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Idr2.6

IDRA-21 Research

Mostly mechanism / observational

5 peer-reviewed studies

What the evidence says

Mostly mechanism / observational

Most IDRA-21 studies are mechanism or observational rather than RCTs that measure a clinical effect — keep findings provisional.

Most evidence is from mixed-quality studies published 1995–2005.

Based on 5 studies

Confidence

Low confidence

By outcome

Learning & memory (ampakine, preclinical only — unproven in humans)An ampakine (AMPA-receptor positive allosteric modulator) that enhances learning/memory in animals and primates only; UNPROVEN in humans, with no human safety data and a theoretical excitotoxicity/seizure risk. · Not established (no human data)
Mostly mechanism / observational5 studies
Safety profile
Mostly mechanism / observational5 studies
Excitotoxicity & neurotoxicity (theoretical harm)
Mostly mechanism / observational3 studies
Focus & attention (ampakine class, unproven for IDRA-21)Focus/cognition benefit is extrapolated from the ampakine class and unproven for IDRA-21 in humans; grey-market identity/purity/dose risk. · Not established (no human data)
Too few graded studies1 study

Older research base

Newest study from 2005

199520002005

1In Vitro1997

In plain English: IDRA-21 ... facilitate[s] AMPA receptor function ... while dose dependently, 5-25 microM cyclothiazide in the presence of AMPA is highly neurotoxic, IDRA-21 (up to 100 microM) is devoid of neurotoxicity ... IDRA-21 is a potent cognition-enhancing drug virtually devoid of neurotoxic liability because it acts as a partial negative allosteric modulator of AMPA receptor desensitization.

Impagnatiello F, Oberto A, Longone P, Costa E, Guidotti A. · Proceedings of the National Academy of Sciences of the United States of America (1997)

IN-VITRO MECHANISM: in cultured rat cerebellar granule neurons, IDRA-21 facilitated AMPA-receptor function by slowing desensitization, raising intracellular Na+ and Ca2+ — direct evidence of the ampakine mechanism
Acted as a 'partial' modulator with lower intrinsic activity and shorter-lasting Ca2+ transients than cyclothiazide — a key reason its safety margin appears wider
CRITICAL SAFETY NUANCE: the related stronger modulator cyclothiazide was overtly neurotoxic at 5-25 microM, whereas IDRA-21 was devoid of neurotoxicity up to 100 microM — so excitotoxicity is a real, dose- and compound-dependent hazard of the class, not eliminated

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2Animal1995

In plain English: (+/-)-IDRA 21 administered orally to rats subjected to a water maze cognition test elicited a performance enhancing effect ... (+)-IDRA 21 was identified as being pharmacologically active in the water maze performance test, whereas (-)-IDRA 21 was completely devoid of activity.

Uzunov DP, Zivkovich I, Pirkle WH, Costa E, Guidotti A. · Journal of Pharmaceutical Sciences (1995)

RODENT: orally administered racemic IDRA-21 enhanced rat water-maze performance — a second, independent animal cognition signal for the compound
Activity resided in the (+)-enantiomer, with the (-)-enantiomer essentially inactive — a stereoselective pharmacology consistent with a defined molecular target rather than a non-specific effect
Frames IDRA-21 as a 'cognition-enhancing benzothiadiazine derivative' and reports the chromatographic resolution of its enantiomers

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3Animal1995

In plain English: IDRA 21 (3 or 5.6 mg/kg p.o.) and aniracetam (30 mg/kg p.o.) administered 60 min before alprazolam ... antagonized the large disruptive effects of alprazolam on learning ... it can be estimated that IDRA 21 is approximately 10-fold more potent than aniracetam ... Very likely IDRA 21 exerts its behavioral effects by antagonizing AMPA receptor desensitization.

Thompson DM, Guidotti A, DiBella M, Costa E. · Proceedings of the National Academy of Sciences of the United States of America (1995)

NON-HUMAN PRIMATE: in patas monkeys, oral IDRA-21 reversed an alprazolam-induced deficit in a repeated-acquisition ('learning') task — the strongest preclinical cognition signal for the compound, but in monkeys, not humans
IDRA-21 was estimated ~10-fold more potent than the prototype ampakine aniracetam at antagonizing the learning deficit, supporting the 'more potent than aniracetam' framing
Had no effect when given alone — it rescued a drug-induced impairment rather than boosting baseline learning, an important nuance for 'nootropic' claims

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4Review2005

In plain English: Positive AMPA modulators enhance glutamate transmission via the AMPA receptor by altering the rate of desensitization; alone they have no intrinsic activity ... they were first studied in models of short- and long-term memory ... In general, these agents were procognitive.

Black MD. · Psychopharmacology (Berlin) (2005)

CLASS REVIEW (PRECLINICAL): situates IDRA-21 within the positive-AMPA-modulator ('ampakine') class, which enhances glutamate transmission by slowing desensitization and is generally procognitive in animal memory models
Explains that effects depend on AMPA-receptor subunit composition and that the class also shows preclinical signals in schizophrenia, depression, neuroprotection and Parkinson's models
Explicitly a review of PRECLINICAL data — it characterises class potential, not demonstrated human efficacy or safety for IDRA-21

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5In Vitro1998

In plain English: The increase on the expression of GluR1 FLIP and FLOP and of GluR4 FLOP mRNA variants during development is associated with a 10-fold increase in AMPA-mediated Na+ currents and in the increased amplification of this current by ... IDRA21 or by ... cyclothiazide.

Longone P, Impagnatiello F, Mienville JM, Costa E, Guidotti A. · Journal of Molecular Neuroscience (1998)

IN-VITRO MECHANISM: links IDRA-21's amplification of AMPA-mediated Na+ currents to specific AMPA-receptor splice variants (GluR1/GluR4 FLIP/FLOP) in maturing cerebellar granule cells
Shows the magnitude of IDRA-21's effect depends on AMPA-receptor subunit/splice-variant composition — a determinant of where and how strongly an ampakine acts
Reinforces the molecular ampakine mechanism underlying the animal cognition findings, at receptor-pharmacology level

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IDRA-21 Research

Mostly mechanism / observational

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.

Enantiomeric resolution with a new chiral stationary phase of 7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide, a cognition-enhancing benzothiadiazine derivative.

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.

Therapeutic potential of positive AMPA modulators and their relationship to AMPA receptor subunits. A review of preclinical data.

Changes in AMPA receptor-spliced variant expression and shift in AMPA receptor spontaneous desensitization pharmacology during cerebellar granule cell maturation in vitro.