Identification, design, synthesis, and pharmacological activity of (4-ethyl-piperazin-1-yl)-phenylmethanone derivatives with neuroprotective properties against beta-amyloid-induced toxicity.
In search of novel therapeutic approaches for Alzheimer's disease (AD), we report herein the identification, design, synthesis, and pharmacological activity of (4-ethyl-piperaz-1-yl)-phenylmethanone derivatives with neuroprotective properties against beta-amyloid-induced toxicity. (4-ethyl-piperaz-1-yl)-phenylmethanone is a common substructure shared by molecules isolated from plants of the Asteraceae genus, traditionally used as restorative of lost or declining mental functions. (4-Ethyl-piperaz-1-yl)-phenylmethanone displayed strong neuroprotective properties against Abeta1-42 and reversed Abeta1-42-induced ATP depletion on neuronal cells, suggesting a mitochondrial site of action. Abeta1-42 has been described to induce a hyperactivity of the glutamate network in neuronal cells. (4-Ethyl-piperaz-1-yl)-phenylmethanone also inhibited the neurotoxic effect that glutamate displayed on PC12 cells, suggesting that the reduction of glutamate-induced neurotoxicity may be one of the mechanisms by which this compound exerts its neuroprotective properties against the deleterious effects of the Abeta1-42. These data suggest that the identified (4-ethyl-piperaz-1-yl)-phenylmethanone chemical entity exerts neuroprotective properties and may serve as a lead compound for the development of novel therapies for AD.
Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20057, USA.
Laurent
L
Lecanu
Wenguo
W
Yao
Alexander
A
Piechot
Janet
J
Greeson
Dimitrios
D
Tzalis
Vassilios
V
Papadopoulos
D000255:Adenosine Triphosphate / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002855:Chromatography, Thin Layer / Q000379:methods; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005609:Free Radicals / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000633:toxicity; D048789:Phytoestrogens / Q000138:chemical synthesis* / Q000494:pharmacology*; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology; D028321:Plant Preparations; D051381:Rats; D013778:Tetrazolium Salts; D013844:Thiazoles
C505413:4-ethyl-1-(2,3,4-trimethoxybenzoyl)piperazine; D016229:Amyloid beta-Peptides; D005609:Free Radicals; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D048789:Phytoestrogens; D010879:Piperazines; D028321:Plant Preparations; D013778:Tetrazolium Salts; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); D016291:Dizocilpine Maleate; D000255:Adenosine Triphosphate; C022616:thiazolyl blue