Toward a Third Generation of Cholinesterase Inhibitors

  • Ezio Giacobini
  • Donald Linville
  • Erik Messamore
  • Nobuo Ogane
Part of the Advances in Alzheimer Disease Therapy book series (AADT)


The finding of a severely damaged and underactive cholinergic system in the brain of AD patients has led to clinical trials of new cholinomimetics including cholinesterase inhibitors (ChEI) (see Becker and Giacobini, 1988a,b). Based on available experimental and clinical information (Giacobini and Becker, 1989; Pomponi et al., 1990), an ideal ChEI suitable for symptomatic treatment of memory and cognitive impairment in AD should satisfy the following requirements: a) produce a long-term acetylcholinesterase (AChE) inhibition in brain with a steady-state phase of increased cortical ACh; b) not inhibit acetylcholine (ACh) synthesis or release in nerve endings; and c) produce only mild side effects at therapeutic doses. Such requirements have not been met by the ChEI used so far (Becker and Giacobini, 1988a,b). We have studied a number of new ChEI (Giacobini and Becker, 1989) and based on our experimental results in animals, we have proposed three new ChEI for experimental therapy of Alzheimer disease (AD), heptyl-physostigmine (HEP), a physostigmine (PHY) derivative, metrifonate (MTF) and huperzine A (HUP-A) (Hallak and Giacobini, 1987, 1989; DeSarno et al., 1989; Tang et al., 1989). All three compounds are in clinical trials. Both MTF and HEP have a low level of toxicity in humans and only at the 60–80% of plasma butyrylcholinesterase (BuChE) level of inhibition, peripheral side effects are present. No central side effects have been recorded.


Alzheimer Disease Cholinesterase Inhibitor Nucleus Basalis Senile Dementia Acetylcholine Release 
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Copyright information

© Springer Science+Business Media New York 1991

Authors and Affiliations

  • Ezio Giacobini
    • 1
  • Donald Linville
    • 1
  • Erik Messamore
    • 1
  • Nobuo Ogane
    • 1
  1. 1.Department of PharmacologySouthern Illinois University School of MedicineSpringfieldUSA

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