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IDRA-21 CAS:22503-72-6 Nootropic Compound Cognitive Enhancer
Brief Introduction
Brief Introduction
IDRA-21 is a benzothiadiazine derivative and a positive allosteric modulator of glutamate AMPA receptors (1,2,3,4). It is able to increase excitatory synaptic strength by inhibiting AMPA receptor desensitization. IDRA 21 may exhibit therapeutic effects to ameliorate memory deficits in patients with cognitive impairments such as Alzheimer''s disease.
IDRA-21 (7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide) is a benzothiadiazine derivative that acts as a positive allosteric modulator of AMPA receptors. Compared to cyclothiazide, IDRA-21 exhibits better blood-brain barrier penetration and shows significant, long-lasting cognitive enhancement in primate models, with effects persisting up to 48 hours after a single dose . IDRA-21 is an important tool compound in neuroscience research for studying cognitive disorders and age-related memory decline.
Key Scientific Value & Findings
AMPA Receptor Modulation Mechanism: IDRA-21 is a positive AMPA receptor modulator that inhibits rapid desensitization of AMPA receptors, prolonging the decay time of excitatory postsynaptic currents and enhancing glutamatergic neurotransmission. In recombinant human GluR1/2 flip receptors expressed in HEK 293 cells, IDRA-21 doubled charge transfer at 70 μM concentration .
Cognitive Enhancement in Non-Human Primates: Oral administration of IDRA-21 significantly improved delayed matching-to-sample task performance in young adult rhesus monkeys. Over the dose range of 0.15-10 mg/kg, the improvement pattern was maintained up to 48 hours after single-dose administration. Following administration of the individualized Best Dose, task accuracy for Long delay (most difficult) trials increased by 34% of vehicle .
Cognitive Improvement in Aged Primates: In aged monkeys (>20 years), IDRA-21 also improved task accuracy, with up to 18% increase for trials associated with Medium delay intervals. No obvious untoward effects were noted in either study group .
Cumulative Effects with Repeated Dosing: During an intermittent dosing schedule over three weeks (dosing every 3 days), IDRA-21 produced a gradual increase in task accuracy maintained above vehicle performance levels, demonstrating that cognitive-enhancing effects can be sustained with repeated administration .
Dual Modulation of Kainate Receptors: A 2022 study revealed that IDRA-21 not only modulates AMPA receptors but also potentiates kainate receptor-mediated currents. In primary cultures of cerebellar granule neurons, IDRA-21 modulation of kainate receptors primarily involves decreasing receptor desensitization . This discovery provides new perspectives for understanding IDRA-21's comprehensive mechanism of action.
Subunit Selectivity: In HEK293 cells expressing AMPA receptor subunits, IDRA-21 showed significantly higher efficacy in GluA1 homomeric receptors than in GluA2 homomeric receptors, while potency remained unchanged. This subunit selectivity may provide a basis for designing more selective AMPA receptor modulators .
Neurotoxicity Studies: In cerebellar granule neurons treated with AMPA (50 μM, 1 hour), addition of IDRA-21 (1 mM) induced cytotoxicity, which was blocked by AMPA receptor antagonists GYKI 53655 and NBQX . In a rat global cerebral ischemia model, IDRA-21 (6-24 mg/kg) increased G41 neuronal damage . These findings highlight the importance of dose optimization in research.
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