IDRA-21 is a nootropic research chemical that belongs to the ampakine class. Ampakines are groups of chemicals that are derived from aniracetam, which are thought to have a strong correlation with AMPA receptors of ionotropic glutamate (Arai & Kessler, 2007). AMPA receptors are composed of subunits making heterotetrameric complexes that exhibit specific properties related to synaptic plasticity and synaptic transmission by releasing specific neurotransmitters. These are thought to provide an immediate response to regulate glutamate release (Gasbarri & Pompili, 2014), which may mediate pathology involved in psychiatric conditions (Musazzi et al., 2013). Glutamate, a well-known neurotransmitter is released from glial cells and neurons and shows an excitatory effect on neurons, and increases the likelihood of potential action in many conditions. There are few studies that have shown that a decreased level of AMPA receptors plays a significant role in neurodegenerative diseases. As IDRA-21 is involved in the activation of AMPA receptors, which may help to delay the neurodegeneration process thus improving cognition and learning (Frydenvang et al., 2021).

Furthermore, excitatory synaptic transmission is believed to be mediated by the glutamate receptor family and AMPA is a part of this major subdivision. Compounds like IDRA-21 are thought to enhance this transmission and thus play an important role in behavioral improvement. Some of the IDRA-21 derivatives increase the binding capacity of receptor agonists which in turn may increase synaptic transmission thus improving the transmission through the central nervous system which may affect positively important processes and actions (Phillips, 2002).

As AMPA receptors mediate fast excitatory neurotransmission and are distributed through the central nervous system especially in regions of the brain such as the cortex and hippocampus, well known for mood regulation which gives an indication to be used for the evaluation of mood resulting into increased motivation (Gordillo-Salas et al., 2020).

In one study, when underperforming monkeys were given IDRA 21, it has enhanced their performance to complete certain tasks which depended on memory performance (Malkova et al., 2011).

Animal trials

There were some studies carried out by using animal models which include mice and monkeys (Malkova et al., 2011; Thompson et al., 1995).

Because of its high potency to act as an inhibitor for AMPA-receptor, rapid desensitization, and limited intrinsic activity, it has already been tested to enhance cognition which may be further tested for neurodegeneration, after fair testing and trials. Under normal conditions, it may not produce any neurotoxicity, but neurological damage may become worse after the neurodegenerative event (Impagnatiello et al., 1997).

It has been reported that IDRA-21 improved memory in animal models by affecting synaptic transmission and long-term penetration in hippocampal. The hippocampal is a region of the brain embedded in the temporal lobe and has a major role in learning and memory (Arai et al., 1996). Like many other positive modulators of glutamate receptors, IDRA 21 may also show memory-enhancing effects (Kelvin et al., 2004).

A trial has been conducted on monkeys for behavioral and learning abilities after administering IDRA-21. Interestingly, in patas monkeys, it has improved learning by increasing GABAergic tone while behavioral effects may be because of its effect on AMPA receptors, though the mechanism is still unknown. (Thompson et al., 1995).

In another experiment, when IDRA-21 was administered, delayed matching to sample (DMTS) tasks were performed more efficiently by adult rhesus monkeys. These young monkeys maintained task accuracy well above the average. When the same experiment was performed on a group of aged monkeys, IDRA 21 shown an increase of 18 % in the accuracy of DMTS which supports the hypothesis of using AMPA modulators to improve cognition and reversal of memory impairment. Its potency to reverse the cognitive deficits is 10-30 percent more than a similar compound like aniracetam with its effects lasting more than 48 hours (Buccafusco et al., 2003).

In another trial, the performance of rodents in a water maze was studied. It was observed that performance has been improved with fewer errors to exit a maze, after administering IDRA-21. The suggested mechanism for this improved cognition is increased strength of excitatory synapses by selective AMPA-selective glutamate receptors. These results indicate the ability of IDRA-21 to cross the blood-brain barrier (Black et al., 2005) and act on specific receptors which control the behavior. This study indicated an improvement of cognition in rodents and the ability to perform better in a challenging situation (Zivkovic et al., 1995).

Human trials

As of today, no human trials had been performed with IDRA-21.

References

Arai, A., Guidotti, A., Costa, E. and Lynch, G (1996), Effect of the AMPA receptor modulator IDRA 21 on LTP in hippocampal slices, NeuroReport, 7 (13), 2211-2215. Source

Arai, A.C. and Kessler, M (2007), Pharmacology of ampakine modulators: from AMPA receptors to synapses and behavior, Curr Drug Targets, 8(5), 583-602. doi: 10.2174/138945007780618490. PMID: 17504103.

Black, M.D. Therapeutic potential of positive AMPA modulators and their relationship to AMPA receptor subunits, A review of preclinical data, Psychopharmacology 179, 154–163. (2005). https://doi.org/10.1007/s00213-004-2065-6

Buccafusco, J.J., Weiser, T., Winter, K., Klinder, K. and Terry, A.V (2004), The effects of IDRA 21, a positive modulator of the AMPA receptor, on delayed matching performance by young and aged rhesus monkeys, Neuropharmacology, 46(1), 10-22. doi: 10.1016/j.neuropharm.2003.07.002. PMID: 14654093.

Frydenvang, K., Pickering, D.S and Kastrup, J.S. (2021) Structural basis for positive allosteric modulation of AMPA and kainite receptors, Symposium Review. https://doi.org/10.1113/JP280873

Gasbarri, A. and Pompili, A (2014)  Involvement of Glutamate in Learning and Memory in Identification of Neural Markers Accompanying Memory, Elsevier, pp 63-77. ISBN 9780124081390, https://doi.org/10.1016/B978-0-12-408139-0.00004-3.

Gordillo-Salas, M., Pascual-Antón, R., Ren, J. (2020) Antidepressant-Like Effects of CX717, a Positive Allosteric Modulator of AMPA Receptors, Mol Neurobiol, 57, 3498–3507 https://doi.org/10.1007/s12035-020-01954-x

Impagnatiello, F.,Oberto, A., Longone, P., Costa, E. and  Guidotti, A. (1997), 7-Chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide: A partial modulator of AMPA receptor desensitization devoid of neurotoxicity, Proceedings of the National Academy of Sciences, 94 (13) 7053-7058; DOI: 10.1073/pnas.94.13.7053

Kelvin, A.,Yamada, M.D., Chung, Y., Hsu, M.D.,  Rong, Hu., Yuefei, Hu.,  Yong, Y. and He, M.D (2004), The diazoxide derivative IDRA 21 enhances ischemic hippocampal neuron injury, Annals of Neurology, 43(5), 664-669.  https://doi.org/10.1002/ana.410430517

Malkova, L., Kozikowski, A.P. and Gale, K. (2011) The effects of huperzine A and IDRA 21 on visual recognition memory in young macaques, Neuropharmacology, 60(7-8), 1262-8. doi: 10.1016/j.neuropharm.2010.12.018.

Musazzi, L., Treccani, G., Mallei, A. and Popoli, M. (2013), The Action of Antidepressants on the Glutamate System: Regulation of Glutamate Release and Glutamate Receptors, Biological Psychiatry, 73 (12), 1180-1188.  https://doi.org/10.1016/j.biopsych.2012.11.009.

Phillips, D., Sonnenberg, J., Arai, A.C., Vaswani, R., Krutzik, P.O., Kleisli, T., Kessler, M., Granger, R., Lynch, G. and Chamberlin, A.R (2002), 5′-Alkyl-benzothiadiazides: A New Subgroup of AMPA Receptor Modulators with Improved Affinity, Bioorganic & Medicinal Chemistry, 10 (5), 1229-1248. https://doi.org/10.1016/S0968-0896(01)00405-9.

Thompson, D.M., Guidotti, A., DiBella, M. and Costa, E (1995), 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, Proceedings of the National Academy of Sciences, 92 (17), 7667-7671. DOI: 10.1073/pnas.92.17.7667

Zivkovic I, Thompson DM, Bertolino M, Uzunov D, DiBella M, Costa E, Guidotti A. 7-Chloro-3-methyl-3-4-dihydro-2H-1,2,4 benzothiadiazine S,S-dioxide (IDRA 21): a benzothiadiazine derivative that enhances cognition by attenuating DL-alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA) receptor desensitization, J Pharmacol Exp Ther, 272(1), 300-9. PMID: 7815345.