Abstract
Recent studies on sphingolipids suggest that acid sphingomyelinase (ASM), which plays a central role in the pathogenesis of major depression, is emerging to be a novel target for developing antidepressants. Herein we first described the design, synthesis, and biological evaluation of hydroxamic acid-based direct inhibitors of ASM with the effort of validating their antidepressant effects in vivo. As a result, a series of novel ASM inhibitors were developed using a structure-based approach. Our studies demonstrated that the administration of 21b improved depression-like behaviors of rats. Importantly, this positive result was relevant to the inhibition of ASM and the increasing neurogenesis in hippocampus. To the best of our knowledge, this is the first time that direct inhibitors of ASM were developed to support the possibility of ASM as a potential therapeutic target for depression.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antidepressive Agents / chemical synthesis
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Antidepressive Agents / metabolism
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Antidepressive Agents / therapeutic use*
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Cell Line, Tumor
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Cerebral Cortex / metabolism
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Depression / chemically induced
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Depression / drug therapy*
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Drug Design
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / therapeutic use*
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Female
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Hippocampus / metabolism
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Humans
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Hydroxamic Acids / chemical synthesis
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Hydroxamic Acids / metabolism
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Hydroxamic Acids / therapeutic use*
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Molecular Docking Simulation
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Molecular Structure
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Neurogenesis / drug effects
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Protein Binding
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Rats, Sprague-Dawley
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Reserpine
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Sphingomyelin Phosphodiesterase / antagonists & inhibitors*
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Sphingomyelin Phosphodiesterase / metabolism
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Structure-Activity Relationship
Substances
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Antidepressive Agents
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Enzyme Inhibitors
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Hydroxamic Acids
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Reserpine
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Sphingomyelin Phosphodiesterase