Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer's disease

J Med Chem. 2009 May 14;52(9):2724-32. doi: 10.1021/jm801292b.

Abstract

Tacripyrines (1-14) have been designed by combining an AChE inhibitor (tacrine) with a calcium antagonist such as nimodipine and are targeted to develop a multitarget therapeutic strategy to confront AD. Tacripyrines are selective and potent AChE inhibitors in the nanomolar range. The mixed type inhibition of hAChE activity of compound 11 (IC(50) 105 +/- 15 nM) is associated to a 30.7 +/- 8.6% inhibition of the proaggregating action of AChE on the Abeta and a moderate inhibition of Abeta self-aggregation (34.9 +/- 5.4%). Molecular modeling indicates that binding of compound 11 to the AChE PAS mainly involves the (R)-11 enantiomer, which also agrees with the noncompetitive inhibition mechanism exhibited by p-methoxytacripyrine 11. Tacripyrines are neuroprotective agents, show moderate Ca(2+) channel blocking effect, and cross the blood-brain barrier, emerging as lead candidates for treating AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / enzymology
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism
  • Butyrylcholinesterase / metabolism
  • Calcium / metabolism
  • Calcium Channel Blockers / chemistry
  • Calcium Channel Blockers / metabolism
  • Calcium Channel Blockers / pharmacology
  • Calcium Channel Blockers / therapeutic use
  • Catalytic Domain
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / metabolism
  • Cholinesterase Inhibitors / pharmacology
  • Cholinesterase Inhibitors / therapeutic use
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Dihydropyridines / chemistry*
  • Dihydropyridines / metabolism
  • Dihydropyridines / pharmacology*
  • Dihydropyridines / therapeutic use
  • Humans
  • Hydrogen Peroxide / metabolism
  • Kinetics
  • Ligands
  • Models, Molecular
  • Peptide Fragments / metabolism
  • Permeability / drug effects
  • Tacrine / analogs & derivatives*

Substances

  • Amyloid beta-Peptides
  • Calcium Channel Blockers
  • Cholinesterase Inhibitors
  • Dihydropyridines
  • Ligands
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • Tacrine
  • 1,4-dihydropyridine
  • Hydrogen Peroxide
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Calcium