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HomeProduct name listCYCLOTHIAZIDE

CYCLOTHIAZIDE

Synonym(s):6-Chloro-3,4-dihydro-3-(2-norbornen-5-yl)-2H-1,2-4-benzothiadiazine-7-sulfonamide 1,1-dioxide

  • CAS NO.:2259-96-3
  • Empirical Formula: C14H16ClN3O4S2
  • Molecular Weight: 389.88
  • MDL number: MFCD00210192
  • EINECS: 218-859-7
  • SAFETY DATA SHEET (SDS)
  • Update Date: 2024-11-06 15:28:16
CYCLOTHIAZIDE Structural

What is CYCLOTHIAZIDE?

Toxicity

Oral LD50 in mouse is > 10000 mg/kg, and > 4000 mg/kg in rat. Signs of overdose include those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered hypokalemia may accentuate cardiac arrhythmias.

Description

Cyclothiazide (2259-96-3) is a positive allosteric modulator of AMPA receptors acting at a site distinct from that of 2,3-benzodiazepines.1,2 Clinically useful diuretic and antihypertensive agent.3 Induces robust epileptiform activity, inducing seizures but without neuronal death.4,5 Can be used to produce a new animal model for epilepsy.5

Originator

Anhydron,Lilly,US,1963

The Uses of CYCLOTHIAZIDE

Diuretic; antihypertensive. A subunit-specific inhibitor of GABAC receptors.

The Uses of CYCLOTHIAZIDE

Cyclothiazide has been used as a α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) desensitization blocker to study the effects of γ2 on receptor desensitization.

What are the applications of Application

Cyclothiazide is a potent inhibitor of desensitization of AMPA receptors

Indications

Cyclothiazide is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. It is also indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe forms of hypertension.

Background

As a diuretic, cyclothiazide inhibits active chloride reabsorption at the early distal tubule via the Na-Cl cotransporter, resulting in an increase in the excretion of sodium, chloride, and water. Thiazides like cyclothiazide also inhibit sodium ion transport across the renal tubular epithelium through binding to the thiazide sensitive sodium-chloride transporter. This results in an increase in potassium excretion via the sodium-potassium exchange mechanism. The antihypertensive mechanism of cyclothiazide is less well understood although it may be mediated through its action on carbonic anhydrases in the smooth muscle or through its action on the large-conductance calcium-activated potassium (KCa) channel, also found in the smooth muscle. Cyclothiazide is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. It is also indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe forms of hypertension.

Definition

ChEBI: 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide substituted at positions 3, 5 and 6 by a 2-norbornen-5-yl group, chlorine, and a sulfonamide group, respectively. A thiazide diuretic, it has been used in the management of hypertension a d oedema.

Manufacturing Process

A mixture of 8.5 g (0.03 mol) of 6-chloro-4-amino-benzene-1,3- disulfonamide, 4.0 g (0.033 mol) of 2,5-endomethylene-δ3- tetrahydrobenzaldehyde and 25 cc of diethyleneglycol-dimethyl ether was heated for 2 hours at 100°C. During this time the major portion of the initially undissolved crystals went into solution; thereafter, the reaction mixture was allowed to stand for 14 hours at room temperature, during which the remaining undissolved crystals also went into solution. The reddish, clear solution thus obtained was admixed with 50 cc of chloroform. The greyishwhite precipitate formed thereby was separated by vacuum filtration, washed with a small amount of chloroform, dried and recrystallized from aqueous methanol. 7.5 g of white crystalline needles having a melting point of 229° to 230°C were obtained.

brand name

Anhydron (Lilly).

Therapeutic Function

Diuretic, Antihypertensive

General Description

Cyclothiazide is a benzothiadiazine, which has a similar structure to diazoxide.

Biological Activity

Positive allosteric modulator of AMPA receptors that potently inhibits AMPA receptor desensitization. Selective for the flip variant of each of the four receptor subunits. Also available as part of the AMPA Receptor Tocriset™ .

Biochem/physiol Actions

Blocks the rapid desensitization of the AMPA glutamate receptors and markedly prolongs the decay time of the evoked excitatory post-synaptic current.

Pharmacokinetics

Like other thiazides, cyclothiazide promotes water loss from the body (diuretics). It inhibits Na+/Cl- reabsorption from the distal convoluted tubules in the kidneys. Thiazides also cause loss of potassium and an increase in serum uric acid. Thiazides are often used to treat hypertension, but their hypotensive effects are not necessarily due to their diuretic activity. Thiazides have been shown to prevent hypertension-related morbidity and mortality although the mechanism is not fully understood. Thiazides cause vasodilation by activating calcium-activated potassium channels (large conductance) in vascular smooth muscles and inhibiting various carbonic anhydrases in vascular tissue. Cyclothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosages, all thiazides are approximately equal in their diuretic efficacy. Cyclothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate.

Metabolism

Not Available

storage

Room temperature

References

1) Donevan and Rogawski (1998), Allosteric regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors by thiocyanate and cyclothiazide at a common modulatory site distinct from that of 2,3-benzodiazepines; Neuroscience 87 615 2) Desai et al. (1995), Cyclothiazide acts at a site on the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor complex that does not recognize competitive or noncompetitive AMPA receptor antagonists; J. Pharmacol. Exp. Ther. 272 38 3) Jeunemaitre et al. (1988), Long-term metabolic effects of spironolactone and thiazides combined with potassium-sparing agents for treatment of essential hypertension; Am. J. Cardiol. 62 1072 4) Qi et al. (2006), Cyclothiazide induces robust epileptiform activity in rat hippocampal neurons both in vitro and in vivo; J. Physiol. 571 605 5) Kong et al. (2010), Cyclothiazide induces seizure behavior in freely moving rats; Brain Res. 1355 207

Properties of CYCLOTHIAZIDE

Melting point: 234°
Density  1.3781 (rough estimate)
refractive index  1.6100 (estimate)
storage temp.  2-8°C
solubility  Soluble in DMSO (up to 35 mg/ml) or in Ethanol (up to 9 mg/ml)
form  White to off-white solid.
pka pKa 9.1(30% EtOH) (Uncertain)
color  Off-white
λmax 273nm(lit.)
Merck  14,2754
Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 3 months.
EPA Substance Registry System 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3-bicyclo[2.2.1]hept-5-en-2-yl-6-chloro-3,4-dihydro-, 1,1-dioxide (2259-96-3)

Safety information for CYCLOTHIAZIDE

Computed Descriptors for CYCLOTHIAZIDE

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