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Chemical compound
Cyclothiazide
ATC code
Legal status
In general: ℞ (Prescription only)
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
PubChem
CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (
EPA )
ECHA InfoCard
100.017.146
Formula C 14 H 16 Cl N 3 O 4 S 2
Molar mass 389.87 g·mol−1 3D model (
JSmol )
O=S(=O)(c1c(Cl)cc2c(c1)S(=O)(=O)NC(N2)C4[C@@H]3\C=C/[C@@H](C3)C4)N
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
N Key:BOCUKUHCLICSIY-QJWLJZLASA-N
N
N Y
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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
GABAA receptor
negative allosteric modulator , potently inhibiting GABAA -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
Cyclothiazide synthesis:
[11]
[12]
See also
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
Ionotropic
GABAA Tooltip γ-Aminobutyric acid A receptor
Positive modulators (abridged; see
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α-EMTBL
Alcohols (e.g.,
drinking alcohol ,
2M2B )
Anabolic steroids
Avermectins (e.g.,
ivermectin )
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Quinazolinones (e.g.,
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Volatiles /
gases (e.g.,
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Negative modulators:
1,3M1B
3M2B
11-Ketoprogesterone
17-Phenylandrostenol
α3IA
α5IA (LS-193,268)
β-CCB
β-CCE
β-CCM
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(+)-DMBB
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EBOB
Etbicyphat
FG-7142 (ZK-31906)
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oroxylin A )
Flumazenil
Fluoroquinolones (e.g.,
ciprofloxacin )
Flurothyl
Furosemide
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IPTBO
Isopregnanolone (sepranolone)
L-655,708
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MRK-016
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Oenanthotoxin
Pentylenetetrazol (pentetrazol)
Phenylsilatrane
Picrotoxin (i.e.,
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picrotoxinin and
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Propybicyphat
PWZ-029
Radequinil
Ro 15-4513
Ro 19-4603
RO4882224
RO4938581
Sarmazenil
SCS
Suritozole
TB-21007
TBOB
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TCS-1105
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U-93631
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GABAA -ρ Tooltip γ-Aminobutyric acid A-rho receptor
Metabotropic
GABAB Tooltip γ-Aminobutyric acid B receptor
AMPAR Tooltip α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
KAR Tooltip Kainate receptor
NMDAR Tooltip N-Methyl-D-aspartate receptor
Group I
mGluR1 Tooltip Metabotropic glutamate receptor 1
mGluR5 Tooltip Metabotropic glutamate receptor 5
Group II
mGluR2 Tooltip Metabotropic glutamate receptor 2
mGluR3 Tooltip Metabotropic glutamate receptor 3
Group III
mGluR4 Tooltip Metabotropic glutamate receptor 4
mGluR6 Tooltip Metabotropic glutamate receptor 6
mGluR7 Tooltip Metabotropic glutamate receptor 7
mGluR8 Tooltip Metabotropic glutamate receptor 8