IDRA-21

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IUPAC_name = 7-chloro-3-methyl-3,4-dihydro-2H-benzo [e] [1,2,4] thiadiazine 1,1-dioxide


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CAS_number = 163936-78-5
synonyms = IDRA-21
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PubChem = 3688
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C = 8 | H = 9 | Cl = 1 | N = 2 | O = 2 | S = 1
molecular_weight = 232.68726 g/mol
smiles = CC1NC2=C(C=C(C=C2)Cl)S(=O)(=O)N1
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legal_status = Investigational New Medicine
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IDRA-21 is an ampakine drug derived from aniracetam. IDRA-21 is a chiral molecule, with (+)-IDRA-21 being the active form. [Uzunov DP, Zivkovich I, Pirkle WH, Costa E, Guidotti A. 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. "Journal of Pharmaceutical Sciences". 1995 Aug;84(8):937-42. [http://www.ncbi.nlm.nih.gov/pubmed/7500277 PMID 7500277] ]

IDRA-21 shows nootropic effects in animal studies, significantly improving learning and memory. It is around 10-30x more potent than aniracetam in reversing cognitive deficits induced by alprazolam or scopolamine, [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. "Proceedings of the National Academy of Sciences U S A". 1995 Aug 15;92(17):7667-71. [http://www.ncbi.nlm.nih.gov/pubmed/7644474 PMID 7644474] ] [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. "Journal of Pharmacology and Experimental Therapeutics". 1995 Jan;272(1):300-9. [http://www.ncbi.nlm.nih.gov/pubmed/7815345 PMID 7815345] ] and produces sustained effects lasting for up to three days after a single dose. [Buccafusco JJ, Weiser T, Winter K, Klinder K, Terry AV. The effects of IDRA 21, a positive modulator of the AMPA receptor, on delayed matching performance by young and aged rhesus monkeys. "Neuropharmacology". 2004 Jan;46(1):10-22. [http://www.ncbi.nlm.nih.gov/pubmed/14654093 PMID 14654093] ] The mechanism for this action is thought to be through promoting the induction of long-term potentiation between synapses in the brain. [Arai A, Guidotti A, Costa E, Lynch G. Effect of the AMPA receptor modulator IDRA 21 on LTP in hippocampal slices. "Neuroreport". 1996 Sep 2;7(13):2211-5. [http://www.ncbi.nlm.nih.gov/pubmed/8930991 PMID 8930991] ]

IDRA-21 does not produce neurotoxicity under normal conditions, [Impagnatiello F, Oberto A, Longone P, Costa E, Guidotti A. 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 U S A". 1997 Jun 24;94(13):7053-8. [http://www.ncbi.nlm.nih.gov/pubmed/9192690 PMID 9192690] ] although it may worsen neuronal damage following global ischemia after stroke or seizures. [Yamada KA, Covey DF, Hsu CY, Hu R, Hu Y, He YY. The diazoxide derivative IDRA 21 enhances ischemic hippocampal neuron injury. "Annals of Neurology". 1998 May;43(5):664-9. [http://www.ncbi.nlm.nih.gov/pubmed/9585363 PMID 9585363] ]

In comparison to the benzoylpiperidine derived ampakine drugs, IDRA-21 was more potent than CX-516, but less potent than CX-546. [Nagarajan N, Quast C, Boxall AR, Shahid M, Rosenmund C. Mechanism and impact of allosteric AMPA receptor modulation by the ampakine CX546. "Neuropharmacology". 2001 Nov;41(6):650-63. [http://www.ncbi.nlm.nih.gov/pubmed/11640919 PMID 11640919] ] Newer benzothiadiazide derivatives with greatly increased potency compared to IDRA-21 have been developed, [Phillips D, Sonnenberg J, Arai AC, Vaswani R, Krutzik PO, Kleisli T, Kessler M, Granger R, Lynch G, Richard Chamberlin A. 5'-alkyl-benzothiadiazides: a new subgroup of AMPA receptor modulators with improved affinity. "Bioorganic and Medicinal Chemistry". 2002 May;10(5):1229-48. [http://www.ncbi.nlm.nih.gov/pubmed/11886787 PMID 11886787] ] [Arai AC, Xia YF, Kessler M, Phillips D, Chamberlin R, Granger R, Lynch G. Effects of 5'-alkyl-benzothiadiazides on (R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor biophysics and synaptic responses. "Molecular Pharmacology". 2002 Sep;62(3):566-77. [http://www.ncbi.nlm.nih.gov/pubmed/12181433 PMID 12181433] ] but these have not been researched to the same extent, with the benzoylpiperidine and benzoylpyrrolidine CX- series of drugs being favoured for clinical development, most likely due to more favourable toxicity profiles at high doses. [Black MD. Therapeutic potential of positive AMPA modulators and their relationship to AMPA receptor subunits. A review of preclinical data. "Psychopharmacology (Berlin)". 2005 Apr;179(1):154-63. [http://www.ncbi.nlm.nih.gov/pubmed/15672275 PMID 15672275] ]

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