A novel heterocyclic compound targeting the dopamine transporter improves performance in the radial arm maze and modulates dopamine receptors D1-D3.
A series of compounds targeting the dopamine transporter (DAT) haS been shown to improve memory performance most probably by re-uptake inhibition. Although specific DAT inhibitors are available, there is limited information about specificity, mechanism and in particular the effect on dopamine receptors. It was therefore the aim of the study to test the DAT inhibitor 4-(diphenyl-methanesulfinylmethyl)-2-methyl-thiazole (code: CE-111), synthetized in our laboratory for the specificity to target DAT, for the effects upon spatial memory and for induced dopamine receptor modulation. Re-uptake inhibition was tested for DAT (IC50=3.2μM), serotonin transporter, SERT (IC50=272291μM) and noradrenaline transporter, NET (IC50=174μM). Spatial memory was studied in the radial arm maze (RAM) in male Sprague-Dawley rats that were intraperitoneally injected with CE-111 (1 or 10mg/kg body weight). Performance in the RAM was improved using 1 and 10mg/kg body weight of CE-111. Training and treatment effects on presynaptic, postsynaptic and extrasynaptic D1 and D2- receptors and dopamine receptor containing complexes as well as on activated DAT were observed. CE-111 was crossing the blood-brain barrier comparable to modafinil and was identified as effective to improve memory performance in the RAM. Dopamine re-uptake inhibition along with modulations in dopamine receptors are proposed as potential underlying mechanisms.
Department of Pediatrics, Medical University of Vienna, 1090 Vienna, Austria; Department of Cell Biology, Duke University School of Medicine, NC 27710, USA.
Sivaprakasam R
SR
Saroja
Department of Pediatrics, Medical University of Vienna, 1090 Vienna, Austria; Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria; Core Unit of Biomedical Research, Division of Laboratory Animal Science and Genetics, Medical University of Vienna, A-2325 Himberg, Austria.
Yogesh D
YD
Aher
Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria.
Predrag
P
Kalaba
Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria.
Nilima Y
NY
Aher
Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria.
Martin
M
Zehl
Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria.
Volker
V
Korz
Department of Pediatrics, Medical University of Vienna, 1090 Vienna, Austria.
Saraswathi
S
Subramaniyan
Department of Pediatrics, Medical University of Vienna, 1090 Vienna, Austria.
Andras G
AG
Miklosi
Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria.
Lisa
L
Zanon
Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria; Department of Anaesthesia and Critical Care, University Hospital Wuerzburg, 97080 Wuerzburg, Germany; Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria.
Winfried
W
Neuhaus
Core Unit of Biomedical Research, Division of Laboratory Animal Science and Genetics, Medical University of Vienna, A-2325 Himberg, Austria.
Harald
H
Höger
Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria.
Thierry
T
Langer
Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria.
Ernst
E
Urban
Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria.
Johann
J
Leban
Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria. Electronic address: gert.lubec@univie.ac.at.
Gert
G
Lubec
D000818:Animals; D001559:Benzhydryl Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D057809:HEK293 Cells; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology*
D001559:Benzhydryl Compounds; C000625578:CE-111; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D006571:Heterocyclic Compounds; D016601:RNA-Binding Proteins; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C482440:Sert1 protein, rat; D013844:Thiazoles; D004298:Dopamine
Dopamine receptor; Dopamine reuptake inhibitor; Extrasynaptic; Hippocampus; Presynaptic; Radial arm maze