Abstract
Atypical dopamine reuptake inhibitors, such as modafinil, are used for the treatment of sleeping disorders and investigated as potential therapeutics against cocaine addiction and for cognitive enhancement. Our continuous effort to find modafinil analogues with higher inhibitory activity on and selectivity toward the dopamine transporter (DAT) has previously led to the promising thiazole-containing derivatives CE-103, CE-111, CE-123, and CE-125. Here, we describe the synthesis and activity of a series of compounds based on these scaffolds, which resulted in several new selective DAT inhibitors and gave valuable insights into the structure-activity relationships. Introduction of the second chiral center and subsequent chiral separations provided all four stereoisomers, whereby the S-configuration on both generally exerted the highest activity and selectivity on DAT. The representative compound of this series was further characterized by in silico, in vitro, and in vivo studies that have demonstrated both safety and efficacy profile of this compound class.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Dopamine Plasma Membrane Transport Proteins / antagonists & inhibitors*
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Dopamine Plasma Membrane Transport Proteins / metabolism
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Dopamine Uptake Inhibitors / chemical synthesis
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Dopamine Uptake Inhibitors / metabolism
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Dopamine Uptake Inhibitors / pharmacokinetics
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Dopamine Uptake Inhibitors / pharmacology*
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HEK293 Cells
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Humans
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Male
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Modafinil / analogs & derivatives*
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Modafinil / metabolism
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Modafinil / pharmacokinetics
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Modafinil / pharmacology*
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Molecular Docking Simulation
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Molecular Structure
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Norepinephrine Plasma Membrane Transport Proteins / antagonists & inhibitors
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Protein Binding
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Rats, Sprague-Dawley
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Serotonin Plasma Membrane Transport Proteins / metabolism
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Serotonin and Noradrenaline Reuptake Inhibitors / chemical synthesis
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Serotonin and Noradrenaline Reuptake Inhibitors / metabolism
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Serotonin and Noradrenaline Reuptake Inhibitors / pharmacokinetics
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Serotonin and Noradrenaline Reuptake Inhibitors / pharmacology*
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Stereoisomerism
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Structure-Activity Relationship
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Thiazoles / chemical synthesis
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Thiazoles / metabolism
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Thiazoles / pharmacokinetics
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Thiazoles / pharmacology*
Substances
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Dopamine Plasma Membrane Transport Proteins
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Dopamine Uptake Inhibitors
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Norepinephrine Plasma Membrane Transport Proteins
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Serotonin Plasma Membrane Transport Proteins
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Serotonin and Noradrenaline Reuptake Inhibitors
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Thiazoles
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Modafinil