Abstract
Modafinil is a wake promoting compound with high potential for cognitive enhancement. It is targeting the dopamine transporter (DAT) with moderate selectivity, thereby leading to reuptake inhibition and increased dopamine levels in the synaptic cleft. A series of modafinil analogues have been reported so far, but more target-specific analogues remain to be discovered. It was the aim of this study to synthesize and characterize such analogues and, indeed, a series of compounds were showing higher activities on the DAT and a higher selectivity toward DAT versus serotonin and norepinephrine transporters than modafinil. This was achieved by substituting the amide moiety by five- and six-membered aromatic heterocycles. In vitro studies indicated binding to the cocaine pocket on DAT, although molecular dynamics revealed binding different from that of cocaine. Moreover, no release of dopamine was observed, ruling out amphetamine-like effects. The absence of neurotoxicity of a representative analogue may encourage further preclinical studies of the above-mentioned compounds.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Methyl-4-phenylpyridinium / metabolism
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Animals
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Benzhydryl Compounds / chemical synthesis
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Benzhydryl Compounds / pharmacology*
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Binding Sites
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Dopamine / metabolism
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Dopamine Plasma Membrane Transport Proteins / antagonists & inhibitors*
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Dopamine Uptake Inhibitors / chemical synthesis
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Dopamine Uptake Inhibitors / pharmacology*
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HEK293 Cells
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Heterocyclic Compounds / chemical synthesis
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Heterocyclic Compounds / pharmacology*
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Humans
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Male
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Modafinil
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Molecular Docking Simulation
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Molecular Dynamics Simulation
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Norepinephrine Plasma Membrane Transport Proteins / antagonists & inhibitors
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Rats, Sprague-Dawley
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Serotonin and Noradrenaline Reuptake Inhibitors / chemical synthesis
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Serotonin and Noradrenaline Reuptake Inhibitors / pharmacology
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Structure-Activity Relationship
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Sulfoxides / chemical synthesis
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Sulfoxides / pharmacology
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Thiophenes / chemical synthesis
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Thiophenes / pharmacology
Substances
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2-((benzhydrylsulfinyl)methyl)thiophene
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Benzhydryl Compounds
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Dopamine Plasma Membrane Transport Proteins
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Dopamine Uptake Inhibitors
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Heterocyclic Compounds
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Norepinephrine Plasma Membrane Transport Proteins
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SLC6A2 protein, human
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Serotonin and Noradrenaline Reuptake Inhibitors
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Sulfoxides
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Thiophenes
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Modafinil
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1-Methyl-4-phenylpyridinium
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Dopamine