Abstract
We report herein the synthesis and biological evaluation of dimethyl-carbamic acid 2,3-bis-dimethylcarbamoyloxy-6-(4-ethyl-piperazine-1-carbonyl)-phenyl ester (SP-04), a new drug candidate that is designed to offer a multi-target therapeutic neuroprotective approach as a treatment for Alzheimer's disease (AD). SP-04 inhibits acetylcholinesterase (AchE) activity both in vitro and in vivo, and induces a dose-dependent increase in Ach levels. SP-04 releases the metabolite 4-(4-ethyl-piperazin-1-yl)-1-(2,3,4-trihydroxy-phenyl)-butan-1-one (SP-04m). Both SP-04 and SP-04m are s1-receptor antagonists supporting their interest in relieving symptoms related to psychosis, a non-cognitive condition often associated with AD. SP-04m displays important antioxidant properties and both SP-04 and SP-04m offers neuroprotection against Ab42 toxicity in various neuronal cell lines. In addition, both SP-04 and SP-04m protect neuronal cells and rat brain mitochondria exposed to various mitochondrial respiratory chain complex toxins. Taken together these data suggest that the SP-04 multi-targeting approach might offer a novel therapeutic strategy for the treatment of AD.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholinesterase
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Alzheimer Disease / drug therapy
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Alzheimer Disease / metabolism
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Amyloid beta-Peptides / metabolism
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Animals
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Antioxidants / chemical synthesis
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Antioxidants / pharmacology
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Brain / drug effects
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Carbamates / chemical synthesis
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Cholinesterase Inhibitors / chemical synthesis*
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Cholinesterase Inhibitors / pharmacology*
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GPI-Linked Proteins / antagonists & inhibitors
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Gallic Acid / analogs & derivatives
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Gallic Acid / chemical synthesis
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HEK293 Cells
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Humans
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Male
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Mitochondria / drug effects
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Neuroprotective Agents / chemical synthesis*
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Neuroprotective Agents / pharmacology*
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PC12 Cells
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Peptide Fragments / metabolism
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Piperazines / chemical synthesis
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Prodrugs / chemical synthesis
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Rats
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Rats, Long-Evans
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Receptors, sigma / antagonists & inhibitors*
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Sigma-1 Receptor
Substances
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4-(4-ethyl-piperazin-1-yl)-1-(2,3,4-trihydroxyphenyl)butan-1-one
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Amyloid beta-Peptides
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Antioxidants
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Carbamates
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Cholinesterase Inhibitors
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GPI-Linked Proteins
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Neuroprotective Agents
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Peptide Fragments
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Piperazines
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Prodrugs
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Receptors, sigma
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amyloid beta-protein (1-42)
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dimethyl-carbamic acid 2,3-bis-dimethylcarbamoyloxy-6-(4-ethylpiperazine-1-carbonyl)phenyl ester
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Gallic Acid
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Acetylcholinesterase
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Ache protein, rat