CE-123, a novel dopamine transporter inhibitor, attenuates locomotor hyperactivity and improves cognitive functions in rat model of fetal alcohol spectrum disorders

Gibuła‐Tarłowska, Ewa; Korz, Volker; Łopatyńska-Mazurek, Małgorzata; Chlopas-Konowalek, Agnieszka; Grochecki, Paweł; Kalaba, Predrag; Dragačević, Vladimir; Kotlinski, Robert; Kujawski, Radosław; Szulc, Michał; Czora-Poczwardowska, Kamila; Mikołajczak, Przemysław Ł.; Lübec, Gert; Kotlińska, Jolanta

doi:10.1016/j.bbr.2021.113326

Cited by 11 publications

(18 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, increase in locomotor activity is restricted to adolescence because it was not observed in the adult (PND61) rats in our study (Table 1). This finding supports previous evidence [32][33][34] that hyperactivity is characteristic mostly for children with FASD [35] and becomes subtler when they become older.…”

Section: Rapamycin Prevents Ethanol-induced Fear Learning and Memory Impairmentssupporting

confidence: 92%

Aversive Learning Deficits and Depressive-Like Behaviors Are Accompanied by an Increase in Oxidative Stress in a Rat Model of Fetal Alcohol Spectrum Disorders: The Protective Effect of Rapamycin

Łopatyńska-Mazurek

Komsta

Gibuła‐Tarłowska

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

Fetal alcohol spectrum disorders (FASDs) are one of the most common consequences of ethanol exposure during pregnancy. In adulthood, these disorders can be manifested by learning and memory deficits and depressive-like behavior. Ethanol-induced oxidative stress may be one of the factors that induces FASD development. The mammalian target of the Rapamycin (mTOR) signaling pathway that acts via two distinct multiprotein complexes, mTORC1 and mTORC2, can affect oxidative stress. We investigated whether mTOR-dependent or mTOR-independent mechanisms are engaged in this phenomenon. Thus, Rapamycin—a selective inhibitor of mTORC1, Torin-2—a non-selective mTORC1/mTORC2 inhibitor, and FK-506—a drug that impacts oxidative stress in an mTOR-independent manner were used. Behavioral tests were performed in adult (PND60-65) rats using a passive avoidance (PA) task (aversive learning and memory) and forced swimming test (FST) (depressive-like behaviors). In addition, the biochemical parameters of oxidative stress, such as lipid peroxidation (LPO), as well as apurinic/apyrimidinic (AP)-sites were determined in the hippocampus and prefrontal cortex in adult (PND65) rats. The rat FASD model was induced by intragastric ethanol (5 g/kg/day) administration at postnatal day (PND)4–9 (an equivalent to the third trimester of human pregnancy). All substances (3 mg/kg) were given 30 min before ethanol. Our results show that neonatal ethanol exposure leads to deficits in context-dependent fear learning and depressive-like behavior in adult rats that were associated with increased oxidative stress parameters in the hippocampus and prefrontal cortex. Because these effects were completely reversed by Rapamycin, an mTORC1 inhibitor, this outcome suggests its usefulness as a preventive therapy in disorders connected with prenatal ethanol exposure.

show abstract

Section: Rapamycin Prevents Ethanol-induced Fear Learning and Memory Impairmentssupporting

confidence: 92%

Aversive Learning Deficits and Depressive-Like Behaviors Are Accompanied by an Increase in Oxidative Stress in a Rat Model of Fetal Alcohol Spectrum Disorders: The Protective Effect of Rapamycin

Łopatyńska-Mazurek

Komsta

Gibuła‐Tarłowska

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Somewhat similar working memory decline is also observed in adult zebrafish with reduced DAT expression following a dopamine D1/D5 receptor agonist SKF-38393 treatment at young ages (Cleal et al, 2021a). Natural rise of zebrafish locomotion in the habituation test was reduced by GBR 12909 at all doses used here (Supplemental Table S1), paralleling similar effects of a relatively novel DAT inhibitor, CE-123, thus attenuating an alcohol-induced hyperactivity in rats (Gibula-Tarlowska et al, 2021). Furthermore, so-called locomotor habituation analyses are often included in the neurobehavioral studies (Brenes et al, 2009;Spielewoy et al, 2000), especially related to the open field tasks, highly relevant to short-term spatial cognition (Typlt et al, 2013;Willi et al, 2012).…”

Section: Discussionsupporting

confidence: 68%

Behavioral profile of adult zebrafish acutely exposed to a selective dopamine uptake inhibitor, GBR 12909

et al. 2023

View full text Add to dashboard Cite

Background: The dopamine transporter (DAT) is the main regulator of dopamine concentration in the extrasynaptic space. The pharmacological inhibition of the DAT results in a wide spectrum of behavioral manifestations, which have been identified so far in a limited number of species, mostly in rodents. Aim: Here, we used another well-recognized model organism, the zebrafish ( Danio rerio), to explore the behavioral effects of GBR 12909, a highly-affine selective DAT blocker. Methods: We evaluated zebrafish locomotion, novelty-related exploration, spatial cognition, and social phenotypes in the novel tank, habituation and shoaling tests, following acute 20-min water immersion in GBR 12909. Results: Our findings show hypolocomotion, anxiety-like state, and impaired spatial cognition in fish acutely treated with GBR 12909. This behavioral profile generally parallels that of the DAT knockout rodents and zebrafish, and it overlaps with behavioral effects of other DAT-inhibiting drugs of abuse, such as cocaine and D-amphetamine. Conclusion: Collectively, our data support the utility of zebrafish in translational studies on DAT targeting neuropharmacology and strongly implicate DAT aberration as an important mechanisms involved in neurological and psychiatric diseases.

show abstract

“…The blended batch was washed with cyclohexane/toluene 10/1 (10 mL per g of product) five additional times. 1040 g of the blended product (7) characterized upon batch delivery as reported earlier (please refer to the Supporting Information).…”

Section: ■ Conclusionmentioning

confidence: 99%

“…The enantioselectivity of asymmetric syntheses of the final compound (7) batch was assessed via an HPLC system (Diacel Inc., Tokyo, Japan) using a Chiralpack IA analytical column (4.6 × 250 mm 2 , 5 μm) with the column oven temperature set to 25 °C. HPLC-grade ethyl acetate at 1 mL/ min flow rate was used as the mobile phase, and the running time was set to 20 min.…”

Section: ■ Conclusionmentioning

confidence: 99%

See 1 more Smart Citation

Process Development and Scale-Up of a Novel Atypical DAT Inhibitor (S)-CE-123

Perez Gonzalez,

Reck,

Kalaba

et al. 2024

ACS Omega

Self Cite

View full text Add to dashboard Cite

Large-scale syntheses of small molecules and kilo laboratories are crucial steps in drug development, especially in advanced stages. (S)-5-((Benzhydrylsulfinyl)methyl)thiazole, (S)-CE-123, a potent, selective, and novel atypical DAT inhibitor, has undergone iterative testing as part of the preclinical evaluation step. This required the process transfer, scale-up, and synthesis of a 1 kg preclinical batch. The Kagan protocol for asymmetric sulfide to sulfoxide oxidation was successfully applied within a four-step synthetic process for the successful upscaling of (S)-CE-123. During the scale-up of the last step, several changes were made to the original synthetic procedure, as with every increase in batch size, new problems had to be overcome. These include, among others, the workup optimization of the last step, the simplification of chromatographic purification, elution modification to improve the purity of the product and saving of workup time. Two washing steps were added to the original procedure to enhance both the yield and the enantiomeric excess value of the final product. The modifications introduced allowed access to a 1 kg (S)-CE-123 batch with a purity >99% and an enantiomeric excess value of 95%.

show abstract

CE-123, a novel dopamine transporter inhibitor, attenuates locomotor hyperactivity and improves cognitive functions in rat model of fetal alcohol spectrum disorders

Cited by 11 publications

References 85 publications

Aversive Learning Deficits and Depressive-Like Behaviors Are Accompanied by an Increase in Oxidative Stress in a Rat Model of Fetal Alcohol Spectrum Disorders: The Protective Effect of Rapamycin

Aversive Learning Deficits and Depressive-Like Behaviors Are Accompanied by an Increase in Oxidative Stress in a Rat Model of Fetal Alcohol Spectrum Disorders: The Protective Effect of Rapamycin

Behavioral profile of adult zebrafish acutely exposed to a selective dopamine uptake inhibitor, GBR 12909

Process Development and Scale-Up of a Novel Atypical DAT Inhibitor (S)-CE-123

Contact Info

Product

Resources

About