Quinolizidinyl Derivatives of Bi- And Tricyclic Systems as Potent Inhibitors of Acetyl- And Butyrylcholinesterase With Potential in Alzheimer's Disease

Eur J Med Chem. 2011 Jun;46(6):2170-84. doi: 10.1016/j.ejmech.2011.02.071. Epub 2011 Mar 5.


On the pattern of the potent and selective butyrylcholinesterase (BChE) inhibitors ethopropazine and Astra1397, sets of quinolizidinyl derivatives of bi- and tricyclic (hetero)aromatic systems were studied as dual, or BChE-selective inhibitors. All compounds exhibited activity against both cholinesterases, but inhibition of BChE was generally stronger, with submicromolar IC50 values for most of them (e.g. 15: IC50 versus BChE=0.15 μM; SI=47). However, in a subset of quinolizidinyl derivatives of 6-hydroxycoumarin an inverted selectivity for acetylcholinesterase (AChE) was observed (e.g. 46: IC50 versus AChE=0.35 μM; SI=0.06). Docking studies furnished a sound interpretation of the observed different enzyme activity. Several of the studied compounds have shown, in the past, additional pharmacological properties (as antagonism on presynaptic muscarinic autoreceptor; inhibition of enkephaline aminopeptidase and antipsychotic activity) of some relevance in Alzheimer's disease, and may, therefore, represent hits for the development of interesting single-entity multi-target drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / enzymology
  • Animals
  • Butyrylcholinesterase / metabolism*
  • Cattle
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Erythrocytes / enzymology
  • Models, Molecular
  • Molecular Structure
  • Quinolizidines / chemical synthesis
  • Quinolizidines / chemistry
  • Quinolizidines / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship


  • Cholinesterase Inhibitors
  • Quinolizidines
  • Acetylcholinesterase
  • Butyrylcholinesterase