Neuroprotective and cholinergic properties of multifunctional glutamic acid derivatives for the treatment of Alzheimer's disease

J Med Chem. 2009 Nov 26;52(22):7249-57. doi: 10.1021/jm900628z.

Abstract

Novel multifunctional compounds have been designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer's disease (AD). With an L-glutamic moiety as a suitable biocompatible linker, three pharmacophoric groups were joined: (1) an N-benzylpiperidine fragment selected to inhibit acetylcholinesterase by interacting with the catalytic active site (CAS), (2) an N-protecting group of the amino acid, capable of interacting with the acetylcholinesterase (AChE)-peripheral anionic site (PAS) and protecting neurons against oxidative stress, and (3) a lipophilic alkyl ester that would facilitate penetration into the central nervous system by crossing the blood-brain barrier. At submicromolar concentration, they inhibit AChE and butyrylcholinesterase (BuChE) of human origin, displace the binding of propidium iodide from the PAS of AChE, and could thus inhibit Abeta aggregation promoted by AChE. They also display neuroprotective properties against mitochondrial free radicals, show low toxicity, and could be able to penetrate into the CNS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / enzymology
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Blood-Brain Barrier / metabolism
  • Catalytic Domain
  • Cattle
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cholinergic Agents / chemistry
  • Cholinergic Agents / metabolism
  • Cholinergic Agents / pharmacology*
  • Cholinergic Agents / therapeutic use
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / metabolism
  • Cholinesterase Inhibitors / pharmacology
  • Cholinesterase Inhibitors / therapeutic use
  • Esters / chemistry
  • Glutamic Acid / analogs & derivatives*
  • Glutamic Acid / metabolism
  • Glutamic Acid / pharmacology*
  • Glutamic Acid / therapeutic use
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Permeability
  • Piperidines / chemistry
  • Protein Binding / drug effects

Substances

  • Amyloid beta-Peptides
  • Cholinergic Agents
  • Cholinesterase Inhibitors
  • Esters
  • Neuroprotective Agents
  • Piperidines
  • Glutamic Acid
  • piperidine
  • Acetylcholinesterase