Description

CE-123 Nootropic Powder

 

CAS Number	1879038-73-9
Other Names	CE123, CE 123
IUPAC Name	(S)-5-(benzhydrylsulfinylmethyl)-1,3-thiazole
Molecular Formula	C₁₇H₁₅NOS₂
Molecular Weight	313.43
Purity	≥99% Pure (LC-MS)
Liquid Availability
Powder Availability
Gel Availability	N/A
Storage	Store cold between 2º – 8º C
Terms	All products are for laboratory developmental research USE ONLY. Products are not for human consumption.

 

What is CE-123?

5-((benzhydrylsulfinyl)methyl) thiazole, commonly referred to as CE-123 is a modafinil analog that has been shown to have enhanced affinity and selectivity for dopamine transporters, allowing for the improvement of cognitive and motivational processes [1]. Modafinil itself belongs to a class of cognitive enhancing nootropic compounds that have a mild psychostimulant effect. That being said, current research focuses on the potential for Modafinil and its analogs, such as CE-123, to treat disorders such as narcolepsy, ADHD, and various other neuropsychiatric conditions related to regulation of dopamine transporters [2].

 

Main Research Findings

1) Data collected during the study supports the hypothesized procognitive effects of the S-enantiomer of CE-123, while also indicating a minor impact on reward-based dopaminergic areas.

2) Administration of CE-123 was found to inhibit hyperactivity and resolve impairments related to the reversal of learning in rats exposed to alcohol, indicating that CE-123 may act as a potential intervention for deficits related to fetal alcohol syndrome.

 

Selected Data

1) The research team of Sagheddu et al conducted various in vivo electrophysiological, neurochemical, and behavioral experiments in adult male rats in order to assess the cognition enhancing abilities of CE-123 and how its mechanism of action relates to the dopaminergic reward based system in the brain. This experiment also focused on the comparison between the S-enantiomer of CE-123 and the R-enantiomer of its parent compound, Modafinil [1].

Male Sprague-Dawley rats with weights ranging from 250-350 grams each were maintained under standard laboratory conditions and provided ad libitum access to food and water until the initiation of the experiment. On the first day of the trial, S-CE-123 and R-modafinil were dissolved in DMSO 4%, TWEEN 80.5%, and a physiological solution of NaCl 0.9% and randomly assigned to the test subjects for treatment. For purposes of electrophysiological experiments, the compounds were intravenously administered in cumulative doses of 1.25 to 10 mg/kg/mL, or the compounds were intraperitoneally injected in doses of 1, 5, or 10 mg/kg in 3 mL for the purpose of ultrasonic vocalization and microdialysis studies [1].

Prior to intravenous administration of the different treatments, rats were anesthetized using 1.3 g/kg or urethane and a cannula was inserted into the femoral vein. The rats were then placed in a stereotaxic apparatus while the extracellular activity of the neurons were recorded with micropipettes containing 2% Pontamine blue dissolved in sodium acetate. Single action potentials were isolated, amplified, and displayed for evaluation with a digital storage oscilloscope while neurons located in layers III-VI in the cortical surface were recorded [1].

That being said, the electrophysiological characteristics of the cells corresponded to pyramidal neurons and were presented as “regular-spiking” or “intrinsically bursting” activity, a firing rate that did not exceed 10 Hz, and an action potential >2 ms wide. Additionally, single unit neuronal activity located in the ventral tegmental area was recorded and putative dopaminergic neurons were isolated and identified based on an observed firing rate of <10 Hz and an action potential of >2.5 ms duration. Bursting was defined by the research team as an occurrence of two spikes at an interspike interval of <80 ms that was terminated when the interspike interval was >160 ms [1].

Performance of brain microdialysis allowed the research team to observe and monitor the extracellular concentration of various endogenous transmitters and how they relate to neurotransmission. Test subjects were anesthetized using a combination of 3 mL/kg chloral hydrate 2.1 g, sodium pentobarbital 0.46 g, MgSO4 1.06 grams, propylene glycol 21.4 mL, ethanol 5.7 mL, and h2O 3 mL, in order for the researcher to properly evaluate extracellular levels of dopamine [1]. Following anaesthetization, microdialysis probes were implanted in the NAc shell or the IL/PrL cortex.

On the first day of the experiment the probes were perfused with Ringer’s solution and dialysate samples were injected into an HPLC equipped with a coulometric detector and reverse-phase column for the purpose of identifying and quantifying dopamine. After basal levels were determined, the test subjects were randomly assigned to receive treatment with S-CE-123, R-modafinil, or a vehicle. Treatment administration was followed by 3 hours of monitoring the animals and observing any changes in extracellular dopamine levels [1]. Additionally, ultrasonic vocalization emissions were recorded from the rats throughout the duration of the microdialysis experiment through the use of ultrasonic microphones connected to a specific recording apparatus. Intensity gain remained consistent during the recordings and emissions were monitored for 3 hours after administration of the assigned treatment.

2) Fetal alcohol spectrum disorder is typically diagnosed in early childhood and characterized by impulsivity, hyperactivity, memory and learning disabilities that are hypothesized to be rooted in the dysfunction of dopaminergic signaling. The research team of Gibula-Tarlowska et al examined the potential of CE-123 to overcome behavioral defects induced by ethanol in an animal model of fetal alcohol spectrum disorder.

163 Wistar rates were used for this study; the test subjects were maintained under standard laboratory conditions and provided ad libitum access to food and water. In order to promote breeding, one male and one female test subject were housed in a cage together for one week; after three weeks monitoring of the female rats began in order to assess for parturition. An equal number of male and female pups from the new litters were retained, however, only male rats were used in the behavioral studies due to their increased vulnerability to fetal and neonatal exposure to ethanol [2].

The S-enantiomer of CE-123 was synthesized in the Lubec laboratory at the University of Vienna, and on the first day of the experiment the compound was dissolved in a solution of 1% DMSO, and 3.3% TWEEN 80 diluted by 0.9% NaCl. CE-123 was administered intraperitoneally in doses of 1, 5, or 10 mg/kg, 30 minutes before the beginning of the behavioral trials. Ethanol was then dissolved in milk solution at a dose of 5 g/kg and given to the animals randomly assigned to the ethanol-exposed treatment group via intragastric intubation. Test subjects not assigned to the ethanol exposed group were assigned to a sham intubated treatment group where no ethanol-milk mixture was provided to the rats [2].

The researchers weighed and examined the rat pups each morning and found that the doses of ethanol produced significant neurotoxicity with the potential for the development of neurobehavioral deficits. All pups were weaned off of milk and randomly assigned to experimental groups for the purpose of completing various behavioral tests such as the locomotor activity test, elevated plus maze test, the Barnes maze task, the probe trial, and reversal learning. The locomotor activity of the rats was measured by placing the rats in transparent, 60 x 60 cm, soundproof rooms with infrared sensors placed at 45 and 100 mm above the floor to assess horizontal activity and distance traveled in meters. 1, 3, and 10 mg/kg doses of CE-123 were administered to the rats 30 minutes before the test to evaluate the effects of ethanol on locomotion [2]. The distance traveled in the horizontal plane was recorded for 30 minutes after the animals were placed in the apparatus.

This behavioral trial was followed by the elevated plus maze (EPM) test performed by placing the rats in the center of a plus-shaped maze with 2 open and 2 closed arms at a height of 50 cm above the floor. The maze apparatus was placed in a quiet, dark room and the rats were handled by the researchers for 5 minutes per day, 3 days before the official trial began. The rats were placed at the center of the EPM facing the open arm while the research team took note of the number of times a rat entered an open arm with all four paws, as well as the amount of time that was spent there over the course of 5 minutes in order to observe anxiety-like behavior in response to ethanol exposure [2].

The next behavioral task was the Barnes maze involving an apparatus formed from a circular gray metal plate that was elevated 100 cm above the floor with 20 holes located in its periphery, each with a diameter of 10 cm. All holes except for one were covered, which led to an escape box made of the same material as the platform apparatus. The open hole was not apparent until the animal was placed right next to it; the researchers placed several visual cues along the walls of the maze in order to assist in evoking the escape response in the test subjects. There are four main phases to the Barnes maze task starting with habituation, where the subjects were allowed to acclimate to the platform and the escape box the day before the acquisition phase began.

The acquisition phase occurred 24 hours after the rats were habituated to the maze. This phase involved one training session per day for five consecutive days, consisting of two 180 second trials and a 5 minute inter-trial interval. Each trial began by placing the rat in the center of the platform and letting it explore for 180 seconds or until it found the escape platform. The hole was then covered for 30 seconds and animals were guided back to their home cages. The following phase included a probe trial to evaluate spatial memory. This phase began 24 hours after the acquisition phase and included the subjects receiving a 180 second probe trial while the primary errors and latency to reach the escape box were recorded by the researchers [2]. In terms of changes elicited in learning processes and spatial memory due to ethanol exposure, a probe trial was carried out after 5 days of learning took place.

The final stage of the Barnes maze test was reversal learning. The reversal learning trials were identical to acquisition trials and took place 24 hours after the probe trial. The position of the escape hole was rotated 180 degrees and the rats were allowed to learn the new location of the hole for 3 days before the trial occurred. Before the first reversal learning trial, the test subjects were randomly assigned to four treatment groups including a vehicle group, 10 mg/kg of CE-123 + vehicle group, ethanol group + vehicle, and ethanol group + 10 mg/kg of CE-123. The treatments were administered once daily, 30 minutes prior to the reversal learning sessions; data obtained from the trials were combined and used to determine primary latency and errors, as well as the effects of CE-123 on cognitive flexibility following exposure to ethanol [2].

 

Discussion

1) When evaluating the electrophysiological effects of S-CE-123 and R-modafinil on pyramidal neurons recorded in the IL/PrL cortex of test subjects the research team of Sagheddu et al found that intravenous administration of doses ranging from 1.25-10 mg/kg of S-CE-123 resulted in a dose dependent decrease in cell firing rate. This was compared to treatment with R-modafinil that did not produce any remarkable effect on the firing rate of the involved neurons. Similar findings were reported for the test subjects administered a vehicle as well [1].

 

Figure 1: Effects of treatment with S-CE-123 and R-modafinil on electrical activity of pyramidal cells from A) rats that received intravenous injection of the vehicle, S-CE-123, or R-modafinil; and B) dose-dependent changes in the the firing rate in response to treatment with the vehicle, S-CE-123, or R-modafinil

Next, when assessing the effects of S-CE-123 and R-modafinil on the firing activity of dopaminergic neurons in the ventral tegmental area, it was found that neither S-CE-123 or R-modafinil elicited significant changes in the firing frequency of neurons in this region. The same findings were noted when interpreting the results gathered from the control group of subjects that were administered a vehicle compound [1].

Figure 2: Effects of treatment with S-CE-123 and R-modafinil on dopaminergic neurons in the ventral tegmental area in A) rats that received intravenous injection of the vehicle, S-CE-123, or R-modafinil; B) changes in the the firing rate in response to treatment with the vehicle, S-CE-123, or R-modafinil; and C) changes in the burst firing activity in response to treatment with the vehicle, S-CE-123, or R-modafinil.

Furthermore, extracellular levels of dopamine in the IL/PrL cortex were studied to determine the effects of doses of 1, 5, and 10 mg/kg of S-CE-123 or R-modafinil. Analysis with three-way ANOVA reveals significant interactions between treatment and time of injection as well as dose and time of injection and treatment, dose, and time of injection. A Tukey’s post hoc analysis found a marked increase in dialysate dopamine only 40 minutes after treatment with 10 mg/kg of S-CE-123 or 10 mg/kg of R-modafinil was administered [1]. These findings were in comparison to base values, the control group administered a vehicle, and the experimental group administered a 1 mg/kg dose of S-CE-123.

Tukey’s post hoc analysis also highlighted a significant increase in dopamine levels measured at 100, 120, and 160 minutes after administration of 10 mg/kg of R-modafinil. These findings were in comparison to the base values, dopamine levels of the control group 100 and 160 minutes after administration of a vehicle compound, and dopamine levels of the experimental group 80, 100, 120, and 160 minutes after administration of a 1 mg/kg dose of R-modafinil. Additionally, notable differences were seen at 160 and 180 minutes after administration of 5 mg/kg of R-modafinil in comparison to base values, test subjects treated with a vehicle, and the differences seen in the animals at 160 minutes after administrations of 10 mg/kg S-CE-123 or 10 mg/kg of R-modafinil [1].

Figure 3: Effects of a vehicle, S-CE-123, and R-modafinil administered in doses of 1, 5, and 10 mg/kg on dopamine levels in relationship to base levels.

Finally, the effects of S-CE-123 and R-modafinil administered in doses of 1, 5, and 10 mg/kg on the emission of 50-kHz ultrasonic vocalizations acting as a drug-induced reward as well as a behavioral marker of positive affect. Administration of all doses of S-CE-123 did not result in an increase in the number of ultrasonic vocalizations emitted in comparison to the vehicle control group. Two-way ANOVA statistical analysis did not indicate a significant interaction effect between treatment and time, however, there was a significant effect of time that was noted by the research team. Similar results were observed with acute administration of R-modafinil as there was no significant increase in ultrasonic vocalization emitted, nor was there a significant effect of treatment, time, or an interaction between treatment and time [1].

Figure 4: Effects of treatment with a vehicle, S-CE-123, and R-modafinil on the emission of 50-kHz ultrasonic vocalizations.

2) When assessing the influence of CE-123 on locomotor activity following ethanol exposure, two-way ANOVA statistical analysis reported a significant difference between the four different experimental treatment groups. In addition to two-way ANOVA, a Bonferroni post-hoc test suggested the exposure to ethanol significantly increased locomotor activity, however, CE-123 administered in doses of 3 or 10 mg/kg had the potential to inhibit this abnormally increased level of locomotor activity. However, the data obtained and analyzed through a Student’s t-test revealed no significant difference between the treatment groups and the number of entries or amount of time they spent with all four paws within the plus shaped apparatus [2].

Figure 5: Changes in locomotor activity in rats exposed to ethanol.

The research team also used the Barnes maze task to observe the effects of CE-123 on reversal learning as it’s related to primary latency and number of errors. In regards to primary latency, mixed effect models were fitted to the dataset assigning animal number as a random effect and concentration of CE-123, presence of ethanol, and day of treatment were defined as fixed effects. Results reported that there was a significant difference between the ethanol and vehicle groups and the time it took for the subjects in each group to reach the target hole.

Overall, the administration of ethanol was found to increase latency in test subjects, proving that ethanol results in memory impairment. When ethanol or CE-123 was administered there were no remarkable changes in the learning slope, however, there was a drastic change in latency as a function of CE-123 when ethanol is administered. These findings allowed the researchers to conclude that CE-123 elicits its effects after administration of ethanol, and the compound is capable of eliciting effects quickly and consistently across treatment days [2].

Figure 6: Changes in primary latency during A) the acquisition phase and C) the probe trial, in response to ethanol exposure

When looking at the number of errors that occurred as the test subjects attempted to find the escape platform, mixed effect models were fitted to an entire datasheet and assigned animal number as a random effect and the concentration of CE-123, ethanol exposure, and treatment day were defined as fixed effects. The results reported that there was a slight difference between rats exposed to ethanol versus exposure to a vehicle, however, the difference was not deemed significant to the research team. However, it is important to note that the researchers were able to observe an overall decrease of 1.58 errors, suggesting the ability of the animals to learn over time. Similar to the primary latency findings, the learning slope demonstrated no significant changes across the experimental groups [2]. However, the amount of errors was found to significantly lower in a dose-dependent manner when CE-123 was administered in cases of ethanol exposure.

Figure 7: Changes in the number of errors during A) the acquisition phase and C) the probe trial, in response to ethanol exposure

 

Disclaimer

**LAB USE ONLY**
*This information is for educational purposes only and does not constitute medical advice. THE PRODUCTS DESCRIBED HEREIN ARE FOR RESEARCH USE ONLY. All clinical research must be conducted with oversight from the appropriate Institutional Review Board (IRB). All preclinical research must be conducted with oversight from the appropriate Institutional Animal Care and Use Committee (IACUC) following the guidelines of the Animal Welfare Act (AWA).

 

Citations

[1] Sagheddu C, Pintori N, Kalaba P, Dragačević V, Piras G, Lubec J, Simola N, De Luca MA, Lubec G, Pistis M. Neurophysiological and Neurochemical Effects of the Putative Cognitive Enhancer (S)-CE-123 on Mesocorticolimbic Dopamine System. Biomolecules. 2020 May 18;10(5):779. doi: 10.3390/biom10050779. PMID: 32443397; PMCID: PMC7277835.

[2] Gibula-Tarlowska E, Korz V, Lopatynska-Mazurek M, Chlopas-Konowalek A, Grochecki P, Kalaba P, Dragacevic V, Kotlinski R, Kujawski R, Szulc M, Czora-Poczwardowska K, Mikolajczak PL, Lubec G, Kotlinska JH. CE-123, a novel dopamine transporter inhibitor, attenuates locomotor hyperactivity and improves cognitive functions in rat model of fetal alcohol spectrum disorders. Behav Brain Res. 2021 Jul 23;410:113326. doi: 10.1016/j.bbr.2021.113326. Epub 2021 Apr 30. PMID: 33940050.

 

CE-123 is sold for laboratory research use only. Terms of sale apply. Not for human consumption, nor medical, veterinary, or household uses. Please familiarize yourself with our Terms & Conditions prior to ordering.

 

 

 

 

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