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.
Subject(s)
Benzhydryl Compounds/pharmacology , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Dopamine Uptake Inhibitors/pharmacology , Heterocyclic Compounds/pharmacology , 1-Methyl-4-phenylpyridinium/metabolism , Animals , Benzhydryl Compounds/chemical synthesis , Binding Sites , Dopamine/metabolism , Dopamine Uptake Inhibitors/chemical synthesis , HEK293 Cells , Heterocyclic Compounds/chemical synthesis , Humans , Male , Modafinil , Molecular Docking Simulation , Molecular Dynamics Simulation , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Rats, Sprague-Dawley , Serotonin and Noradrenaline Reuptake Inhibitors/chemical synthesis , Serotonin and Noradrenaline Reuptake Inhibitors/pharmacology , Structure-Activity Relationship , Sulfoxides/chemical synthesis , Sulfoxides/pharmacology , Thiophenes/chemical synthesis , Thiophenes/pharmacologyABSTRACT
The present paper describes the one-pot procedure for the formation of self-assembled thin films of two silanes on the model oxidized silicon wafer, SiO2/Si. SiO2/Si is a model system for other surfaces, such as glass, quartz, aerosol, and silica gel. MALDI-TOF MS with and without a matrix, XPS, and AFM have confirmed the formation of self-assembled thin films of both 3-imidazolylpropyltrimethoxysilane (3-IPTS) and 4-(N-propyltriethoxysilane-imino)pyridine (4-PTSIP) on the SiO2/Si surface after 30 min. Longer adsorption times lead to the deposition of nonreacted 3-IPTS precursors and the formation of agglomerates on the 3-IPTS monolayer. The formation of 4-PTSIP self-assembled layers on SiO2/Si is also demonstrated. The present results for the flat SiO2/Si surface can lead to a better understanding of the formation of a stationary phase for affinity chromatography as well as transition-metal-supported catalysts on silica and their relationship with surface roughness and ordering. The 3-IPTS and 4-PTSIP modified SiO2/Si wafers can also be envisaged as possible built-on-silicon thin-layer chromatography (TLC) extraction devices for metal determination or N-heterocycle analytes, such as histidine and histamine, with "on-spot" MALDI-TOF MS detection.
