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 ;
PubChem CID	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	389.87 g·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 ;
	(what is this?) (verify)

The printable version is no longer supported and may have rendering errors. Please update your browser bookmarks and please use the default browser print function instead.

Cyclothiazide (Anhydron, Acquirel, Doburil, Fluidil, Renazide, Tensodiural, Valmiran), sometimes abbreviated CTZ, is a benzothiadiazide (thiazide) diuretic and antihypertensive that was originally introduced in the United States in 1963 by Eli Lilly and was subsequently also marketed in Europe and Japan.^[1]^[2] Related drugs include diazoxide, hydrochlorothiazide, and chlorothiazide.^[3]

In 1993, it was discovered that cyclothiazide is a positive allosteric modulator of the AMPA and kainate receptors, capable of reducing or essentially eliminating rapid desensitization of the former receptor, and potentiating AMPA-mediated glutamate currents by as much as 18-fold at the highest concentration tested (100 μM).^[3]^[4]^[5]^[6] Additionally, in 2003, cyclothiazide was also found to act as a GABA_A receptor negative allosteric modulator, potently inhibiting GABA_A-mediated currents.^[7] In animals it is a powerful convulsant, robustly enhancing epileptiform activity and inducing seizures, but without producing any apparent neuronal death.^[8]^[9]

Cyclothiazide has been found to act as a non-competitive antagonist of the mGluR1.^[10] It is selective for mGluR1 over other metabotropic glutamate receptors.^[10]

Synthesis

References

^ 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 ^b 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.
^ 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. PMC 6576449. 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. PMC 240738. 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. PMC 1805799. 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. PMC 2947190. PMID 20678492.
^ ^a ^b 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. PMC 1876747. 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 to Boehringer 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. PMC 6576449. 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. PMC 240738. 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. PMC 1805799. 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. PMC 2947190. 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. PMC 1876747. 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 to Boehringer Ingelheim

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

Synthesis

See also

References