Author: Urban, Ernst ; Pifl, Christian ; Singewald, Nicolas ; Kalaba, Predrag ; Dragačević, Vladimir ; Roller, Alexander ; Beyl, Stanislav ; Aher, Nilima Y. ; Hering, Steffen ; Ilić, Marija ; Wieder, Marcus ; Sartori, Simone B. ; Sitte, Harald H. ; Lukic, Natalie ; Khan, Jawad Akbar ; Zehl, Martin ; Gonzalez, Eduardo Rene Perez ; Wackerlig, Judith ; Lubec, Jana ; Neill, Philip ; Beryozkina, Tetyana ; Leban, Johann Jakob ; Bakulev, Vasiliy ; Lubec, Gert ; Langer, Thierry ; Ebner, Karl

Atypical dopamine reuptake inhibitors, such as modafinil, are used for the treatment of sleeping disorders and investigated as potential therapeutics against cocaine addiction and for cognitive enhancement. Our continuous effort to find modafinil analogues with higher inhibitory activity on and selectivity toward the dopamine transporter (DAT) has previously led to the promising thiazole-containing derivatives CE-103, CE-111, CE-123, and CE-125. Here, we describe the synthesis and activity of a series of compounds based on these scaffolds, which resulted in several new selective DAT inhibitors and gave valuable insights into the structure-activity relationships. Introduction of the second chiral center and subsequent chiral separations provided all four stereoisomers, whereby the S-configuration on both generally exerted the highest activity and selectivity on DAT. The representative compound of this series was further characterized by in silico, in vitro, and in vivo studies that have demonstrated both safety and efficacy profile of this compound class.

01 Aug 2017·Behavioural Brain ResearchQ3 · PSYCHOLOGY

A novel heterocyclic compound improves working memory in the radial arm maze and modulates the dopamine receptor D1R in frontal cortex of the Sprague-Dawley rat

Q3 · PSYCHOLOGY

Article

Author: Abdel Baset M.A. Ahmed ; Johann Leban ; Ahmed M. Hussein ; Predrag Kalaba ; Bojana Radoman ; Nilima Y. Aher ; Marija Ilić ; Thierry Langer ; Ernst Urban ; Vladimir Dragačević ; Gert Lubec ; Tetyana Beryozkina ; Yogesh D. Aher

A series of compounds have been shown to enhance cognitive function via the dopaminergic system and indeed the search for more active and less toxic compounds is continuing. It was therefore the aim of the study to synthetise and test a novel heterocyclic compound for cognitive enhancement in a paradigm for working memory. Specific and effective dopamine re-uptake inhibition DAT (IC50=4,1±0,8μM) made us test this compound in a radial arm maze (RAM) in the rat. CE-125 (4-((benzhydrylsulfinyl)methyl)-2-cyclopropylthiazole), was tested for dopamine (DAT), serotonin and norepinephrine re-uptake inhibition by a well-established system. The working memory index (WMI) was evaluated in male Sprague Dawley rats that were intraperitoneally injected with CE-125 (1 or 10mg/kg body weight). In order to evaluate basic neurotoxicity, the open field, elevated plus maze, rota rod studies and the forced swim test were carried out. Frontal cortex was taken at the last day of the RAM test and dopamine receptors D1R and D2R, DAT and phosphorylated DAT protein levels were determined. On the 10th day both doses were increasing the WMI as compared to the vehicle-treated group. In both, trained and treated groups, D1R levels were significantly reduced while D2R levels were unchanged. DAT levels were comparable between all groups while phosphorylated DAT levels were increased in the trained group treated with 1mg/kg body weight. CE-125 as a probably non-neurotoxic compound and specific reuptake inhibitor was shown to increase performance (WMI) and modulation of the dopaminergic system is proposed as a possible mechanism of action.

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Indication	Highest Phase	Country/Location	Organization	Date
Lymphoma	Preclinical	United States	Cello Therapeutics, Inc.	-

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