IDRA-21

IDRA-21 is a positive allosteric modulator of the AMPA receptor and a benzothiadiazine derivative. It is a chiral molecule, with (+)-IDRA-21 being the active form.[1]

IDRA-21
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Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
ChEMBL
Chemical and physical data
FormulaC8H9ClN2O2S
Molar mass232.68726 g/mol g·mol−1
3D model (JSmol)
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IDRA-21 shows nootropic effects in animal studies, significantly improving learning and memory. It is around 10–30 times more potent than aniracetam in reversing cognitive deficits induced by alprazolam or scopolamine,[2][3] and produces sustained effects lasting for up to 48 hours after a single dose.[4] The mechanism for this action is thought to be through promoting the induction of long-term potentiation between synapses in the brain.[5]

IDRA-21 does not produce neurotoxicity under normal conditions,[6] although it may worsen neuronal damage following global ischemia after stroke or seizures.[7]

In comparison to the ampakines or benzoylpiperidine-derived AMPA receptor potentiators, IDRA-21 was more potent than CX-516, but less potent than CX-546.[8] Newer benzothiadiazide derivatives with greatly increased potency compared to IDRA-21 have been developed,[9][10] 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.[11]

See also

References
  1. Uzunov, DP; Zivkovich, I; Pirkle, WH; Costa, E; Guidotti, A (August 1995). "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. 84 (8): 937–942. doi:10.1002/jps.2600840807. ISSN 0022-3549. PMID 7500277.
  2. Thompson, DM; Guidotti, A; Dibella, M; Costa, E (August 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 of the United States of America. 92 (17): 7667–71. doi:10.1073/pnas.92.17.7667. ISSN 0027-8424. PMC 41206. PMID 7644474.
  3. Zivkovic, I; Thompson, DM; Bertolino, M; Uzunov, D; Dibella, M; Costa, E; Guidotti, A (January 1995). "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". The Journal of Pharmacology and Experimental Therapeutics. 272 (1): 300–309. ISSN 0022-3565. PMID 7815345.
  4. Buccafusco, JJ; Weiser, T; Winter, K; Klinder, K; Terry, AV (January 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. ISSN 0028-3908. PMID 14654093.
  5. Arai, A; Guidotti, A; Costa, E; Lynch, G (September 1996). "Effect of the AMPA receptor modulator IDRA 21 on LTP in hippocampal slices". NeuroReport. 7 (13): 2211–2215. doi:10.1097/00001756-199609020-00031. ISSN 0959-4965. PMID 8930991.
  6. Impagnatiello, F; Oberto, A; Longone, P; Costa, E; Guidotti, A (June 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 of the United States of America. 94 (13): 7053–8. doi:10.1073/pnas.94.13.7053. ISSN 0027-8424. PMC 21283. PMID 9192690.
  7. Yamada, KA; Covey, DF; Hsu, CY; Hu, R; Hu, Y; He, YY (May 1998). "The diazoxide derivative IDRA 21 enhances ischemic hippocampal neuron injury". Annals of Neurology. 43 (5): 664–669. doi:10.1002/ana.410430517. ISSN 0364-5134. PMID 9585363.
  8. Nagarajan, N; Quast, C; Boxall, AR; Shahid, M; Rosenmund, C (November 2001). "Mechanism and impact of allosteric AMPA receptor modulation by the ampakine CX546". Neuropharmacology. 41 (6): 650–663. doi:10.1016/S0028-3908(01)00133-2. ISSN 0028-3908. PMID 11640919.
  9. Phillips, D; Sonnenberg, J; Arai, AC; Vaswani, R; Krutzik, PO; Kleisli, T; Kessler, M; Granger, R; et al. (May 2002). "5'-alkyl-benzothiadiazides: a new subgroup of AMPA receptor modulators with improved affinity". Bioorganic & Medicinal Chemistry. 10 (5): 1229–48. CiteSeerX 10.1.1.113.7845. doi:10.1016/S0968-0896(01)00405-9. ISSN 0968-0896. PMID 11886787.
  10. Arai, AC; Xia, YF; Kessler, M; Phillips, D; Chamberlin, R; Granger, R; Lynch, G (September 2002). "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. 62 (3): 566–77. doi:10.1124/mol.62.3.566. ISSN 0026-895X. PMID 12181433.
  11. Black, MD (April 2005). "Therapeutic potential of positive AMPA modulators and their relationship to AMPA receptor subunits. A review of preclinical data". Psychopharmacology. 179 (1): 154–163. doi:10.1007/s00213-004-2065-6. ISSN 0033-3158. PMID 15672275.
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