The compound 7‑chloro‑3,4‑dihydro‑3‑methyl‑2H‑1,2,4‑benzothiadiazine 1,1‑dioxide, commonly referred to as IDRA‑21, was first reported in the mid‑1990s as a derivative of benzothiadiazine that acts as a positive allosteric modulator of AMPA‑type glutamate receptors. It was synthesized by introducing a methyl group at the 3‑position and chlorine at the 7‑position on the benzothiadiazine 1,1‑dioxide scaffold, yielding a molecule which significantly attenuates rapid desensitization of AMPA receptors and thereby enhances excitatory synaptic transmission.
The discovery emerged from efforts to identify nootropic compounds capable of improving learning and memory by modulating glutamatergic signaling. In rats, oral administration of IDRA‑21 improved performance in water maze and passive avoidance tests, showing stronger efficacy than aniracetam. Only the (+) enantiomer was behaviorally active, demonstrating both stereoselective binding and functional effect. Subsequent studies in monkeys showed that IDRA‑21 at low micromolar doses could reverse alprazolam‑induced cognitive deficits and enhance delayed matching performance tasks, with potency 10–30 times greater than aniracetam.
The principal mechanism of action is potentiation of AMPA receptor currents by slowing desensitization, which facilitates synaptic plasticity and long‑term potentiation underlying memory encoding. The enhancement of synaptic responses has been observed in cultured hippocampal neurons, and IDRA‑21 promotes induction of LTP under conditions where stimulation alone is insufficient.
There are also important safety considerations. Although IDRA‑21 appears to be relatively non‑toxic at cognition‑enhancing doses, studies found that it can exacerbate neuronal injury following ischemic events. In rodent models of global cerebral ischemia, administration of IDRA‑21 at 12–24 mg/kg increased CA1 hippocampal neuron loss, likely due to potentiation of AMPA‑mediated excitotoxicity under pathological conditions.
Beyond its neuropharmacological interest, IDRA‑21 and related benzothiadiazine derivatives have been studied as tools in medicinal chemistry to explore structure‑activity relationships. They helped characterize how small substituents on the benzothiadiazine scaffold affect receptor modulation and toxicity. Although IDRA‑21 itself never entered clinical development, it has served as a model for designing newer ampakines with improved safety profiles.
Applications of IDRA‑21 remain experimental. Its cognitive enhancing properties have been valuable in preclinical models of learning and memory, especially for understanding AMPA receptor modulation. It has been used to probe synaptic plasticity mechanisms, LTP induction thresholds, and receptor pharmacology in central nervous system research. To date, no approved therapeutic uses exist for IDRA‑21, and its potential in neurological disorders has not been translated to clinical practice.
In summary, 7‑chloro‑3,4‑dihydro‑3‑methyl‑2H‑1,2,4‑benzothiadiazine 1,1‑dioxide is a benzothiadiazine derivative discovered in the 1990s as a potent AMPA receptor positive allosteric modulator. It improves cognition in animal models by attenuating AMPA receptor desensitization and promoting synaptic plasticity. However, it may exacerbate neurotoxicity under pathological conditions involving ischemia. While not developed as a drug, it remains a prominent experimental compound in neuroscience research.
References
Yamada KA, Covey DF, Hsu CY, Hu R, Hu Y, He YY (1998) The diazoxide derivative IDRA 21 enhances ischemic hippocampal neuron injury. Annals of Neurology 43 5 664–669 DOI: 10.1002/ana.410430517
Losi G, Puia G, Baraldi M, Braghiroli D (2004) IDRA‑21, a positive AMPA receptor modulator, inhibits synaptic and extrasynaptic NMDA receptor mediated events in cultured cerebellar granule cells. Neuropharmacology 46 8 1105–1113 DOI: 10.1016/j.neuropharm.2004.02.011
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