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Chemical Compound Review

Anhydron     9-(6-bicyclo[2.2.1]hept-2- enyl)-3-chloro-7...

Synonyms: Renazide, Valmiran, Aquirel, Doburil, Fluidil, ...
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Disease relevance of Renazide

  • Cyclothiazide selectively enhanced the AMPA/KA receptor-mediated component of ganglion cells EPSCs, suggesting that desensitization of AMPA/KA receptors shape transient L-EPSCs [1].
  • Cyclothiazide, which inhibits AMPA receptor desensitization, enhanced steady state current responses to AMPA and increased the toxicity of AMPA [2].
  • In particular, coadministration of bicuculline (118 pmol) with either carbachol (328 pmol) or cyclothiazide (1.2 nmol) triggered continuous self-sustaining seizures (status epilepticus; SE) [3].

High impact information on Renazide

  • At the endbulb of Held, a fast central calyceal synapse in the auditory pathway, cyclothiazide (CTZ) abolished marked paired pulse depression (PPD) by acting presynaptically to enhance transmitter release, rather than by blocking postsynaptic receptor desensitization [4].
  • The sensitivity for attenuation of desensitization by cyclothiazide for homomeric GluR-A was solely dependent upon exchange of Ser-750 (flip) and Asn-750 (flop), and was unaffected by mutagenesis of other divergent residues [5].
  • Modulation by cyclothiazide was abolished by mutation of Ser-750 to Gin, the residue found at the homologous site in kainate-preferring subunits, whereas introduction of Ser at this site in GluR6 imparted sensitivity to cyclothiazide [5].
  • Further experiments demonstrated that cyclothiazide, previously thought to affect only AMPA receptor kinetics, also enhances synaptic release [6].
  • AMPA receptors were found to be directly involved in intracellular Ca2+ and NGFI-A mRNA regulation, because the effects of kainate were greatly enhanced by cyclothiazide, an allosteric modulator that selectively suppresses desensitization of AMPA but not kainate receptors [7].

Chemical compound and disease context of Renazide

  • In isolated ganglion cells, cyclothiazide (10 microM), which blocks desensitization in non-NMDA receptors, enhanced both the amplitude and the duration of currents evoked by puffs of AMPA or glutamate [1].
  • Cyclothiazide-treated cultures were now vulnerable to AMPA as well as KA; moreover, AMPA was unable to block KA toxicity completely, suggesting that cyclothiazide impaired AMPA/KA receptor desensitization [8].
  • In the presence of cyclothiazide (CTZ), kainate or AMPA was toxic (30 min exposure), or the toxic effect was significantly enhanced (24 h exposure), but in this case LY 303070 did not completely protect the cells against kainate-induced toxicity [9].
  • The N-methyl-D-aspartate (NMDA) antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (MK801) also blocked cyclothiazide-enhanced kainate toxicity, but only partially [10].
  • Current responses elicited by puffing glycine onto ganglion cell dendrites were not affected by cyclothiazide, indicating that the enhancement of glycinergic IPSCs was not due to a direct effect on glycine receptors [11].

Biological context of Renazide


Anatomical context of Renazide


Associations of Renazide with other chemical compounds

  • In DRG neurons cyclothiazide and aniracetam had no effect on desensitization and instead produced weak inhibition of responses to kainate [20].
  • We have recently demonstrated that chronic stimulation with cyclothiazide (CTZ) or kainic acid (KA) induces robust epileptiform activity in hippocampal neurons both in vitro and in vivo [22].
  • alpha-amino-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptor in rat cultured microglia were analyzed precisely using flop- and flip-preferring allosteric modulators of AMPA receptors, 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide (PEPA) and cyclothiazide (CTZ), respectively [23].
  • CTZ (1.25-5 microM) caused an appreciable and significant increase in EPSPs mediated by non-NMDA receptors and in both AMPA- and NMDA-induced locomotor frequency, but no effects on EPSPs mediated by NMDA receptors [24].
  • 1. The kinetics of onset of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization by glutamate, and the extent of attenuation of AMPA receptor desensitization by cyclothiazide, showed pronounced cell-to-cell variation in cultures of rat hippocampal neurons [25].

Gene context of Renazide

  • In the GLAST-deficient mice, however, the application of cyclothiazide that reduces desensitization of AMPA receptors increased the peak amplitude of the EPSC and prolonged its decay more markedly than in both wild-type and EAAT4-deficient mice [26].
  • We found that in the presence of cyclothiazide, AMPA caused a robust and direct (no involvement of NMDA receptors or L-type voltage-sensitive Ca(2+) channels) Ca(2+)-dependent activation of MAPK through MAPK kinase (MEK) [27].
  • When AMPA was applied together with cyclothiazide the maximal enhancement of AP-1 binding was reached much faster, within 120 min [28].
  • Cyclothiazide and two analogs in which the norbornenyl part was replaced with a cyclohexyl or a cyclohexenyl moiety were examined with regard to their preference for flop vs. flip splice variants of the (+/-)-alphaamino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunits GluR2, 3 and 4 [29].
  • 4. Coexpression of the flip and flop splice variants of GluR-A, in the absence of GluR-B, revealed that heteromeric AMPA receptors with intermediate sensitivity to cyclothiazide, similar to responses observed for the combinations GluR-AoBi or GluR-AiBo, could be generated independently of the presence of the GluR-B subunit [25].

Analytical, diagnostic and therapeutic context of Renazide


  1. Desensitizing glutamate receptors shape excitatory synaptic inputs to tiger salamander retinal ganglion cells. Lukasiewicz, P.D., Lawrence, J.E., Valentino, T.L. J. Neurosci. (1995) [Pubmed]
  2. AMPA receptor desensitization predicts the selective vulnerability of cerebellar Purkinje cells to excitotoxicity. Brorson, J.R., Manzolillo, P.A., Gibbons, S.J., Miller, R.J. J. Neurosci. (1995) [Pubmed]
  3. AMPA receptor desensitization as a determinant of vulnerability to focally evoked status epilepticus. Fornai, F., Busceti, C.L., Kondratyev, A., Gale, K. Eur. J. Neurosci. (2005) [Pubmed]
  4. A novel presynaptic inhibitory mechanism underlies paired pulse depression at a fast central synapse. Bellingham, M.C., Walmsley, B. Neuron (1999) [Pubmed]
  5. Structural determinants of allosteric regulation in alternatively spliced AMPA receptors. Partin, K.M., Bowie, D., Mayer, M.L. Neuron (1995) [Pubmed]
  6. Asynchronous release of synaptic vesicles determines the time course of the AMPA receptor-mediated EPSC. Diamond, J.S., Jahr, C.E. Neuron (1995) [Pubmed]
  7. Glutamate regulates intracellular calcium and gene expression in oligodendrocyte progenitors through the activation of DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Pende, M., Holtzclaw, L.A., Curtis, J.L., Russell, J.T., Gallo, V. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  8. Cyclothiazide treatment unmasks AMPA excitotoxicity in rat primary hippocampal cultures. May, P.C., Robison, P.M. J. Neurochem. (1993) [Pubmed]
  9. Role of desensitization of AMPA receptors on the neuronal viability and on the [Ca2+]i changes in cultured rat hippocampal neurons. Ambrósio, A.F., Silva, A.P., Malva, J.O., Mesquita, J.F., Carvalho, A.P., Carvalho, C.M. Eur. J. Neurosci. (2000) [Pubmed]
  10. Characterization of cyclothiazide-enhanced kainate excitotoxicity in rat hippocampal cultures. Ohno, K., Okada, M., Tsutsumi, R., Matsumoto, N., Yamaguchi, T. Neurochem. Int. (1998) [Pubmed]
  11. AMPA receptor kinetics limit retinal amacrine cell excitatory synaptic responses. Tran, M.N., Higgs, M.H., Lukasiewicz, P.D. Vis. Neurosci. (1999) [Pubmed]
  12. Benzothiadiazides inhibit rapid glutamate receptor desensitization and enhance glutamatergic synaptic currents. Yamada, K.A., Tang, C.M. J. Neurosci. (1993) [Pubmed]
  13. Excitotoxicity mediated by Ca2+-permeable GluR4-containing AMPA receptors involves the AP-1 transcription factor. Santos, A.E., Duarte, C.B., Iizuka, M., Barsoumian, E.L., Ham, J., Lopes, M.C., Carvalho, A.P., Carvalho, A.L. Cell Death Differ. (2006) [Pubmed]
  14. Cyclothiazide differentially modulates desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor splice variants. Partin, K.M., Patneau, D.K., Mayer, M.L. Mol. Pharmacol. (1994) [Pubmed]
  15. Interactions among GYKI-52466, cyclothiazide, and aniracetam at recombinant AMPA and kainate receptors. Johansen, T.H., Chaudhary, A., Verdoorn, T.A. Mol. Pharmacol. (1995) [Pubmed]
  16. Ampakine CX546 bolsters energetic response of astrocytes: a novel target for cognitive-enhancing drugs acting as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulators. Pellerin, L., Magistretti, P.J. J. Neurochem. (2005) [Pubmed]
  17. Modulation of spontaneous quantal release of neurotransmitters in the hippocampus. Bouron, A. Prog. Neurobiol. (2001) [Pubmed]
  18. AMPA receptor activation is rapidly toxic to cortical astrocytes when desensitization is blocked. David, J.C., Yamada, K.A., Bagwe, M.R., Goldberg, M.P. J. Neurosci. (1996) [Pubmed]
  19. Differential expression of glutamate receptor subtypes in rat pancreatic islets. Weaver, C.D., Yao, T.L., Powers, A.C., Verdoorn, T.A. J. Biol. Chem. (1996) [Pubmed]
  20. Differential modulation by cyclothiazide and concanavalin A of desensitization at native alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid- and kainate-preferring glutamate receptors. Wong, L.A., Mayer, M.L. Mol. Pharmacol. (1993) [Pubmed]
  21. 4H-1,2,4-Pyridothiadiazine 1,1-dioxides and 2,3-dihydro-4H-1,2, 4-pyridothiadiazine 1,1-dioxides chemically related to diazoxide and cyclothiazide as powerful positive allosteric modulators of (R/S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid receptors: design, synthesis, pharmacology, and structure-activity relationships. Pirotte, B., Podona, T., Diouf, O., de Tullio, P., Lebrun, P., Dupont, L., Somers, F., Delarge, J., Morain, P., Lestage, P., Lepagnol, J., Spedding, M. J. Med. Chem. (1998) [Pubmed]
  22. Downregulation of tonic GABA currents following epileptogenic stimulation of rat hippocampal cultures. Qi, J.S., Yao, J., Fang, C., Luscher, B., Chen, G. J. Physiol. (Lond.) (2006) [Pubmed]
  23. Heterogeneity and potentiation of AMPA type of glutamate receptors in rat cultured microglia. Hagino, Y., Kariura, Y., Manago, Y., Amano, T., Wang, B., Sekiguchi, M., Nishikawa, K., Aoki, S., Wada, K., Noda, M. Glia (2004) [Pubmed]
  24. Role of AMPA receptor desensitization and the side effects of a DMSO vehicle on reticulospinal EPSPs and locomotor activity. Tsvyetlynska, N.A., Hill, R.H., Grillner, S. J. Neurophysiol. (2005) [Pubmed]
  25. AMPA receptor heterogeneity in rat hippocampal neurons revealed by differential sensitivity to cyclothiazide. Fleck, M.W., Bähring, R., Patneau, D.K., Mayer, M.L. J. Neurophysiol. (1996) [Pubmed]
  26. Differential roles of glial and neuronal glutamate transporters in Purkinje cell synapses. Takayasu, Y., Iino, M., Kakegawa, W., Maeno, H., Watase, K., Wada, K., Yanagihara, D., Miyazaki, T., Komine, O., Watanabe, M., Tanaka, K., Ozawa, S. J. Neurosci. (2005) [Pubmed]
  27. Ca(2+)-permeable AMPA receptors induce phosphorylation of cAMP response element-binding protein through a phosphatidylinositol 3-kinase-dependent stimulation of the mitogen-activated protein kinase signaling cascade in neurons. Perkinton, M.S., Sihra, T.S., Williams, R.J. J. Neurosci. (1999) [Pubmed]
  28. Characterization of NMDA- and AMPA-induced enhancement of AP-1 DNA binding activity in rat cerebellar granule cells. Hou, Y.N., Cebers, G., Terenius, L., Liljequist, S. Brain Res. (1997) [Pubmed]
  29. The norbornenyl moiety of cyclothiazide determines the preference for flip-flop variants of AMPA receptor subunits. Kessler, M., Rogers, G., Arai, A. Neurosci. Lett. (2000) [Pubmed]
  30. Modulation of AMPA receptor kinetics differentially influences synaptic plasticity in the hippocampus. Arai, A.C., Xia, Y.F., Suzuki, E. Neuroscience (2004) [Pubmed]
  31. Determinants of the sensitivity of AMPA receptors to xenon. Plested, A.J., Wildman, S.S., Lieb, W.R., Franks, N.P. Anesthesiology (2004) [Pubmed]
  32. Excavations in drug chirality: 1. Cyclothiazide. Nusser, E., Banerjee, A., Gal, J. Chirality. (1991) [Pubmed]
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