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Neuropharmacology. 2016 Mar;102:186-96. doi: 10.1016/j.neuropharm.2015.07.039. Epub 2015 Sep 25.

A heterocyclic compound CE-103 inhibits dopamine reuptake and modulates dopamine transporter and dopamine D1-D3 containing receptor complexes.

Author information

1
Department of Paediatrics, Medical University of Vienna, 1090 Vienna, Austria.
2
Institute of Pharmacology, Centre of Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria.
3
Core Unit of Biomedical Research, Division of Laboratory Animal Science and Genetics, Medical University of Vienna, Himberg, Austria.
4
TOSlab, Ural Federal University named after the first President of Russia, B. N. Yeltsin, Mira Str., 28, 620002 Yekaterinburg, Russia.
5
Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria.
6
Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria. Electronic address: gert.lubec@univie.ac.at.

Abstract

A series of compounds have been reported to enhance memory via the DA system and herein a heterocyclic compound was tested for working memory (WM) enhancement. 2-((benzhydrylsulfinyl)methyl)thiazole (CE-103) was synthesized in a six-step synthesis. Binding of CE-103 to the dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporters and dopamine reuptake inhibition was tested as well as blood brain permeation and a screen for GPCR targets. 60 male Sprague Dawley rats were divided into six groups: CE-103 treated 1-10 mg/kg body weight, trained (TDI) and yoked (YDI) and vehicle treated, trained (TVI) and yoked (YVI) rats. Daily single intraperitoneal injections for a period of 10 days were administered and rats were tested in a radial arm maze (RAM). Hippocampi were taken 6 h following the last day of training and complexes containing the unphosphorylated or phosphorylated dopamine transporter (DAT) and complexes containing the D1-3 dopamine receptor subunits were determined. CE-103 was binding to the DAT but insignificantly to SERT or NET and dopamine reuptake was blocked specifically (IC50 = 14.73 μM). From day eight the compound was decreasing WM errors in the RAM significantly at both doses tested as compared to the vehicle controls. In the trained CE-103-treated group levels of the complex containing the phosphorylated dopamine transporter (pDAT) as well as D1R were decreased while levels of complexes containing D2R and D3R were significantly increased. CE-103 was shown to enhance spatial WM and DA reuptake inhibition with subsequent modulation of D1-3 receptors is proposed as a possible mechanism of action.

KEYWORDS:

CE-103; Cognitive enhancer; Dopamine receptors; Dopamine reuptake inhibitor; Radial arm maze; Working memory

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