Cyclothiazide
Clinical data
ATC code
C03AA09 (WHO )
Legal status
Legal status
Identifiers
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 Y
PubChem (CID)
2910
IUPHAR/BPS
4167
DrugBank
DB00606 N
ChemSpider
4535011 N
UNII
P71U09G5BW Y
KEGG
D01256 Y
ChEMBL
CHEMBL61593 N
ECHA InfoCard
100.017.146
Chemical and physical data
Formula
C 14 H 16 Cl N 3 O 4 S 2
Molar mass
389.88 g/mol
3D model (Jmol )
Interactive image
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 (what is this?) (verify)
Cyclothiazide (Anhydron , Acquirel , Doburil , Fluidil , Renazide , Tensodiural , Valmiran ) 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 [ 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 3-88763-075-0 .
^ Sittig, Marshall (1988). Pharmaceutical manufacturing encyclopedia . Park Ridge, N.J., U.S.A: Noyes Publications. p. 1756. ISBN 0-8155-1144-2 .
^ a b Skolnick, Phil; Palfreyman, Michael G.; Reynolds, Ian J. (1994). Direct and allosteric control of glutamate receptors . Boca Raton: CRC Press. p. 174. ISBN 0-8493-8307-2 .
^ Yamada KA, Tang CM (September 1993). "Benzothiadiazides inhibit rapid glutamate receptor desensitization and enhance glutamatergic synaptic currents" . Journal of Neuroscience . 13 (9): 3904–15. PMID 8103555 .
^ Bertolino M, Baraldi M, Parenti C, et al. (1993). "Modulation of AMPA/kainate receptors by analogues of diazoxide and cyclothiazide in thin slices of rat hippocampus". Receptors & Channels . 1 (4): 267–78. PMID 7915948 .
^ Ströhle, Andreas; Bilkei-Gorzo, A.; Holsboer, Florian (2005). Anxiety and anxiolytic drugs . Berlin: Springer. p. 566. ISBN 3-540-22568-4 .
^ 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): 13025–9. 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): 605–18. doi :10.1113/jphysiol.2005.103812 . PMC 1805799 . PMID 16423850 .
^ Kong S, Qian B, Liu J, Fan M, Chen G, Wang Y (July 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 (2007). "Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists" . Neuropharmacology . 52 (3): 744–54. doi :10.1016/j.neuropharm.2006.09.018 . PMC 1876747 . PMID 17095021 .
^ Whitehead, C. W.; Traverso, J. J.; Sullivan, H. R.; Marshall, F. J. (1961). "Diuretics. V. 3,4-Dihydro-1,2,4-benzothiadiazine 1,1-Dioxides". The Journal of Organic Chemistry . 26 (8): 2814. doi :10.1021/jo01066a046 .
Receptor
(ligands )
AMPA
NMDA
Antagonists: Competitive antagonists: AP5 (APV)
AP7
CGP-37849
CGP-39551
CGP-39653
CGP-40116
CGS-19755
CPP
LY-233,053
LY-235,959
LY-274,614
MDL-100,453
Midafotel (d-CPPene)
NPC-12,626
NPC-17,742
PBPD
PEAQX
Perzinfotel
PPDA
SDZ-220581
Selfotel ; Noncompetitive antagonists: ARR-15,896
Caroverine
Dexanabinol
FPL-12495
FR-115,427
Hodgkinsine
Magnesium
MDL-27,266
NPS-1506
Psychotridine
Zinc ; Uncompetitive pore blockers: 2-MDP
3-HO-PCP
3-MeO-PCE
3-MeO-PCMo
3-MeO-PCP
4-MeO-PCP
8A-PDHQ
18-MC
α-Endopsychosin
Alaproclate
Amantadine
Aptiganel
Arketamine
ARL-12,495
ARL-15,896-AR
ARL-16,247
Budipine
Conaridine
Delucemine
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Tenocyclidine
Tiletamine
Tramadol
Xenon ; Glycine site antagonists: 4-Cl-KYN (AV-101)
5,7-DCKA
7-CKA
ACC
ACEA-1011
ACEA-1328
AV-101
Carisoprodol
CGP-39653
CNQX
DNQX
Felbamate
Gavestinel
GV-196,771
Kynurenic acid
Kynurenine
L-689,560
L-701,324
Licostinel (ACEA-1021)
LU-73,068
MDL-105,519
Meprobamate
MRZ 2/576
PNQX
ZD-9379 ; NR2B subunit antagonists: Besonprodil
CERC-301 (MK-0657)
CO-101,244 (PD-174,494)
Eliprodil
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Isoxsuprine
Nylidrin
Ro8-4304
Ro25-6981
Traxoprodil ; Polyamine site antagonists: Arcaine
Co 101676
Diaminopropane
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Ro 25-6981 ; Unclassified/unsorted antagonists: Bumetanide
Chloroform
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Trichloroethanol
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Xylene
Kainate
mGlu1
mGlu2
mGlu3
mGlu4
mGlu5
mGlu6
mGlu7
mGlu8
Transporter
(blockers )
Enzyme
(inhibitors )
Others
Receptor
(ligands )
Agonists
PAMs
(Abridged; see here for a full list) : α-EMTBL
Alcohols (e.g., ethanol )
Anabolic steroids
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Barbiturates (e.g., phenobarbital )
Benzodiazepines (e.g., diazepam )
Bromide compounds (e.g., potassium bromide )
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Etazepine
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Flavonoids (e.g., apigenin , hispidulin )
Fluoxetine
Flupirtine
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Kava constituents (e.g., kavain )
Lanthanum
Loreclezole
Monastrol
Neuroactive steroids (e.g., allopregnanolone , cholesterol )
Niacin
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Nonbenzodiazepines (e.g., β-carbolines (e.g., abecarnil ), cyclopyrrolones (e.g., zopiclone ), imidazopyridines (e.g., zolpidem ), pyrazolopyrimidines (e.g., zaleplon ))
Norfluoxetine
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ROD-188
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Stiripentol
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Topiramate
Valerian constituents (e.g., valerenic acid )
Volatiles /gases (e.g., chloral hydrate , chloroform , diethyl ether , paraldehyde , sevoflurane )
Antagonists
NAMs
1,3M1B
3M2B
11-Ketoprogesterone
17-Phenylandrostenol
α5IA (LS-193,268)
β-CCB
β-CCE
β-CCM
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(+)-DMBB
DMCM
DMPC
EBOB
Etbicyphat
FG-7142 (ZK-31906)
Fiproles (e.g., fipronil )
Flavonoids (e.g., amentoflavone , oroxylin A )
Flumazenil
Fluoroquinolones (e.g., ciprofloxacin )
Flurothyl
Furosemide
Iomazenil (123 I)
Isoallopregnanolone
Isopregnanolone (sepranolone)
L-655,708
Laudanosine
Leptazol
Lindane
MaxiPost
Morphine
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MRK-016
Naloxone
Naltrexone
Nicardipine
Non-steroidal antiandrogens (e.g., apalutamide , bicalutamide , enzalutamide , flutamide , nilutamide )
Oenanthotoxin
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Phenylsilatrane
Picrotoxin (i.e., picrotin and picrotoxinin )
Pregnenolone sulfate
Propybicyphat
PWZ-029
Radequinil
Ro 15-4513
Ro 19-4603
RO4882224
RO4938581
Sarmazenil
SCS
Suritozole
TB-21007
TBOB
TBPS
TCS-1105
Terbequinil
TETS
Thujone
U-93631
Zinc
ZK-93426
Agonists
PAMs
Antagonists
NAMs
Agonists
Antagonists
NAMs
PAMs
Transporter
(blockers )
Enzyme
(inhibitors )
Others
Precursors
Analogues
Others