Description

TAK-653 Nootropic Powder

 

 

 

CAS Number	1358751-06-0
Other Names	9E3Toe5riz, 9E3TOE5RIZ, UNII-9E3TOE5RIZ, SCHEMBL622985, CHEMBL4594403, PXJBHEHFVQVDDS-UHFFFAOYSA-N, EX-A6607
IUPAC Name	9-(4-cyclohexyloxyphenyl)-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide
Molecular Formula	C₁₉H₂₃N₃O₃S
Molecular Weight	373.47
Purity	≥99% Pure (LC-MS)
Liquid Availability	30mL liquid (5mg/mL, 150mg bottle)
Powder Availablity	500 milligrams, 1 gram
Gel Availablity	N/A
Storage	Store in cool dry environment, away from direct sunlight.
Terms	All products are for laboratory developmental research USE ONLY. Products are not for human consumption.

 

What is TAK-653?

TAK-653 is a novel receptor of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Activation of AMPA receptors has been found to stimulate the signaling of mTOR and BDNF in the brain to elicit anti-depressive effects and improve various aspects of neurological and cognitive functioning. Previous research regarding the compound has found that when compared to other AMPA receptor agonists and N-methyl-D-aspartate (NMDA) receptor antagonists, TAK-653 elicits benefits with a lower occurrence of adverse effects, indicating that it has the potential to act as an effective treatment for both depressive disorders and cognitive deficits [1].

 

Main Research Findings

1) TAK-653 improves cognitive functioning and synaptic responses through the strict regulation and activation of AMPA receptors.

2) TAK-653 was found to increase corticospinal excitability, assessed by transcranial magnetic stimulation in both rats and humans.

 

Selected Data

1) The research team of Suzuki et al assessed the pharmacological characteristics of the AMPA receptor TAK-653 in order to better understand the ability of the compound to improve synaptic connections and cognitive functioning. For the purpose of this study several different animals were utilized, including ICR and C57BL/6 J mice, Sprague-Dawley and Long-Evans rats, and male cynomolgus monkeys. All animals were maintained under standard laboratory conditions in a light-controlled room and allowed to habituate for 1 week prior to experimentation.

The first behavioral test performed was the novel object recognition test using 6 week old male Long-Evans rats. On the first day of the experiment the rats individually habituated to the empty testing apparatus for 10 minutes and randomly assigned to an experimental treatment group. The initial acquisition trial occurred on day 2 where the rats were allowed to explore two identical objects denoted A1 and A2, for 3 minutes. 48 hours later the retention trial took place where the rats were allowed to explore a familiar object, A3, and a novel object, denoted as B, for 3 minutes. TAK-653 was administered orally and AMPA was administered intraperitoneally, either 2 hours or 0.5 hours prior to both the acquisition and retention trials [2].

The radial arm maze test was carried out using 9-week-old male Long-Evans rats. The maze apparatus was 10 cm wide, 40 cm high, and elevated 50 cm above the floor. Throughout the experimental period the rats had their food restricted to 85% of their free-feeding body weight and were trained to collect food pellets from the arms of the maze apparatus. The testing sessions began by placing each rat in the maze apparatus facing the fixed arm in order for the research team to record the entry of the rats into the different arms until all pellets were consumed or 5 minutes had passed. The test subjects were administered either TAK-653, LY451646, or AMPA 1.5 hours, 1 hour, or immediately prior to the delivery of a vehicle compound or MK-801. 30 minutes after the vehicle was administered the rats were placed on the maze for testing and recording to take place [2].

4-6 year old male cynomolgus monkeys weighing 4-6 kg were used to perform delayed match-to-sample tasks using a Cambridge Neuropsychological Test Automated Battery system. The researchers mentioned that throughout the experiment the animals were maintained at 80% of their free-feeding body weight. DMTS tasks were followed by the induction of maternal immune activation. The procedures included administering pregnant female C57BL/6J mice with 5 mg/kg of poly-I:C dissolved in sterile 0.9% NaCl solution on gestation day 15. The compound was administered intravenously through the tail vein in a volume of 5 ml/kg [2].

The social approach and avoidance test included a three-chamber apparatus and was conducted using C57BL/6J mice. The apparatus included clear dividing walls and transparent cylinders placed in the outer chambers to avoid direct physical contact between a target animal and test animal. The target animals were defined as mice of the same age as the test animals without having any previous contact with them. One hour prior to testing, TAK-653 or a vehicle compound was administered perorally in a 0.3 mg/kg dose. Each test animal was placed in the middle chamber of the apparatus and allowed to habituate for 3 minutes with all clear partitions closed [2]. This was followed by the gradual removal of all partitions and allowing the animals to explore freely for 5 minutes while the research team calculated the sniffing index as a measure of sociability.

2) The research team of O’Donnell et al assessed the effects of TAK-653 on neurostimulation measured through the use of transcranial magnetic stimulation (TMS). For the purpose of this study, 20 adult male Sprague-Dawley rats were maintained under standard laboratory conditions with ad libitum access to food and water. The nootropic was prepared by dissolving doses of the compound in a formulation of 0.5% methylcellulose in double distilled water. Treatments were administered perorally via oral gavage in 10 ml/kg doses. 2 hours later brain specimens and intracardiac-blood plasma samples were collected for further examination [3].

spTMS was performed in 31 rats treated with TAK-653 to test whether the nootropic increases corticospinal excitability. The researchers mentioned that they chose to utilize MMG rather than needle EMG in order to avoid the use of heavy anesthetic and excessive pain responses that may affect motor-evoked potential responses. Changes in MMG amplitude were measured by attaching accelerometers to the rats’ hind paws. Prior to anesthetization the rats were administered either a vehicle or TAK-653 in doses ranging from 0.1, 0.3, 1, 8, or 50 mg/kg [3].

Following intraperitoneal administration of pentobarbital in 30 minute intervals to maintain stable anesthesia, the rats were placed on a platform and restrained with velcro straps to ensure proper placement of the accelerometers. spTMS was then delivered through a figure-eight coil centered over the midsagittal plane in order to reliably reproduce bilateral hindlimb activation. This procedure occurred 75-135 minutes after administration of the nootropic compound in 10 minute intervals; at each interval, 10 single pulses at 80% of the maximum machine output were applied [3]. MMG signals were converted to voltage values and vector amplitudes, and animals with a >6/10 MMG signals from at least one hind paw were used for further analysis.

The second portion of the study considered a randomized, double blind, placebo controlled, three-period crossover phase, and an open-label ketamine period. Healthy males and females of non-childbearing potential ranging from 18-55 years old were selected to participate during the study; during the crossover period the test subjects were assigned to one of three groups and administered an oral placebo, 0.5 mg of TAK-653, or 6 mg of TAK-653. Prior to treatment with the nootropic, physical examinations, urine drug screening, urinalysis, ECG, vital signs, and safety chemistry and hematology assessments were performed. TMG-EMG measurements were collected 40 minutes before dosing, 30 minutes after dosing, and 2.5 hours after dosing at the expected half-life of the nootropic. 6 hours after the dose of TAK-653 was given all participants were discharged.

In addition to the performance of safety assessments, each participant completed a TMS safety question and were excluded if there were significant contradictions present. Other exclusion criteria for this portion of the study included a resting motor threshold higher than 75% of the maximum stimulator output, a DSM-5 diagnosis of a clinically significant psychiatric disorder, or a history of alcohol consumption that exceeded the average standard of two drinks per day. Additionally, participants were not allowed to use concomitant medications or consume alcohol for 7 days before initiation of the trial; participants were not allowed to drink caffeine for 24 hour before screening and after each dose, but were allowed up to six servings of caffeine each day between treatment periods; and finally, participants were not allowed to smoke cigarettes 24 hours before each dose, but were allowed to smoke 5 cigarettes per day between treatment periods [3].

Blood samples were collected from the test subjects prior to treatment, 30 minutes after dosing, and 2.5 hours after dosing in order to measure plasma concentrations of TAK-653. Concentrations of the nootropic were assessed using validated high-performance liquid chromatography with tandem mass spectrometry assay. Next, transcranial magnetic stimulation was performed using a MagPro R30 with MagOption stimulator. The motor cortex of the dominant hemisphere was stimulated to elicit a motor response; throughout the process participants were instructed not to move their heads and keep their eyes open.

MEPs were measured by placing two Ag/AgCl electrodes in the musculotendinous junction of the abductor digiti minimi muscle. Single pulses starting at 40% MSO were used to manually stimulate the region and when no MEP was present the intensity was increased by 5% until the motor hotspot was identified. After the research team found the hotspot the stimulation increased by 1% until at least 5 out every 10 TMS pulses elicited an MEP with a peak-to-peak amplitude of at least 50 uV. spTMS consisting of 50 single pulses at 120% of baseline rMT was performed in the morning of each treatment period with randomized intervals between 3.5 and 4.5 seconds. The protocol was followed by 50 pairs of randomized pulses with inter-stimulus intervals of 2, 5, 50, 100, 200, and 300 ms. MEPs within 20-45 ms post-spTMS intervals were highlighted and analyzed post hoc by the research team, and peak-to-peak EMG amplitudes over 50 repetitions were averaged [3].

 

Discussion

1) As it was previously mentioned, the research team of Suzuki et al used the novel object recognition task in order to assess visual learning and memory in rats. Peroral administration of TAK-653 at doses of 0.03, 0.1, and 0.3 mg/kg were shown to significantly improved NDI scores. These findings suggested that the nootropic may have the potential to enhance visual learning and memory in doses greater than 0.03 mg/kg. Comparatively, when the rats were perorally treated with LY451646 at doses greater than 1 mg/kg visual learning and memory improved, however, the compound induced seizures when delivered in doses of 10 and 30 mg/kg. Similar findings were reported when the animals were given AMPA; 30 mg/kg doses administered intraperitoneally induced seizures while 10 mg/kg doses resulted in abnormal behavior like head turning. Administration of lower doses of AMPA did not result in any improvements in visual learning or memory [2].

Figure 1: Changes in the NDI assessed through the novel object recognition task in response to A) 0.01 mg/kg, 0.03 mg/kg, 0.1 mg/kg, and 0.3 mg/kg of TAK-653 administered perorally, in comparison to B) 0.3 mg/kg, 1 mg/kg, and 3 mg/kg of AMPA administered intraperitoneally.

The radial arm maze task was performed to evaluate the effects of TAK-653 on working memory in rats with a MK-801 induced memory deficit. MK-801 disrupted memory performance in trained rats when administered subcutaneously in doses of 0.08 mg/kg. TAK-654 delivered perorally in doses of 0.1 0.3, 3, and 10 mg/kg were all found to significantly reduce the induced deficits. These findings suggest that treatment with the nootropic enhances working memory in the presence of a broad range of hypoglutamatergic conditions. It is important to mention that the researchers also evaluated the effectiveness of AMPA receptor potentiator, PF-04958242. In rat hippocampal cells, this potentiator was shown to produce an increase in calcium in the absence of AMPA. In a manner similar to LY451646, doses of the compound greater than or equal to 0.1 mg/kg improved visual learning and memory measured by the novel object recognition test, however, working memory evaluated by the radial arm maze task remained unchanged [2].

Figure 2: Changes in the mean number of errors calculated during the radial arm maze task in response C) 0.1 mg/kg, 0.3 mg/kg, 3 mg/kg, and 10 mg/kg of TAK-653 administered perorally; in comparison to D) 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, and 1 mg/kg of LY451646 administered perorally; and E) 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, and 3 mg/kg of AMPA administered intraperitoneally, following a 0.08 mg/kg dose of MK-801 to induce memory deficits.

Changes in working memory induced by administration of TAK-653 was also assessed in monkeys through the delayed match-to-sample paradigm. While fasted, the monkeys were perorally administered 0.06 mg/kg of the nootropic. TAK-653 was found to increase delayed match-to-sample accuracy at a 16 second delay interval. In order to ensure the results were not attributable to a training effect, the monkeys were tested 48 hours later to find that the improvement in accuracy returned to baseline levels after 24 hours. These findings suggest that TAK-653 may have the potential to improve working memory in monkeys at concentrations similar to those observed in rats with both improved visual learning, working memory and recognition memory [2].

Figure 3: Changes in DMTS accuracy over 48 hours defined by the percent of trials correct in response to treatment with TAK-653 administered perorally in a dose of 0.06 mg/kg.

Next, the 5-choice serial reaction time task was performed to evaluate the effects of TAK-653 on attention in rats. The researchers determined that the poor performing animals could be included in a model of ADHD, thus resulting in sub-population analyses that included splitting the population into high and poor performing animals. When perorally administered 2 hours prior to the initiation of the trials, TAK-653 in a dose of 0.3 mg/kg did not elicit significant improvements in attention throughout the entire population. That being said, when looking specifically at the sub-population of poorly performing rats, the nootropic increased the number of correct responses and decreased the number of omissions, indicating that TAK-653 may enhance attention. Similarly, the social approach-avoidance test was conducted to assess the effects of TAK-63 on sociability deficits in the poly-I:C mouse, used as an animal model of schizophrenia. Social activity was measured by the sniffing index which was shown to significantly improve after peroral administration of a 0.3 mg/kg dose of TAK-653 [2].

Figure 4: Changes in sniffing index in response to a 0.3 mg/kg peroral dose of TAK-653 in poly I:C mice.

2) When evaluating the data collected from the first portion of the study, the research team of O’Donnell et al found that there was a significant improvement in corticospinal excitability in rats treated with 0.3 mg/kg doses, or higher, of TAK-653. In the satellite animals utilized, the lowest effective dose of the nootropic resulted in a concentration 5.32 ng/ml of TAK-653 in the plasma samples; 1 mg/kg of TAK-653 yielded 49.9 ng/ml in plasma samples, 8 mg/kg of TAK-653 yielded 298.2 ng/ml in plasma samples, and 50 mg/kg of TAK-653 yielded 391 ng/ml in plasma samples [3].

Figure 5: Changes in TAK-653 concentrations in the brain and plasma levels in response to administration of 0.3 mg/kg, 1 mg/kg, 8 mg/kg, or 50 mg/kg doses of TAK-653.

Additionally, brain concentrations of TAK-653 were 3.53 ng/g when a 0.3 mg/kg dose of the nootropic was administered; 1 mg/kg of TAK-653 yielded brain concentrations of 36.5 ng/g, 8 mg/kg of TAK-653 yielded brain concentrations of 210.6 ng/g, and 50 mg/kg of TAK-653 yielded brain concentrations of 264.2 ng/g. Repeated-measures ANOVA reported the significant effects of dose and time, as well as an interaction effect between time and dose, however, the research team was not able to observe a dose-response effect. That being said, the results of the study found that effective doses of TAK-653 resulted in MMG amplitudes that measured 30-70% higher than vehicle-treated animals [3].

Figure 6: Changes in MMG amplitude following oral administration of a vehicle (black), or TAK-653 in doses of 0.1 mg/kg (orange), 0.3 mg/kg (green), 1 mg/kg (blue), 8 mg/kg (purple), and 50 mg/kg (white).

In regards to the second portion of the study, plasma levels of TAK-653 at 30 minutes post-dose were measured at 0.99 ng/ml and at 2.5 hours post-dose were measured at 4.19 ng/ml for the experimental group treated with 0.5 mg of the nootropic. For the group treated with 6 mg/kg of TAK-653, plasma levels of the nootropic at 30 minutes and 2.5 hours post-dose were measured at 2.57 ng/ml and 45.99 ng/ml, respectively. It is important to mention that TAK-653 treatment was overall well tolerated by the participants with no report of any serious adverse events.

When observing peak-to-peak MEP amplitude, there were no statistically significant changes observed between the placebo group and both the 0.5 mg/kg and 6 mg/kg TAK-653 experimental groups at the 30 minute post-dose mark. However, there was a significant increase in the MEP amplitudes when comparing the placebo group and the 6 mg/kg TAK-653 experimental group at 2.5 hours post-dose. Additionally, there were no significant changes from baseline rMT levels between either TAK-653 experimental group or the placebo group [3].

Figure 7: Changes in MEP amplitude from baseline in response to treatment with a placebo (red), 0.5 mg/kg of TAK-653 (green), or 6.0 mg/kg of TAK-653 (blue).

Figure 8: Changes in rMT levels from baseline in response to treatment with a placebo (red), 0.5 mg/kg of TAK-653 (green), or 6.0 mg/kg of TAK-653 (blue).

 

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] Hara H, Suzuki A, Kunugi A, Tajima Y, Yamada R, Kimura H. TAK-653, an AMPA receptor potentiator with minimal agonistic activity, produces an antidepressant-like effect with a favorable safety profile in rats. Pharmacol Biochem Behav. 2021 Dec;211:173289. doi: 10.1016/j.pbb.2021.173289. Epub 2021 Oct 14. PMID: 34655652.

[2] Suzuki A, Kunugi A, Tajima Y, Suzuki N, Suzuki M, Toyofuku M, Kuno H, Sogabe S, Kosugi Y, Awasaki Y, Kaku T, Kimura H. Strictly regulated agonist-dependent activation of AMPA-R is the key characteristic of TAK-653 for robust synaptic responses and cognitive improvement. Sci Rep. 2021 Jul 15;11(1):14532. doi: 10.1038/s41598-021-93888-0. Erratum in: Sci Rep. 2021 Jul 21;11(1):15255. doi: 10.1038/s41598-021-94772-7. PMID: 34267258; PMCID: PMC8282797.

[3] Jannati A, Ryan MA, Kaye HL, Tsuboyama M, Rotenberg A. Biomarkers Obtained by Transcranial Magnetic Stimulation in Neurodevelopmental Disorders. J Clin Neurophysiol. 2022 Feb 1;39(2):135-148. doi: 10.1097/WNP.0000000000000784. PMID: 34366399; PMCID: PMC8810902.

 

TAK-653 is an AMPA receptor positive allosteric modulator that has shown promise in treating major depressive disorder and treatment-resistant depression in rodents. Researchers have long associated mood disorders with the effects of AMPA receptors and related compounds such as the neurotransmitters glutamate and brain derived neurotrophic factor (BDNF). Presently, ketamine, an antagonist to NMDA receptors, is being examined for its potent antidepressive effects. Studies have found that treatment with ketamine leads to a stimulatory effect on AMPA receptors. This results in increased levels of glutamate in the brain as well as the mechanistic target of rapamycin mTOR signaling. Glutamate is associated with the pathology of mood disorders and how they are related to synaptic plasticity and the secretion of BDNF. As ketamine stimulates the mechanisms of AMPA receptors, researchers hypothesize that they are potentially related to the treatment of depression (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9509332/).

While ketamine is capable of treating depression on its own, there are often psychotomimetic and dissociative side effects reported while this drug is being used for treatment. Research has found that the AMPA receptor antagonist, NBQX, blocks the majority of the antidepressive effects of ketamine. The effects of ketamine were also reduced depending on rates of BDNF secretion and mTOR signaling. AMPA receptor activators have been found to elicit quick and potent antidepressive effects, however they are not without limitations. That being said, researchers examined how the AMPA receptor potentiator TAK-653 is capable of effectively treating depression with almost no additional agonistic activity.

Researchers Hara et. Al conducted a study examining the antidepressant behavioral effects of TAK-653 in the rat reduction of submissive behavior model (RSBM) Additionally, the psychotomimetic side effects of TAK-653 were compared to those of ketamine. The experimentation period began with an initial evaluation of the rats in order to determine which of the test subjects would be considered dominant and which were submissive. The dominant rats would be receiving a dose of the vehicle while submissive ones would be receiving 30 mg/kg dose of ketamine. The same methods of evaluating dominance were used when determining the rats that would receive the active dose of TAK-653. Submissive rats were given varying doses of TAK-653 while the dominant animals received a vehicle.

The rats were administered the doses of TAK-653 approximately 2 hours before the test period. On each day the rats received the treatment and were subjected to 5 minutes of behavioral testing, followed by 1 hour of free access to food. Results of this study found that TAK-653 is capable of activating mTOR signaling and producing BDNF in a dose-dependent manner. The study also concluded that while antidepressant effects were seen when treating the rats with ketamine, the compound had a higher tendency to be blocked by antagonists like NBQX, and elicit abnormal behaviors such as hyperlocomotion. These findings allowed researchers to conclude that TAK-653 treats major depressive disorder and treatment-resistant depression more efficiently than ketamine due to the absence of side effects in subjects treated with TAK-653 (https://www.sciencedirect.com/science/article/pii/S009130572100188X).

AMPA Receptor Modulation

Further studies regarding the efficacy of TAK-653 evaluate how the compound modulates the activity of AMPA receptors by observing cortical excitability. Researchers O’Donnell et. Al used transcranial magnetic stimulation (TMS)-induced motor responses to identify these biomarkers as well as the various pharmacodynamic and pharmacokinetic qualities of TAK-653.

The study included 31 adult Sprague Dawley rats and each subject received doses varying from 0.3 to 50 mg/kg of TAK-653. TMS testing took place 75-135 minutes after TAK-653 administration, and at each time point 10 pulses at 80% power were applied to the subjects. Plasma and brain specimens were collected approximately 2-3 hours after TAK-653 administration. Results of the study found that all doses of TAK-653 increased the rate of cortical excitability at a greater degree than the vehicle. However, the most effective dose was 50 mg/kg which resulted in 264.2 ±81.9 ng/g of TAK-653 in the plasma.

Overall, the researchers were able to conclude that using noninvasive stimulation in the brain can lead to accurate identification and generation of neurocircuitry biomarkers, as well as modulate the resulting effects of AMPA receptor activity. As it was previously mentioned AMPA receptors are shown to regulate variables such as glutamate activity, mTOR signaling, and BDNF expression. That being said, this study primarily focused on glutamate activity and through the use of TMS, researchers were granted further insight on glutamate receptor-mediated effects and glutamate synaptic activity in relation to TAK-653 (https://www.nature.com/articles/s41398-021-01451-2).

The nootropics sold by Umbrella Labs are sold for laboratory research only. The description above is not medical advice and is for informative purposes only.

TAK-653 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.

 

A Novel Contender In The Fight Against Treatment-Resistant Depression

 

 

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