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

Authors/others:Sase, Ajinkya (Medizinische Universität Wien); Aher, Yogesh D; Saroja, Sivaprakasam R (Medizinische Universität Wien); Ganesan, Minu Karthika (Medizinische Universität Wien); Sase, Sunetra (Medizinische Universität Wien); Holy, Marion (Medizinische Universität Wien); Höger, Harald; Bakulev, Vasiliy (Ural Federal University); Ecker, Gerhard F; Langer, Thierry; Sitte, Harald H; Leban, Johann (Medizinische Universität Wien); Lubec, Gert

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.

Number of pages:11
Date of publication:3.2016
Journal title:Neuropharmacology
Peer reviewed:true
Digital Object Identifier (DOI):http://dx.doi.org/10.1016/j.neuropharm.2015.07.039
Bibliographical note:Copyright © 2015. Published by Elsevier Ltd.
Publication Type:Article