Cyclothiazide

Cyclothiazide
Clinical data
ATC code	C03AA09(WHO);
Legal status
Legal status	In general: ℞ (Prescription only);
Identifiers
	IUPAC name 3-(bicyclo[2.2.1]hept-5-en-2-yl)-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide;
CAS Number	2259-96-3;
PubChemCID	2910;
IUPHAR/BPS	4167;
DrugBank	DB00606;
ChemSpider	4535011;
UNII	P71U09G5BW;
KEGG	D01256;
ChEMBL	ChEMBL61593;
CompTox Dashboard(EPA)	DTXSID3022871;
ECHA InfoCard	100.017.146
Chemical and physical data
Formula	C14H16ClN3O4S2
Molar mass	389.87g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=S(=O)(c1c(Cl)cc2c(c1)S(=O)(=O)NC(N2)C4[C@@H]3\C=C/[C@@H](C3)C4)N;
	InChI InChI=1S/C14H16ClN3O4S2/c15-10-5-11-13(6-12(10)23(16,19)20)24(21,22)18-14(17-11)9-4-7-1-2-8(9)3-7/h1-2,5-9,14,17-18H,3-4H2,(H2,16,19,20)/t7-,8+,9?,14?/m0/s1; Key:BOCUKUHCLICSIY-QJWLJZLASA-N;
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Cyclothiazide(Anhydron,Acquirel,Doburil,Fluidil,Renazide,Tensodiural,Valmiran), sometimes abbreviatedCTZ,is abenzothiadiazide(thiazide)diureticandantihypertensivethat was originally introduced in the United States in 1963 byEli Lillyand was subsequently also marketed inEuropeandJapan.^[1]^[2]Relateddrugsincludediazoxide,hydrochlorothiazide,andchlorothiazide.^[3]

In 1993, it was discovered that cyclothiazide is apositive allosteric modulatorof theAMPAandkainate receptors,capable of reducing or essentially eliminating rapiddesensitizationof the former receptor, and potentiating AMPA-mediatedglutamatecurrents by as much as 18-fold at the highest concentration tested (100μM).^[3]^[4]^[5]^[6]Additionally, in 2003, cyclothiazide was also found to act as aGABA_Areceptor negative allosteric modulator,potently inhibiting GABA_A-mediated currents.^[7]In animals it is a powerfulconvulsant,robustly enhancingepileptiformactivity and inducingseizures,but without producing any apparentneuronal death.^[8]^[9]

Cyclothiazide has been found to act as anon-competitive antagonistof themGluR1.^[10]It is selective for mGluR1 over othermetabotropic glutamate receptors.^[10]

Synthesis[edit]

References[edit]

^Swiss Pharmaceutical Society (2000).Index Nominum 2000: International Drug Directory (Book with CD-ROM).Boca Raton: Medpharm Scientific Publishers. p. 1932.ISBN 978-3-88763-075-1.
^Sittig M (1988).Pharmaceutical manufacturing encyclopedia.Park Ridge, N.J., U.S.A: Noyes Publications. p. 1756.ISBN 978-0-8155-1144-1.
^^a ^bSkolnick P, Palfreyman MG, Reynolds IJ (1994).Direct and allosteric control of glutamate receptors.Boca Raton: CRC Press. p. 174.ISBN 978-0-8493-8307-6.
^Yamada KA, Tang CM (September 1993)."Benzothiadiazides inhibit rapid glutamate receptor desensitization and enhance glutamatergic synaptic currents".The Journal of Neuroscience.13(9): 3904–3915.doi:10.1523/JNEUROSCI.13-09-03904.1993.PMC6576449.PMID 8103555.
^Bertolino M, Baraldi M, Parenti C, Braghiroli D, DiBella M, Vicini S, Costa E (1993). "Modulation of AMPA/kainate receptors by analogues of diazoxide and cyclothiazide in thin slices of rat hippocampus".Receptors & Channels.1(4): 267–278.PMID 7915948.
^Parsons CG, Danysz W, Zieglgänsberger W (2005)."Excitatory Amino Acid Neurotransmission".In Ströhle A, Bilkei-Gorzo A, Holsboer F (eds.).Anxiety and anxiolytic drugs.Berlin: Springer. p. 566.ISBN 978-3-540-22568-3.
^Deng L, Chen G (October 2003)."Cyclothiazide potently inhibits gamma-aminobutyric acid type A receptors in addition to enhancing glutamate responses".Proceedings of the National Academy of Sciences of the United States of America.100(22): 13025–13029.Bibcode:2003PNAS..10013025D.doi:10.1073/pnas.2133370100.PMC240738.PMID 14534329.
^Qi J, Wang Y, Jiang M, Warren P, Chen G (March 2006)."Cyclothiazide induces robust epileptiform activity in rat hippocampal neurons both in vitro and in vivo".The Journal of Physiology.571(Pt 3): 605–618.doi:10.1113/jphysiol.2005.103812.PMC1805799.PMID 16423850.
^Kong S, Qian B, Liu J, Fan M, Chen G, Wang Y (October 2010)."Cyclothiazide induces seizure behavior in freely moving rats".Brain Research.1355:207–213.doi:10.1016/j.brainres.2010.07.088.PMC2947190.PMID 20678492.
^^a ^bSurin A, Pshenichkin S, Grajkowska E, Surina E, Wroblewski JT (March 2007)."Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists".Neuropharmacology.52(3): 744–754.doi:10.1016/j.neuropharm.2006.09.018.PMC1876747.PMID 17095021.
^Whitehead CW, Traverso JJ, Sullivan HR, Marshall FJ (1961). "Diuretics. V. 3,4-Dihydro-1,2,4-benzothiadiazine 1,1-Dioxides".The Journal of Organic Chemistry.26(8): 2814–2818.doi:10.1021/jo01066a046.
^US 3275625,Müller E, Hasspacher K, issued 1966, assigned toBoehringer Ingelheim

[isbn3-88763-075-0-1] Swiss Pharmaceutical Society (2000).Index Nominum 2000: International Drug Directory (Book with CD-ROM).Boca Raton: Medpharm Scientific Publishers. p. 1932.ISBN 978-3-88763-075-1.

[isbn0-8155-1144-2-2] Sittig M (1988).Pharmaceutical manufacturing encyclopedia.Park Ridge, N.J., U.S.A: Noyes Publications. p. 1756.ISBN 978-0-8155-1144-1.

[isbn0-8493-8307-2-3] Skolnick P, Palfreyman MG, Reynolds IJ (1994).Direct and allosteric control of glutamate receptors.Boca Raton: CRC Press. p. 174.ISBN 978-0-8493-8307-6.

[pmid8103555-4] Yamada KA, Tang CM (September 1993)."Benzothiadiazides inhibit rapid glutamate receptor desensitization and enhance glutamatergic synaptic currents".The Journal of Neuroscience.13(9): 3904–3915.doi:10.1523/JNEUROSCI.13-09-03904.1993.PMC6576449.PMID 8103555.

[pmid7915948-5] Bertolino M, Baraldi M, Parenti C, Braghiroli D, DiBella M, Vicini S, Costa E (1993). "Modulation of AMPA/kainate receptors by analogues of diazoxide and cyclothiazide in thin slices of rat hippocampus".Receptors & Channels.1(4): 267–278.PMID 7915948.

[isbn3-540-22568-4-6] Parsons CG, Danysz W, Zieglgänsberger W (2005)."Excitatory Amino Acid Neurotransmission".In Ströhle A, Bilkei-Gorzo A, Holsboer F (eds.).Anxiety and anxiolytic drugs.Berlin: Springer. p. 566.ISBN 978-3-540-22568-3.

[pmid14534329-7] Deng L, Chen G (October 2003)."Cyclothiazide potently inhibits gamma-aminobutyric acid type A receptors in addition to enhancing glutamate responses".Proceedings of the National Academy of Sciences of the United States of America.100(22): 13025–13029.Bibcode:2003PNAS..10013025D.doi:10.1073/pnas.2133370100.PMC240738.PMID 14534329.

[pmid16423850-8] Qi J, Wang Y, Jiang M, Warren P, Chen G (March 2006)."Cyclothiazide induces robust epileptiform activity in rat hippocampal neurons both in vitro and in vivo".The Journal of Physiology.571(Pt 3): 605–618.doi:10.1113/jphysiol.2005.103812.PMC1805799.PMID 16423850.

[pmid20678492-9] Kong S, Qian B, Liu J, Fan M, Chen G, Wang Y (October 2010)."Cyclothiazide induces seizure behavior in freely moving rats".Brain Research.1355:207–213.doi:10.1016/j.brainres.2010.07.088.PMC2947190.PMID 20678492.

[pmid17095021-10] Surin A, Pshenichkin S, Grajkowska E, Surina E, Wroblewski JT (March 2007)."Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists".Neuropharmacology.52(3): 744–754.doi:10.1016/j.neuropharm.2006.09.018.PMC1876747.PMID 17095021.

[11] Whitehead CW, Traverso JJ, Sullivan HR, Marshall FJ (1961). "Diuretics. V. 3,4-Dihydro-1,2,4-benzothiadiazine 1,1-Dioxides".The Journal of Organic Chemistry.26(8): 2814–2818.doi:10.1021/jo01066a046.

[12] US 3275625,Müller E, Hasspacher K, issued 1966, assigned toBoehringer Ingelheim

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Synthesis[edit]

See also[edit]

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