Metrazol

Pentylenetetrazol

Systematic (IUPAC) name
6,7,8,9-Tetrahydro-5H-tetrazolo(1,5-a)azepine
Identifiers
CAS number	54-95-5
ATC code	R07AB03
PubChem	5917
Chemical data
Formula	C6H10N4
Mol. mass	138.171
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	?
Metabolism	?
Half life	?
Excretion	?
Therapeutic considerations
Pregnancy cat.	?
Legal status
Routes	?
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Pentylenetetrazol (INN), also known as metrazol, pentetrazol, pentamethylenetetrazol, Cardiazol or PTZ, is a drug used as a circulatory and respiratory stimulant. High doses cause convulsions, as discovered by the Hungarian-American neurologist and psychiatrist Ladislas J. Meduna in 1934. It has been used in shock therapy, but was never considered to be effective, and side-effects such as seizures were difficult to avoid. Its approval by FDA was revoked in 1982.^[1]

Mechanism

Pentylenetetrazol is considered a GABA antagonist.^[2] The mechanism of the epileptogenic action of pentylenetetrazol at the cellular neuronal level is still unclear. Electrophysiological studies have shown it acts at cell membrane level decreasing the recovery time between action potentials by increasing potassium permeability of the axon. Other studies have implicated an increase in membrane currents of several other ions, such as sodium and calcium, leading to an overall increase in excitability of the neuron membrane.

Uses

Pentylenetetrazol has been used experimentally to study seizure phenomenon and to identify pharmaceuticals that may control seizure susceptibility. Pentylenetetrazol is also a prototypical anxiogenic drug and, has been extensively utilized in animal models of anxiety. Pentylenetetrazol produces a reliable discriminative stimulus which is largely mediated by the GABA_A receptor. Several classes of compounds can modulate the pentylenetetrazol discriminative stimulus including 5-HT_1A, 5-HT₃, NMDA, glycine, and L-type calcium channel ligands.^[3]

Recently, it has been shown that pentylenetetrazol at non-epileptic doses, along with two other compounds (picrotoxin and bilobalide) can restore the cognitive function (learning and memory) of a mouse model of Down syndrome by inhibiting GABA_A receptor without inducing seizures.^[4] These results caused renewed interest in pentylenetetrazol as a potential drug candidate for Down syndrome, although clinical trials are probably still a couple of years away.^[1]

The finding of pentylenetetrazol's effectiveness in treating Down Syndrome has led to it being explored as a means of correcting other learning deficiencies. Specifically, hamsters denied their natural circadian rhythm (though not denied sleep) had their memory restored to near-normal levels when treated with pentylenetetrazol.^[5]

Alternatives

In 1939, pentylenetetrazol was replaced by electroconvulsive therapy as the preferred method for inducing seizures in England's mental hospitals.

References