Abstract
We have previously reported the multifunctional profile of N-(3-chloro-10H-phenothiazin-10-yl)-3-(dimethylamino)propanamide (1) as an effective neuroprotectant and selective butyrylcholinesterase inhibitor. In this paper, we have developed a series of N-acylaminophenothiazines obtained from our compound library or newly synthesised. At micro- and sub-micromolar concentrations, these compounds selectively inhibited butyrylcholinesterase (BuChE), protected neurons against damage caused by both exogenous and mitochondrial free radicals, showed low toxicity, and could penetrate into the CNS. In addition, N-(3-chloro-10H-phenothiazin-10-yl)-2-(pyrrolidin-1-yl)acetamide (11) modulated the cytosolic calcium concentration and protected human neuroblastoma cells against several toxics, such as calcium overload induced by an L-type Ca2+-channel agonist, tau-hyperphosphorylation induced by okadaic acid and Aβ peptide.
Copyright © 2011 Elsevier Masson SAS. All rights reserved.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Alzheimer Disease / drug therapy*
-
Alzheimer Disease / enzymology
-
Amyloid beta-Peptides / antagonists & inhibitors
-
Amyloid beta-Peptides / toxicity
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology*
-
Butyrylcholinesterase / metabolism
-
Calcium / antagonists & inhibitors
-
Calcium / metabolism
-
Cell Death / drug effects
-
Cell Survival / drug effects
-
Cholinesterase Inhibitors / chemical synthesis
-
Cholinesterase Inhibitors / chemistry
-
Cholinesterase Inhibitors / pharmacology*
-
Dose-Response Relationship, Drug
-
Humans
-
Molecular Structure
-
Okadaic Acid / antagonists & inhibitors
-
Okadaic Acid / toxicity
-
Peptide Fragments / antagonists & inhibitors
-
Peptide Fragments / toxicity
-
Phenothiazines / chemical synthesis
-
Phenothiazines / chemistry
-
Phenothiazines / pharmacology*
-
Stereoisomerism
-
Structure-Activity Relationship
-
Tumor Cells, Cultured
Substances
-
Amyloid beta-Peptides
-
Antineoplastic Agents
-
Cholinesterase Inhibitors
-
Peptide Fragments
-
Phenothiazines
-
amyloid beta-protein (1-42)
-
Okadaic Acid
-
Butyrylcholinesterase
-
Calcium