Letter | Published:

Selective inhibitors of biosynthesis of aminergic neurotransmitters

Naturevolume 274pages906908 (1978) | Download Citation

Subjects

Abstract

ALTHOUGH the enzymatic decarboxylation of amino acids is of substantial importance to biochemistry1, there are few inhibitors of the decarboxylase enzymes which combine activity with selectivity. Several of the amines formed by in vivo decarboxylation of amino acids (biogenic amines) have key roles in physiology. The neurotransmitters dopamine, 5-hydroxytryptamine, histamine and γ-aminobutyric acid result from such enzymatic decarboxylation; dopamine in turn serves as the precursor of noradrenaline2. The involvement of catecholamines in peripheral and central control of blood pressure has been the subject of many investigations; for example, elevated catecholamine levels were found in some of the 27 brain regions investigated in spontaneously hypertensive rats. Specifically, elevated noradrenaline and dopamine levels were found in regions implicated in the control of arterial blood pressure3. A widely reported biochemical theory of schizophrenia suggests disturbance of the dopaminergic system as the causative factor.4 Elevated histamine levels are believed to be involved in such diseases as allergy, hypersensitivity, gastric ulcer and inflammation5. Ornithine decarboxylase is also an important target for inhibition, as it is the initial enzyme in the biosynthesis of polyamines and increased levels of the latter have been associated with rapid cell division, including tumour growth6. Thus, selective inhibitors of these key enzymes could be of help in elucidating the complexities of neurophysiology and neurochemistry, as well as of service in medicine by correcting pathological levels of these agonists. We report here examples of the transformation of amino acids (C) into the corresponding substituted 3-fluoro-alanines (B), resulting in potent time-dependent decarboxylase inactivators (Table 1). In addition, we have prepared the fluoromethyl derivatives (D) corresponding to some of the amine products of these decarboxylases and find them also to be inactivators (Table 1).

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Boeker, E. A. & Snell, E. E. Enzymes 6, 217–253 (1972).

  2. 2

    Handbook of Psychopharmacology (eds Iversen, L. L., Iversen, S. D. & Snyder, S. H.) Vols 3 & 4 (Plenum, New York, 1975).

  3. 3

    Versteeg, D. H. G. et al. Prog. Brain Res. 47, 111–116 (1977).

  4. 4

    Snyder, S. H., Banerjee, S. P., Yamamura, H. I. & Greenberg, D. Science 184, 1243–1253 (1974).

  5. 5

    Douglas, W. W. in The Pharmacological Basis of Therapeutics 5th edn (eds Goodman, L. S. & Gilman, A.) 590–629 (MacMillan, New York, 1975).

  6. 6

    Russell, D. H. in Polyamines in Normal and Neoplastic Growth (Russell, D. H. ed.) 1–13 (Raven, New York, 1973).

  7. 7

    Kollonitsch, J., Barash, L., Kahan, F. M. & Kropp, H. Nature 243, 346–347 (1973).

  8. 8

    Kollonitsch, J. & Barash, L. J. Am. chem. Soc. 98, 5591–5593 (1976).

  9. 9

    Kahan, F. M. & Kropp, H. 15th ICAAC, Washington, D.C., #100 (1975).

  10. 10

    Wang, E. & Walsh, C. Biochemistry 17, 1313–1321 (1978).

  11. 11

    Walsh, C. Horizons Biochem. Biophys. 3, 36–81 (1977).

  12. 12

    Abeles, R. H. & Maycock, A. L. Acct. Chem. Res. 9, 313–319 (1976).

  13. 13

    Rando, R. R. Acct. Chem. Res. 8, 281–288 (1975); Science 185, 320–324 (1974); Nature 250, 586–587 (1974).

  14. 14

    Kollonitsch, J., Barash, L. & Doldouras, G. A. J. Am. chem. Soc. 92, 7494–7495 (1970).

  15. 15

    Kollonitsch, J., Marburg, S. & Perkins, L. M. J. org. Chem. 40, 3808–3809 (1975).

  16. 16

    Biochemical Preparations 4, 46–50 (Wiley, New York, 1955).

  17. 17

    Taub, D. & Patchett, A. A. Tetrahedron Lett. 2745–2748 (1977).

  18. 18

    Metcalf, B. W. & Jund, K. Tetrahedron Lett. 3689–3692 (1977).

  19. 19

    Aster, S. D., Maycock, A. L., Patchett, A. A. & Taub, D. 175th National ACS Mtg, Anaheim, California, MEDI 58 (1978).

  20. 20

    Metcalf, B. W., Jung, M. J., Lippert, B., Casara, P. & Danzin, C. 173rd National ACS Mtg New Orleans, Louisiana, MEDI 25 (1977).

  21. 21

    Ellenbogen, L., Markley, E. & Taylor, R. J. Jr Biochem. Pharmac. 18, 683–685 (1969).

  22. 22

    Lineweaver, H. & Burk, D. J. Am. chem. Soc. 56, 658–666 (1934).

  23. 23

    Wu, J.-Y., Matsuda, T. & Roberts, E. J. biol. Chem. 248, 3029–3034 (1973).

  24. 24

    Ono, M., Inoue, H., Suzuki, F. & Takeda, Y. Biochim. biophys. Acta 284, 285–297 (1972).

  25. 25

    Mamont, P. S., Duchesne, M.-C., Grove, J. & Bey, P. Biochem. biophys. Res. Commun. 81, 58–66 (1978).

  26. 26

    Christenson, J. G., Dairman, W. & Udenfriend, S. Archs Biochem. Biophys. 141, 356–367 (1970).

  27. 27

    Håkanson, R. Biochem. Pharmac. 12, 1289–1296 (1963).

  28. 28

    Chang, G. W. & Snell, E. S. Meth. Enzym. 17 B, 663–667 (1971).

  29. 29

    Ulm, E. H. & Duggan, D. E. (in preparation).

Download references

Author information

Affiliations

  1. Merck Sharp & Dohme Research Laboratories, Division of Merck & Co., Inc., PO Box 2000, Rahway, New Jersey, 07065

    • J. KOLLONITSCH
    • , A. A. PATCHETT
    • , S. MARBURG
    • , A. L. MAYCOCK
    • , L. M. PERKINS
    • , G. A. DOLDOURAS
    • , D. E. DUGGAN
    •  & S. D. ASTER
  2. West Point, Pennsylvania, 19486

    • J. KOLLONITSCH
    • , A. A. PATCHETT
    • , S. MARBURG
    • , A. L. MAYCOCK
    • , L. M. PERKINS
    • , G. A. DOLDOURAS
    • , D. E. DUGGAN
    •  & S. D. ASTER

Authors

  1. Search for J. KOLLONITSCH in:

  2. Search for A. A. PATCHETT in:

  3. Search for S. MARBURG in:

  4. Search for A. L. MAYCOCK in:

  5. Search for L. M. PERKINS in:

  6. Search for G. A. DOLDOURAS in:

  7. Search for D. E. DUGGAN in:

  8. Search for S. D. ASTER in:

About this article

Publication history

Received

Accepted

Issue Date

DOI

https://doi.org/10.1038/274906a0

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.