, G. M. (1948) J. Am. Chem. Soc. 70, 3465–3468.Google Scholar
  15. (15).
    Freedman, L. D., Jaffe, H. H. (1965) J. Am. Chem. Soc. 77, 920–921.Google Scholar
  16. (16).
    Doak, G. O., Freedman, L. D. (1952) J. Am. Chem. Soc. 74, 753–754.Google Scholar
  17. (17).
    DHEW Pub. no. (NIH) 76-1093, Bethesda, MD, 1976.Google Scholar
  18. (18).
    Perrin, D. D., Dempsey, B., Serjeant, E. P. (1981) pKa Prediction for Organic Acids and Bases, pp. 109–126. Chapman and Hall Ltd., London.Google Scholar

Copyright information

© Plenum Publishing Corporation 1984

Authors and Affiliations

  • Lindley A. Cates
    • 1
  • Mohamed S. Rashed
    • 2
  1. 1.Department of Medicinal Chemistry, College of PharmacyUniversity of HoustonHouston
  2. 2.School of PharmacyUniversity of WashingtonSeattle

Personalised recommendations