Structural Analogs of AF64A: Synthesis and their Effects on High Affinity Choline Transport and QNB Binding

  • J. S. Mistry
  • D. J. Abraham
  • I. Hanin
Part of the Advances in Behavioral Biology book series (ABBI, volume 29)


A chronic deficiency in central cholinergic function has been demonstrated in a number of neuropsychiatrie diseases, including Alzheimer’s disease.1–6 Until recently, animal models that simulate the neurochemical conditions which appear to cause these diseases in humans, as a result of a direct manipulation of the central cholinergic system, were not available. Over the past few years, however, we have been successful in developing a compound, ethylcholine mustard aziridinium ion (AF64A), which has the potential to serve as a novel toxin in developing animal models of human brain disorders in which a cholinergic hypofunction has been implicated.


Develop Animal Model Choline Acetyl Central Cholinergic System Brain Acetylcholine Quinuclidinyl Benzilate 
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.
    P. Davies and A.J.F. Maloney, Selective loss of central cholinergic neurons in Alzheimer’s Disease. Lancet 2: 1403 (1976).PubMedCrossRefGoogle Scholar
  2. 2.
    K.L. Davis and J.A. Yesavage, Brain Acetylcholine and Disorders of Memory, in “Brain Acetylcholine and Neuropsychiatric Disease”, Plenum Press, New York and London (1978).Google Scholar
  3. 3.
    S. Corkin, Acetylcholine, aging and Alzheimer’s disease. Implication for treatment. Trends in Neurosci., 287 (1981).Google Scholar
  4. 4.
    P.J. Whitehouse, D. Price, A. Clark, J.T. Coyle, and M. Delong, Alzheimer’s disease: evidence for a selective loss of cholinergic neurons in the nucleus basafis. Ann. Neurol. 10: 122 (1981).PubMedCrossRefGoogle Scholar
  5. 5.
    M. McKinney, J. Hedreen and J.T. Coyle, Alzheimer’s Disease: Report of Progress in Research, in “Aging Vol. 19”, Eds. S. Corkin, K. Davis, J. Growdon, G. Usdin and R.J. Wurtman, Raven Press, New York (1982).Google Scholar
  6. 6.
    R.T. Bartus, R.L. Dean, B. Beer, and A.S. Lippa, The cholinergic hypothesis of geriatric memory dysfunction. Science 217: 408 (1982).PubMedCrossRefGoogle Scholar
  7. 7.
    C.R. Mantione, A. Fisher, and I. Hanin, Possible mechanisms involved in the presynaptic cholinotoxicity due to ethylcholine aziridinium (AF64A) in vivo. Life Sci. 35: 33 (1984).PubMedCrossRefGoogle Scholar
  8. 8.
    A. Fisher, C.R. Mantione, D.J. Abraham, and I. Hanin, Long-term central cholinergic hypofunction induced in mice by ethylcholine aziridinium ion (AF64A) in vivo. J. Pharmacol. Exp. Therap., 222: 140 (1982).Google Scholar
  9. 9.
    C.R. Mantione, A. Fisher, and I. Hanin, AF64A-treated mouse: Possible model for central cholinergic hypofunction. Science 213: 579 (1981).PubMedCrossRefGoogle Scholar
  10. 10.
    I. Hanin, W.C. DeGroat, C.R. Mantione, J.T. Coyle, and A. Fisher, Chemically-Induced Cholinotoxicity jji vivo: Studies Utilizing Ethylcholine Aziridinium Ion (AF64A), in “Banbury Report 15: Biological Aspects of Alzeheimer’s Disease”, Ed. R. Katzman, Cold Spring Harbor Laboratory (1983).Google Scholar
  11. 11.
    H.I. Yamamura and S.H. Snyder, High affinity transport of choline into synaptosomes of rat brain. J. Neurochem. 21: 1355 (1973).PubMedCrossRefGoogle Scholar
  12. 12.
    C.R. Bader, R.W. Baughman and J.L. Moore, Different time course of development for high affinity choline uptake and choline acetyl transferase in the chicken ratina. Proc. Natl. Acad. Sci. (U.S.A.) 75: 2525 (1978).CrossRefGoogle Scholar
  13. 13.
    H.I. Yamamura and S.H. Snyder, Muscarinic cholinergic binding in rat brain. Proc. Natl. Acad. Sci. (U.S.A.) 71: 1725 (1974).CrossRefGoogle Scholar
  14. 14.
    C. Chothia, Interaction of acetylcholine with different cholinergic nerve receptors. Nature 225: 36 (1970).PubMedCrossRefGoogle Scholar
  15. 15.
    J.W. Asante, A.J. Cross, J.F.W. Deakin, J.A. Johnson and H.R. Slater, Evaluation of etylcholine mustard aziridinium ion (EMA) as a specific neurotoxin of brain cholinergic neurons. Brit. J. Pharmacol. 80: 573 (1983).Google Scholar
  16. 16.
    A. Levy, G.J. Kant, J.L. Meyerhoff, and L.E. Jarrard, Non-cholinergic neurotoxic effects of AF64A in substantia nigra. Brain Res. 305: 169 (1984).PubMedCrossRefGoogle Scholar
  17. 17.
    L.E. Jarrard, G.J. Kant, J.L. Meyerhoff, and A. Levy, Behavioral and neurochemical effects of intraventricular AF64A administration in rats. Pharmacol. Biochem. and Behavior 22: 273 (1984).CrossRefGoogle Scholar
  18. 18.
    L. Villani AT Contestabile, ÂT Poli, P. Migani, and F. Fonnum, Neurotoxic effects of the presumed cholinergic toxin, AF64A. Neurosci. Lett., Supplement 18, S228 (1984).Google Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • J. S. Mistry
    • 1
  • D. J. Abraham
    • 1
  • I. Hanin
    • 2
  1. 1.Depts. of Medicinal ChemistryUniversity of PittsburghPittsburghUSA
  2. 2.Dept. of Pharmacology and Experimental TherapeuticsLoyola University Stritch School of MedicineChicagoUSA

Personalised recommendations