Cyclothiazide
Encyclopedia
Cyclothiazide 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
. Related drug
s include diazoxide
, hydrochlorothiazide
, and chlorothiazide
.
In 1993, it was discovered that cyclothiazide is a positive allosteric modulator
of the AMPA receptor
, capable of reducing or essentially eliminating rapid desensitization
of the receptor, and potentiating glutamate currents by as much as 18-fold at the highest concentration tested (100 μM). Additionally, in 2003, cyclothiazide was also found to act as a GABAA receptor negative allosteric modulator
, potently inhibiting GABAA-mediated currents. In animals it is a powerful convulsant
, robustly enhancing epileptiform activity and inducing seizure
s, but without producing any apparent neuronal death
.
Thiazide
Thiazide is a term used to describe a type of molecule and a class of diuretics often used to treat hypertension and edema ....
) diuretic
Diuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...
and antihypertensive
Antihypertensive
The antihypertensives are a class of drugs that are used to treat hypertension . Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from...
that was originally introduced in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
in 1963 by Eli Lilly
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
and was subsequently also marketed in Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
and Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
. Related drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
s include diazoxide
Diazoxide
Diazoxide is a potassium channel activator, which causes local relaxation in smooth muscle by increasing membrane permeability to potassium ions...
, hydrochlorothiazide
Hydrochlorothiazide
Hydrochlorothiazide, abbreviated HCTZ, HCT, or HZT, is a first-line diuretic drug of the thiazide class that acts by inhibiting the kidneys' ability to retain water. This reduces the volume of the blood, decreasing blood return to the heart and thus cardiac output and, by other mechanisms, is...
, and chlorothiazide
Chlorothiazide
Chlorothiazide sodium is a diuretic used within the hospital setting or for personal use to manage excess fluid associated with congestive heart failure. It is also used as an antihypertensive....
.
In 1993, it was discovered that cyclothiazide is a positive allosteric modulator
Positive allosteric modulator
A positive allosteric modulator is a drug which increases the activity of a receptor indirectly via activation of an allosteric site on the protein. PAMs are similar to agonists in that they contribute to overall receptor activation, but they are different because they do so in a functionally...
of the AMPA receptor
AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system . Its name is derived from its ability to be activated by the artificial glutamate analog AMPA...
, capable of reducing or essentially eliminating rapid desensitization
Desensitization
Desensitization can refer to:* Desensitization * Desensitization * Desensitization * Desensitization of explosives, see Phlegmatized...
of the receptor, and potentiating glutamate currents by as much as 18-fold at the highest concentration tested (100 μM). Additionally, in 2003, cyclothiazide was also found to act as a GABAA receptor negative allosteric modulator
Negative allosteric modulator
A negative allosteric modulator is a drug which decreases the activity of a receptor indirectly via disactivation of an allosteric site on the protein. NAMs are similar to inverse agonists in that they conteract overall receptor activation, but they are different because they do so in a...
, potently inhibiting GABAA-mediated currents. In animals it is a powerful convulsant
Convulsant
A convulsant is a drug which induces convulsions and/or epileptic seizures, the opposite of an anticonvulsant. These drugs generally act as stimulants at low doses, but are not used for this purpose due to the risk of convulsions and consequent excitotoxicity...
, robustly enhancing epileptiform activity and inducing seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, but without producing any apparent neuronal death
Neurotoxicity
Neurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. This can eventually disrupt or even kill neurons, key cells that transmit and process...
.