title: A heterocyclic compound CE-103 inhibits dopamine reuptake and modulates dopamine transporter and dopamine D1-D3 containing receptor complexes.
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.
authors.affiliation: Department of Paediatrics, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Ajinkya
authors.initials: A
authors.lastname: Sase
authors.affiliation: Department of Paediatrics, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Yogesh D
authors.initials: YD
authors.lastname: Aher
authors.affiliation: Department of Paediatrics, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Sivaprakasam R
authors.initials: SR
authors.lastname: Saroja
authors.affiliation: Department of Paediatrics, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Minu Karthika
authors.initials: MK
authors.lastname: Ganesan
authors.affiliation: Department of Paediatrics, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Sunetra
authors.initials: S
authors.lastname: Sase
authors.affiliation: Institute of Pharmacology, Centre of Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria.
authors.forename: Marion
authors.initials: M
authors.lastname: Holy
authors.affiliation: Core Unit of Biomedical Research, Division of Laboratory Animal Science and Genetics, Medical University of Vienna, Himberg, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Höger
authors.affiliation: TOSlab, Ural Federal University named after the first President of Russia, B. N. Yeltsin, Mira Str., 28, 620002 Yekaterinburg, Russia.
authors.forename: Vasiliy
authors.initials: V
authors.lastname: Bakulev
authors.affiliation: Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Gerhard F
authors.initials: GF
authors.lastname: Ecker
authors.affiliation: Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Thierry
authors.initials: T
authors.lastname: Langer
authors.affiliation: Institute of Pharmacology, Centre of Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria.
authors.forename: Harald H
authors.initials: HH
authors.lastname: Sitte
authors.affiliation: Department of Paediatrics, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Johann
authors.initials: J
authors.lastname: Leban
authors.affiliation: Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria. Electronic address: gert.lubec@univie.ac.at.
authors.forename: Gert
authors.initials: G
authors.lastname: Lubec
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D008297:Male; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: C000611357:2-((benzhydrylsulfinyl)methyl)thiazole; D001559:Benzhydryl Compounds; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017447:Receptors, Dopamine D1; D050637:Receptors, Dopamine D3; D050486:Serotonin Plasma Membrane Transport Proteins; D013844:Thiazoles
keywords: CE-103; Cognitive enhancer; Dopamine receptors; Dopamine reuptake inhibitor; Radial arm maze; Working memory