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

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Arce MP, Rodriguez-Franco MI, Gonzalez-Munoz GC, Perez C, Lopez B, Villarroya M, Lopez MG, Garcia AG, Conde S

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.

PubMed ID

19856923 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Tacrine	Acetylcholinesterase	IC 50 (nM)	350	N/A	N/A	Details