IDRA-21 POWDER (1 GRAM)

Description

IDRA-21 Nootropic Powder

 

 

 

CAS Number	22503-72-6
Other Names	IDRA 21, 22503-72-6, 7-Chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide, 689UW7PT68, (+)-IDRA-21, (-)-IDRA-21, Biomol-NT_000225, D0S0VZ
IUPAC Name	7-chloro-3-methyl-3,4-dihydro-2H-1λ6,2,4-benzothiadiazine 1,1-dioxide
Molecular Formula	C₈H₉ClN₂O₂S
Molecular Weight	232.69
Purity	≥99% Pure (LC-MS)
Liquid Availability	30mL liquid (10mg/mL, 300mg bottle)
Powder Availability	1 gram
Gel Availability	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 IDRA 21?

7-chloro-3-methyl-3-4-dihydro-2H-1,2,4 benzothiadiazine S,S-dioxide (IDRA 21) is a nootropic compound that acts a allosteric modulator of glutamate AMPA receptors. Nootropic agents have shown potential in enhancing cognition through inhibition of the desensitization rate of AMPA receptors. That being said, IDRA 21 relies on the release of endogenous glutamate in order to strengthen glutaminergic synapses. Current research regarding the nootropic shows that the compound has the ability to reverse pretreatment amnesic effects, enhance delayed learning, and attenuate induced learning deficits. [1]

 

Main Research Findings

1) The findings of the study support the use of AMPA modulators such as IDRA 21 in cases of impaired memory or cognitive functioning.

2) The study revealed that IDRA 21 has the potential to reduce pharmacologically induced cognitive impairments.

 

Selected Data

1) The research team of Buccafusco et al examine the ability of IDRA 21 to inhibit the glutamate-induced inactivation of membrane currents in human embryonic kidney (HEK) cells, in a concentration dependent manner. The electrophysiological studies began by stably transfecting recombinant HEK 293 cells with human GLuR ½ flip receptors group in DMEM and 10% fetal calf serum.

The intracellular medium used in this portion of the study consisted of NaCL 15 mM, tetraethylammonium-Cl 20 mM, CsF 110 mM, 1, 2-bis-(2-aminophenoxy)-ethane-tetra-acetic acid (BAPTA) 11 mM, MgCl2 2 mM, CaCl2 1 mM, 1,4 (2-hydroxyethyl)-piperazine-1-ethanesulfonic acid (EHPES) 10 mM, and ATP 1 mM, at pH 7.2. On the other hand the extracellular medium used consisted of NaCL 140 mM, KCl 5.3 mM, CaCl2 1.8 mM, MgCl2 0.8 mM, Glucose 21.5 mM, 1, 4-(2-hydroxyethyl)-piperazine-1-ethanesulfonic acid (HEPES) 10 mM, at pH 7.4. Additionally, both glutamate and IDRA 21 were applied using a piezo-driven flow pipe system, however, the nootropic was pre-applied for 30-60 seconds in the absence of glutamate in order to achieve steady state effects on agonist responses [1].

This study also included an animal model of fourteen rhesus monkeys that were administered IDRA 21 and continuously assessed through the delayed matching-to-sample task (DMTS). The nootropic was administered to the monkeys by having the researchers weigh out the appropriate amount each day to the closest 0.1 mg. The weighed out nootropic was then mixed in 20 mL of a fruit punch flavored primate drink and either an active dose or a vehicle was hand delivered through a syringe, 1 hour prior to the DMTS testing. While the animals underwent the DMTS testing every weekday, there was 5 days between each treatment administration of IDRA 21 or a vehicle [1].

The monkeys were given unlimited access to tap water and were maintained on standard laboratory monkey chow, supplemented with various fruits and vegetables. The feeding schedule allowed for approximately 15% of the daily food intake to be derived from 300 mg of reinforcement food pellets. It was also noted by the researchers that each test subject had previously participated in one or more reversible pharmacological drug study and were permitted a 4 week washout period before IDRA 21 was administered [1].

The animals were tested in their individual home cages using a computer automated training and test system meant to measure and categorize delays and response latency at each matching problem. Each daily session included 96 trials; the trial began when one of three colored discs was illuminated and was pressed by a trained monkey. A similar action terminated the illumination of the sample key during a delay interval. After the delay interval two test keys, not a sample key, were illuminated. One of the two keys was the same color as the sample key and the goal was for the monkey to choose the disc that was the same color as the sample key. If they were able to match then the test subject was rewarded for their correct response [1].

Each trial was split by a 5 second interval and the research team took note to mention several precautions incorporated into the study including: the various combinations of stimulus color, how many times each color and each color combination appeared, the counterbalance between left and right and the colors that were shown, and the stimulus-counterbalancing procedures and how they were matched to the length of the interval delay. That being said, the stimulus colors (red, yellow, and green) were arranged so that each color appeared an equal number of times as a sample and each color appeared an equal number of times as the choice keys. Additionally, when two colors appeared in combination the researchers changed their left/right positioning to a non-predictable pattern. [1]

The daily trials each monkey underwent was presented using three different but fixed sequences of randomized delay intervals and choice colors that were rotated on a daily basis. This procedure reduced the chance that the animals would memorize the first several trials in a session. On an individual level, monkeys have the capability to maintain matching performance following various retention times; the longest delay chosen for a monkey allowed for consistent correct matching above chance level. The length of the delay interval was adjusted for each monkey until various difficulty levels of performance were identified. These levels included: 1) the least difficult zero delay; 2) a short delay interval; 3) a medium delay interval; and 4) a long delay interval representing each monkey’s limit in terms of their performance during DMTS testing [1].

The percent correct on trials with zero, short, medium, and long delay intervals and three different task latencies were recorded for all 96 trials each day. The three task latencies were recorded and included: 1) sample latencies, defined to the time interval between presentation of the sample key and the test subject pressing the sample key to initiate the trial; 2) choice latencies during the trials answered correctly, defined as the time interval between the presentation of the choice stimuli and the test subject pressing the choice key; and 3) choice latencies during the trials answered incorrectly. Raw data was analyzed by use of multi-factorial repeated measures ANOVA, while a Least Squares Means orthogonal multi-comparison t-test was used to compare individual means collected from the animals during DMTS testing [1].

2) The research team of Thompson et al examined the effects of IDRA 21 on cognitive impairments pharmacologically induced in patas monkeys. For the purpose of this study, two female and two male patas monkeys acted as test subjects. Each subject had experience with the behavioral procedures used, and had previous exposure to reversible experimental drugs. That being said the subjects were drug free for at least 2 weeks prior to the start of the study. Water was continuously available to all of the test subjects and the animals were maintained at approximately 90% of their free-feeding weight through a diet of banana-flavored food pellets, monkey chow, and various fruit and vitamin supplementation [2].

The monkeys were treated with both Alprazolam and IDRA 21. Alprazolam was administered orally, twice a week in doses ranging from 0.01 to 0.32 mg/kg. The oral solution was prepared by suspending the compound in a 5% solution of 2-hydroxypropyl-beta-cyclodextrin, mixed with 15 mL of fruit punch that the subject drank every Tuesday and Friday. The monkeys were then pretreated with a racemic mixture of IDRA 21 in doses ranging from 0.3 to 5.6 mg/kg. The nootropic was suspended in Tween80 and given to the subjects in the same manner as alprazolam. Each treatment was tested alone and in combination with each other with exposure to IDRA 21 lasting for 120 minutes and alprazolam exposure lasting for 60 minutes. Additionally, 1 to 30 mg/kg of aniracetam was administered to the subjects for direct comparison to IDRA 21. Each subject was housed in a standard, primate specific individual cage that was equipped with response panels to track activity during the behavioral testing. The acquisition component of the test began with the projection of one of four geometric forms onto a red background on three different response keys [2].

The goal of the test was for the animal to learn a four-response chain by pressing the correct key in the presence of each form. The forms include: a horizontal line, left correct, triangle, right correct, vertical line, center correct, circle, and right correct. Once the four-response chain was completed the lights turned off and a pilot lamp near the pellet dispenser was illuminated. The chain was reset once the pilot light was pressed and a fixed-ratio was set in place that scheduled food presentation after every fifth completion of the chain and pressing of the pilot lamp in order to maintain the four-response chain. In comparison, when one of the test subjects pressed an incorrect key there was a 5-second time out where the keys were dark and all responses were ineffective. That being said, an error did not reset the chain and the stimulus remained the same as before the 5-second time out. During the acquisition phase, the four-response chains were changed from session to session and each chain was selected to be equal in several ways.

During the performance component of the behavioral test, the four geometric forms were projected onto a green background while the left-center-left-right pattern of four-response chain remained the same across sessions. In all other aspects, the procedures of the performance component of the behavioral test were identical to those of the acquisition component of the behavioral test. Sessions were conducted on a daily basis. Each trial started with an acquisition period following the procedures outlined above, followed by a performance component. The subjects were advanced to the performance component after 10 food production reinforcements or after 15 minutes. Each session was terminated after 2 hours or after 60 reinforcements for females and 100 reinforcements for males were achieved [2].

 

Discussion

1) The results of the electrophysiological portion of the study observed changes in the glutamate-mediated membrane currents in response to administration of IDRA21. Typically when 1mM of glutamate is applied to cells expressing GLuR ½ flip receptors the currents rapidly inactivate. However, when IDRA 21 was applied the time constant of inactivation was shown to increase as the concentration of the nootropic increased. The total charge transfer within the first 50 ms of glutamate application was used as a comparative measure for the observed effects of IDRA 21. The charge transfer was found to double at concentrations of 70 uM, indicating that application of the nootropic has the potential to facilitate excitatory neurotransmission via GluR ½ flip receptors [1].

Figure 1: (A) Changes in the membrane current induced by glutamate in cells expressing recombinant human GluR ½ flip receptors. (B) The effects of IDRA 21 on the inactivation of the glutamate response. Inactivation times increased in a concentration-dependent manner. (C) Changes in total charge transfer in response to application of IDRA 21 during the first 50 ms of glutamate application.

In terms of the behavioral studies conducted in rhesus monkeys, the results were categorized in young subjects and aged subjects. IDRA 21 was administered to young subjects in a dosing sequence starting at 0.3 mg/kg, continued by 1.0, 3.0, 6.0, 0.15, and 10.0 mg/kg. The animals underwent testing at 1, 24, and 48 hours after drug administration; no vehicle or nootropic was given to the test subjects prior to testing during the 24 and 48 hours trial sessions. Statistical analysis revealed that there was a significant relationship between drug dose and day of testing, represented by a biphasic improvement in task accuracies. These results were seen in the medium and long delay interval sessions with a low point in the relationship observed with the middle doses of IDRA 21.

For the trials that took place 1 hour after administration of IDRA 21, there was a statistically significant relationship between the overall effect of drug treatment and performance during the trial. Post hoc analysis revealed that the treatment doses of 0.15 mg/kg, 0.3 mg/kg, and 6 mg/kg elicited the most remarkable changes in comparison to the animals treated with a vehicle. Additionally, for the trials that took place 24 hours after administration of IDRA 21, the doses that resulted in the most significant differences compared to treatment with a vehicle were 0.15 mg/kg, 0.3 mg/kg, 6 mg/kg, and 10 mg/kg. Finally, for the trials that took place 48 hours after administration of the nootropic, the doses that resulted in the most significant differences compared to treatment with a vehicle were 0.15 mg/kg, 3 mg/kg, and 10 mg/kg. These findings allowed the research team to conclude that administration of IDRA 21 improves task accuracy in young monkeys at a sustained level for at least 48 hours following administration [1].

Figure 2: The effects of IDRA 21 administered in doses of 0.15, 0.3, 1.0, 3.0, 6.0, and 10 mg/kg on task accuracy at time intervals of 1 hour, 24 hours, and 48 hours after nootropic administration in young monkeys completing the DMTS test.

In terms of the aged subjects, each animal was more than two years older than the young group of test subjects. Age-associated task impairment was also taken into account with the older group and the duration of the delay intervals was reduced to almost half of that of the younger group. The research team also thought it was important to note that the young group consisted of all male monkeys while the aged group included 4 male monkeys and 3 female monkeys. The role of sex was not taken into account during this study, however, none of the females were reported to be in estrous and there were no obvious sex-related effects noticed during their task performance.

Similar to the younger group of monkeys, IDRA 21 was administered to the aged subjects in a dosing sequence of 0.3, 1.0, 30.0, 6.0, 0.15, and 10.0 mg/kg, followed by testing at 1 hour, 24 hours, and 48 hours post-nootropic administration. There was no drug or vehicle delivered to the animals prior to the 24 and 48 hour testing sessions. Statistical analysis of the results revealed that there was a significant effect between the drug dose dependent on the delay interval. There was also a noticeable pattern of improved task accuracies during the trials associated with medium and long delay intervals. The researchers compared back to the younger group of subjects and mentioned that there was a similar biphasic nature to the dose relationships in the older subjects, however it was not as apparent in this group [1].

For the trials performed 1 hour after IDRA 21 was administered there was a trend towards an effect of the nootropic treatment that was independent of dosage and delay interval. Further analysis revealed that these effects were most significantly associated with the 0.15 mg/kg and the 10 mg/kg dose. Additionally, for the trials performed 24 hours after IDRA 21 was administered, there was a significant effect of the nootropic treatment associated with the 1 mg/kg and 10 mg/kg doses. Finally, for the trials performed 48 hours after IDRA 21 was administered, there were no significant effects elicited by the nootropic. The research team marked this as a noticeable difference between the younger and the aged groups of test subjects [1].

Figure 3: The effects of IDRA 21 administered in doses of 0.15, 0.3, 1.0, 3.0, 6.0, and 10 mg/kg on task accuracy at time intervals of 1 hour, 24 hours, and 48 hours after nootropic administration in aged monkeys completing the DMTS test.

2) The results of the study conducted by Thompson et al initially found that there were individual differences in the control response rates in both the acquisition and performance components of the behavioral testing. When alprazolam was administered in doses of 0.32 mg/kg for females and 0.1 mg.kg for male, the response rates were overall decreased in both components, however, the reduction was more noticeable in the acquisition period. Pretreatment with IDRA 21 was found to counteract the error-increasing effects of alprazolam in a dose-dependent manner in both the acquisition and performance components of the behavioral testing. The lowest dose of IDRA 21 that was shown to affect the rate-decreasing effects of alprazolam was either 0.3 mg/kg or 1 mg/kg depending on whether the subject was male or female [2].

While pretreatment with IDRA 21 reduced the error-increasing effects of alprazolam, administration of the nootropic alone did not result in any significant changes in the measure rate in either component of the behavioral test. This was similar to aniracetam, the parent compound of IDRA 21, that did not elicit any changes in rate or accuracy when administered by itself. Also similar to IDRA 21, aniracetam was found to counteract the rate-decreasing effects of alprazolam in a dose-dependent manner. However, it is important to mention that aniracetam was found to be approximately 10 times less potent than IDRA 21. The attenuation of rate-decreasing with a 30 mg/kg dose of aniracetam was equivalent to that seen with IDRA 21 in 3 mg/kg doses [2].

Figure 4: The effects of IDRA 21 in combination with alprazolam on accuracy and error in both the acquisition and performance components of the behavioral test that was conducted.

Figure 5: The effects of aniracetam in combination with alprazolam on accuracy and error in both the acquisition and performance components of the behavioral test that was conducted.

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] Buccafusco, Jerry J., Thomas Weiser, Karin Winter, Klaus Klinder and Alvin V. Terry. “The effects of IDRA 21, a positive modulator of the AMPA receptor, on delayed matching performance by young and aged rhesus monkeys.” Neuropharmacology 46 (2004): 10-22.

[2] Thompson DM, Guidotti A, DiBella M, Costa E. 7-Chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide (IDRA 21), a congener of aniracetam, potently abates pharmacologically induced cognitive impairments in patas monkeys. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7667-71. doi: 10.1073/pnas.92.17.7667. PMID: 7644474; PMCID: PMC41206.

 

 

IDRA-21 is a nootropic compound derived from the chemical structure of benzothiadiazine. Due to its mechanism of action, IDRA-21 is categorized as a member of the ampakine family as the compound primarily works as a positive allosteric modulator of ionotropic glutamate AMPA receptors. AMPA receptors tend to immediately regulate glutamate levels following activation and are widely known for their ability to promote synaptic transmission and plasticity. That being said, IDRA-21 has shown potential in improving cognition and learning while reducing cognitive degeneration typically associated with aging.

As a member of the ampakine family, IDRA-21 is closely related to the compound Aniracetam. Aniracetam is a nootropic that has shown promise in supporting memory formation and retention, mood, and focus. Various animal-based studies have examined how IDRA-21 is capable of reversing cognitive deficits in comparison to Aniracetam. These studies begin by inducing cognitive decline through administration of alprazolam or scopolamine. Subjects, typically rodents, are then treated with either Aniracetam or IDRA-21. Results found that IDRA-21 is not only 10-30 times more potent than Aniracetam, but also stays active for approximately 48 hours.

Effects of IDRA-21 on Memory and Performance

Additional benefits of IDRA-21 are associated with the work of the AMPA receptors that regulate glutamate levels. Cognition and learning tends to be improved through the increase of glutamate levels, leading to the promotion of long term potentiation and synaptic connections throughout the brain. A notable study tested how laboratory rats performed in a water maze following administration of IDRA-21. Results found that the rats receiving IDRA-21 performed far better by exiting the maze faster than those receiving a placebo drug (https://www.linkedin.com/pulse/idra-21-powder-dosage-half-life-benefits-side-effects-wise-powder/).

Another important study conducted by Buccafusco et. Al examined how administering IDRA-21 to both young and old rhesus monkeys affected performance levels. Results of the study were measured by observing the monkeys’ performance of a delayed matching-to-sample (DMTS) test. Doses of IDRA-21 varying from 0.15-10 mg/kg were administered to the test subjects who were then tested at different points of time over a 48 hour testing period. In young monkeys, the most improvement seen in the experimental group was a 34% increase in performance compared to the placebo group. Additional fixed doses given were separated by 3 days in order to see if the compound had a cumulative effect on the monkeys. Researchers observed that over the course of 3 weeks, performance levels gradually increased in the monkeys receiving intermittent doses of the compound.

Aged monkeys, 20-years-old and up, were then given doses of IDRA-21 within the same range as the young monkeys and expected to perform the DMTS test. Results found that over the same dosage range the aged monkeys experienced an increase in overall performance levels, however, the improvement was not as drastic as in the young monkeys. The young monkeys performed at 34% better than those given a vehicle while the aged monkeys performed approximately 18% better than the vehicle. Additionally, the researchers observed that the older monkeys were far more sensitive to variations in the dosage while also exhibiting shorter task latency.

Despite the differences between the old and young experimental groups of monkeys, the data emphasizes the overall improvement seen in both groups without any notable side effects following administration. The improvement in performance in the older monkeys is especially important as it indicates that AMPA receptor modulators such as IDRA-21 can effectively and efficiently assist in combating cognitive decline (https://pubmed.ncbi.nlm.nih.gov/14654093/).

A similar study was conducted specifically in young monkeys that were tasked with completing the same DMTS test as well as a visual recognition test with 4 added delays of 10s, 30s, 60s, and 90s. However, this experiment compared IDRA-21 to a similar cognitive enhancement agent, huperzine A. Huperzine A is known to increase levels of acetylcholine (ACh) in the brain since it acts as an inhibitor of acetylcholinesterase (AChE).

After gathering data on the monkeys’ performance on the two tests, the researchers found huperzine A did not improve performance levels on either task. However, what was interesting about this compound was that it had a negative correlation with the baseline performance levels, so if the monkeys performed poorly at baseline, the drug decreased performance, but if they performed well at baseline there was no additional improvement. On the other hand, the monkeys that were administered IDRA-21 experienced a drastic improvement in performance during the visual recognition task, specifically with the 90s delay. The results of this study solidify the claim that IDRA-21 can work as an effective treatment for cognitive and memory deficiencies (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073152/).

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.

IDRA-21 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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