{{Short description|Chemical compound}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | Verifiedfields = changed | Watchedfields = changed | INN = Pentetrazol | verifiedrevid = 415933541 | IUPAC_name = 6,7,8,9-Tetrahydro-5''H''-tetrazolo(1,5-''a'')azepine | image = Pentylenetetrazol.svg | image_class = skin-invert-image | width = 150 | image2 = File:Pentylenetetrazol ball-and-stick model.png | image_class2 = bg-transparent <!--Clinical data-->| tradename = Metrazol, others | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_US = <!-- A / B / C / D / X --> | pregnancy_category = | legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --> | legal_UK = <!-- GSL / P / POM / CD --> | legal_US = <!-- OTC / Rx-only --> | legal_status = | routes_of_administration = <!--Pharmacokinetic data--> | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion = <!--Identifiers--> | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 54-95-5 | ATC_prefix = R07 | ATC_suffix = AB03 | PubChem = 5917 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} | ChemSpiderID = 5704 | UNII_Ref = {{fdacite|changed|FDA}} | UNII = WM5Z385K7T | ChEBI_Ref = {{ebicite|changed|EBI}} | ChEBI = 34910 | ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL = 116943 | KEGG_Ref = {{keggcite|changed|kegg}} | KEGG = D07409 | synonyms = Pentylenetetrazole; pentetrazol; pentamethylenetetrazol
<!--Chemical data-->| C = 6 | H = 10 | N = 4 | smiles = C1CCc2nnnn2CC1 | StdInChI_Ref = {{stdinchicite|changed|chemspider}} | StdInChI = 1S/C6H10N4/c1-2-4-6-7-8-9-10(6)5-3-1/h1-5H2 | StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} | StdInChIKey = CWRVKFFCRWGWCS-UHFFFAOYSA-N }}
'''Pentylenetetrazol''' ('''PTZ'''), also known as '''pentylenetetrazole''', '''pentetrazol''' (INN), and '''pentamethylenetetrazol''', is a drug formerly used as a circulatory and respiratory stimulant. High doses cause convulsions, as discovered by Hungarian-American neurologist and psychiatrist Ladislas J. Meduna in 1934. It has been used in convulsive therapy, and was found to be effective in treating depression, but side effects, such as uncontrolled seizures, were difficult to avoid.<ref>{{cite journal | vauthors = Read CF |title=Consequences of metrazol shock therapy |journal=American Journal of Psychiatry |volume=97 |issue=3 |year=1940 |pages=667–76 |doi=10.1176/ajp.97.3.667 }}</ref> In 1939, pentylenetetrazol was replaced by electroconvulsive therapy, which is easier to administer, as the preferred method for inducing seizures in England's mental hospitals. In the US, pentylenetetrazol's approval by the Food and Drug Administration (FDA) was revoked in 1982.<ref name="sciam">{{ cite news | author = Minkel JR | title = Drug May Counteract Down Syndrome | url = http://www.scientificamerican.com/article/drug-may-counteract-down/ | newspaper = Scientific American | date = February 25, 2007 | access-date = 2007-03-20}}</ref> It is used in Italy as a cardio-respiratory stimulant in combination with dihydrocodeine in a cough suppressant drug.<ref>{{cite web|url=https://farmaci.agenziafarmaco.gov.it/aifa/servlet/PdfDownloadServlet?pdfFileName=footer_007046_021473_FI.pdf&retry=0&sys=m0b1l3|title=Cardiazol-Paracodina|publisher=Agenzia Italiana del Farmaco|access-date=2020-10-28|archive-date=2021-11-09|archive-url=https://web.archive.org/web/20211109194022/https://farmaci.agenziafarmaco.gov.it/aifa/servlet/PdfDownloadServlet?pdfFileName=footer_007046_021473_FI.pdf&retry=0&sys=m0b1l3}}</ref>
==Side effects== Pentylenetetrazol is anxiogenic and has been known to induce severe anxiety in humans.<ref name="DurantChristmasNutt2009">{{cite book | vauthors = Durant C, Christmas D, Nutt D | title=Current Topics in Behavioral Neurosciences | chapter=The Pharmacology of Anxiety | publisher=Springer Berlin Heidelberg | publication-place=Berlin, Heidelberg | year=2009 | volume=2 | isbn=978-3-642-02911-0 | issn=1866-3370 | doi=10.1007/7854_2009_8 | pages=303–330 | pmid=21309115 | quote=Preliminary evidence that reducing GABAergic transmission induces anxiety came from the early use of pentylenetetrazol (PTZ) a convulsant drug used to induce seizures in the treatment of severe psychiatric disorders before the discovery of ECT. During its use dose titration was difficult, in many cases too little was given and no seizure was caused. This, however, produced a severely anxious state, leading to patients feeling 'as if they were going to die', and trying (often successfully) to escape from the clinic. Memory of this anxiety was extremely strong resulting in resistance to return to therapy and it was later shown that PTZ acts as an antagonist GABAA receptor.}}</ref>
==Mechanism of action== The mechanism of pentylenetetrazol is not well understood, and it may have multiple mechanisms of action. In 1984, Squires et al. published a report analyzing pentylenetetrazol and several structurally related convulsant drugs. They found that ''in vivo'' convulsant potency was strongly correlated to ''in vitro'' affinity to the picrotoxin binding site on the GABA<sub>A</sub> receptor complex. Many GABA<sub>A</sub> receptor ligands, such as diazepam and phenobarbital, are effective anticonvulsants, but pentylenetetrazol presumably has the opposite effect when it binds to the GABA<sub>A</sub> receptor.<ref>{{cite journal | vauthors = Squires RF, Saederup E, Crawley JN, Skolnick P, Paul SM | title = Convulsant potencies of tetrazoles are highly correlated with actions on GABA/benzodiazepine/picrotoxin receptor complexes in brain | journal = Life Sciences | volume = 35 | issue = 14 | pages = 1439–1444 | date = October 1984 | pmid = 6090836 | doi = 10.1016/0024-3205(84)90159-0 }}</ref>
Several studies have focused on the way pentylenetetrazol influences neuronal ion channels. A 1987 study found that pentylenetetrazol increases calcium influx and sodium influx, both of which depolarize the neuron. Because these effects were antagonized by calcium channel blockers, pentylenetetrazol apparently acts at calcium channels, and it causes them to lose selectivity and conduct sodium ions, as well.<ref>{{cite journal | vauthors = Papp A, Fehér O, Erdélyi L | title = The ionic mechanism of the pentylenetetrazol convulsions | journal = Acta Biologica Hungarica | volume = 38 | issue = 3–4 | pages = 349–361 | year = 1987 | pmid = 3503442 }}</ref>
==Research== Pentylenetetrazol has been used experimentally to study seizure phenomena and to identify pharmaceuticals that may control seizure susceptibility. Recent preclinical work has used pentylenetetrazol to evaluate experimental antiseizure compounds. For example, the synthetic molecule BICS01 showed no protective effect against PTZ induced seizures in mice despite suppressing epileptiform activity in hippocampal slice models<ref>{{cite journal | vauthors = Morris G, Heiland M, Lamottke K, Guan H, Hill TD, Zhou Y, Zhu Q, Schorge S, Henshall DC | date = 2022 | title = BICS01 Mediates Reversible Anti-seizure Effects in Brain Slice Models of Epilepsy | journal = Frontiers in Neurology | volume = 12 | article-number = 791608 | doi = 10.3389/fneur.2021.791608 | pmc = 8770400 | pmid = 35069421 | doi-access = free }}</ref> For instance, researchers can induce status epilepticus in animal models. Pentylenetetrazol is also a prototypical anxiogenic drug and has been extensively used in animal models of anxiety. Pentylenetetrazol produces a reliable discriminative stimulus, which is largely mediated by the GABA<sub>A</sub> receptor. Several classes of compounds can modulate the pentylenetetrazol discriminative stimulus, including 5-HT<sub>1A</sub>, 5-HT<sub>3</sub>, NMDA, glycine, and L-type calcium channel ligands.<ref>{{cite journal | vauthors = Jung ME, Lal H, Gatch MB | date = June 2002 | title = The discriminative stimulus effects of pentylenetetrazol as a model of anxiety: recent developments | journal = Neuroscience and Biobehavioral Reviews | volume = 26 | issue = 4 | pages = 429–439 | doi = 10.1016/S0149-7634(02)00010-6 | pmid = 12204190 | s2cid = 26055062 }}</ref>
Pentylenetetrazol is being studied as a wakefulness-promoting agent in the treatment of idiopathic hypersomnia and narcolepsy.<ref name="AdisInsight">{{cite web | title=Pentylenetetrazole - Balance Therapeutics | work = AdisInsight | publisher = Springer Nature Switzerland AG | date=28 June 2020 | url=https://adisinsight.springer.com/drugs/800038901 | access-date=25 September 2024}}</ref><ref name="TakahashiNoriakiMatsumura2018">{{cite journal | vauthors = Takahashi T, Noriaki S, Matsumura M, Li C, Takahashi K, Nishino S | title=Advances in pharmaceutical treatment options for narcolepsy | journal=Expert Opinion on Orphan Drugs | volume=6 | issue=10 | date=3 October 2018 | issn=2167-8707 | doi=10.1080/21678707.2018.1521267 | pages=597–610}}</ref>
== See also == * List of investigational narcolepsy and hypersomnia drugs * GABA<sub>A</sub> receptor negative allosteric modulator * GABA<sub>A</sub> receptor § Ligands
== References == {{Reflist|30em}}
{{Respiratory stimulants}} {{Convulsants}} {{GABA receptor modulators}}
Category:Antidepressants<!--Convulsive therapy--> Category:Anxiogenics Category:Convulsants Category:GABAA receptor negative allosteric modulators Category:Respiratory agents Category:Stimulants Category:Tetrazoles Category:Wakefulness-promoting agents Category:Withdrawn drugs