Pentylenetetrazol: Difference between revisions
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{{Short description|Chemical compound}} |
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{{drugbox | verifiedrevid = 386830665 |
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{{Drugbox |
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| Verifiedfields = changed |
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| IUPAC_name = 6,7,8,9-Tetrahydro-5''H''-tetrazolo(1,5-''a'')azepine |
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| Watchedfields = changed |
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| image = Pentylenetetrazol.svg |
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| verifiedrevid = 415933541 |
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| CASNo_Ref = {{cascite}} |
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| IUPAC_name = 6,7,8,9-Tetrahydro-5''H''-tetrazolo(1,5-''a'')azepine |
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| CAS_number = 54-95-5 |
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| image = Pentylenetetrazol.svg |
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| ATC_prefix = R07 |
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| width = 150 |
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| ATC_suffix = AB03 |
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| image2 = File:Pentylenetetrazol ball-and-stick model.png |
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| PubChem = 5917 |
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<!--Clinical data--> |
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| DrugBank = |
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| tradename = Metrazol, others |
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| smiles = C12=NN=N[N]1CCCCC2 |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| C=6 | H=10 | N=4 |
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| pregnancy_US = <!-- A / B / C / D / X --> |
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| molecular_weight = 138.171 |
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| pregnancy_category = |
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| bioavailability = |
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| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --> |
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| protein_bound = |
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| legal_UK = <!-- GSL / P / POM / CD --> |
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| metabolism = |
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| legal_US = <!-- OTC / Rx-only --> |
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| elimination_half-life = |
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| legal_status = |
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| excretion = |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_US = <!-- A / B / C / D / X --> |
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| pregnancy_category = |
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| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --> |
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| legal_UK = <!-- GSL / P / POM / CD --> |
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| legal_US = <!-- OTC / Rx-only --> |
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| legal_status = |
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| routes_of_administration = |
| routes_of_administration = |
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<!--Pharmacokinetic data--> |
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| bioavailability = |
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| protein_bound = |
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<!--Identifiers--> |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 54-95-5 |
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| ATC_prefix = R07 |
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| ATC_suffix = AB03 |
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| PubChem = 5917 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = |
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| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} |
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| ChemSpiderID = 5704 |
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| UNII_Ref = {{fdacite|changed|FDA}} |
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| UNII = WM5Z385K7T |
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| ChEBI_Ref = {{ebicite|changed|EBI}} |
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| ChEBI = 34910 |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL = 116943 |
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| KEGG_Ref = {{keggcite|changed|kegg}} |
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| KEGG = D07409 |
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<!--Chemical data--> |
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| C = 6 | H = 10 | N = 4 |
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| smiles = C1CCc2nnnn2CC1 |
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| StdInChI_Ref = {{stdinchicite|changed|chemspider}} |
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| StdInChI = 1S/C6H10N4/c1-2-4-6-7-8-9-10(6)5-3-1/h1-5H2 |
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| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} |
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| StdInChIKey = CWRVKFFCRWGWCS-UHFFFAOYSA-N |
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}} |
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'''Pentylenetetrazol''', also known as '''pentylenetetrazole''', '''leptazol''', '''metrazol''', '''pentetrazol''' ([[International Nonproprietary Name|INN]]), '''pentamethylenetetrazol''', '''Corazol''', '''Cardiazol''', '''Deumacard''', or '''PTZ''', 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—primarily for depression—but side effects such as uncontrolled [[seizure]]s were difficult to avoid.<ref>{{cite journal |last1=Read |first1=Charles F. |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, its approval by the [[Food and Drug Administration]] 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 [[codeine]] 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}}</ref> |
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'''Pentylenetetrazol''' ([[International Nonproprietary Name|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 convulsive therapy, but was never considered to be effective, and side-effects such as [[seizure]]s were difficult to avoid. Its approval by the [[Food and Drug Administration|FDA]] was revoked in 1982.<ref name="sciam">{{cite news | author = JR Minkel | title = Drug May Counteract Down Syndrome | url = http://www.sciam.com/article.cfm?chanID=sa003&articleID=F9E196DB-E7F2-99DF-385C9F38537F58D6 | publisher = Scientific American | date = February 25, 2007 | accessdate = 2007-03-20}}</ref> |
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==Mechanism== |
==Mechanism== |
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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-A receptor]] complex. Many GABA-A ligands, such as the [[sedative]]s [[diazepam]] and [[phenobarbital]], are effective [[anticonvulsants]], but presumably pentylenetetrazol has the opposite effect when it binds to the GABA-A 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 Sci. | year = 1984 | volume = 35 | issue = 14 | pages = 1439–44 | pmid = 6090836 | doi=10.1016/0024-3205(84)90159-0}}</ref> |
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Pentylenetetrazol is considered a [[GABA antagonist]].<ref>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=mesh&list_uids=68010433&dopt=Full Entry for Pentylenetetrazole] in the [[Medical Subject Headings|MeSH]] database</ref> The [[mechanism of action|mechanism]] of the [[epileptogenic]] action of pentylenetetrazol at the cellular [[neurons|neuronal]] level is still unclear. [[Electrophysiology|Electrophysiological]] studies have shown it acts at [[cell membrane]] level decreasing the recovery time between [[action potential]]s by increasing [[potassium]] [[Semipermeable membrane|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. |
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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 Biol. Hung. | year = 1987 | volume = 38 | issue = 3–4 | pages = 349–61 | pmid = 3503442 }}</ref> |
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==Uses== |
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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|GABA<sub>A</sub>]] receptor. Several classes of compounds can modulate the pentylenetetrazol discriminative stimulus including [[5-HT1A|5-HT<sub>1A</sub>]], [[5-HT3|5-HT<sub>3</sub>]], [[NMDA]], [[glycine]], and [[L-type calcium channel]] [[ligands]].<ref>{{cite journal |author=Jung M, Lal H, Gatch M |title=The discriminative stimulus effects of pentylenetetrazol as a model of anxiety: recent developments |journal=Neurosci Biobehav Rev |volume=26 |issue=4 |pages=429–39 |year=2002 |pmid=12204190 |doi=10.1016/S0149-7634(02)00010-6}}</ref> |
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==Research== |
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Recently, Stanford University researchers have renewed interest in PTZ as a candidate for pharmacological treatment of [[Down syndrome]]. Published in the April 2007 issue of [[Nature Neuroscience]], their brief communication outlined an experiment designed to test the underlying theory proposed to explain the purported efficacy of [[GABA A receptor|GABA<sub>A</sub>]] antagonists in restoring the [[declarative memory]] deficits associated with the mouse model of human Down Syndrome. Ts65Dn mice injected with a 2-week regiment of either of two compounds [[picrotoxin]] or [[bilobalide]] (both GABA antagonists) showed marked improvements in both exploration and recognition of novel objects over controls injected with only saline. These results were duplicated in a second experiment with mice fed either plain milk or a combination of milk and a non-epileptogenic dose of PTZ daily for 17 days. PTZ-fed mice achieved novel object task scores comparable to wild-type (normal) mice. These improvements persisted at least 1 to 2 months after the treatment regiment. Not surprisingly these compounds' efficacies were accompanied by the normalization of [[Long-term potentiation]] in the [[dentate gyrus]] one month after the end of treatment, further suggesting persistent drug-mediated improvements in learning and memory.<ref>{{cite journal |author=Fernandez F, Morishita W, Zuniga E, Nguyen J, Blank M, Malenka R, Garner C |title=Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome |journal=Nat Neurosci |volume=10 |issue=4 |pages=411–413 |year=2007 |url=http://med.stanford.edu/nbc/articles/7%20-%20Pharmacotherapy%20for%20Cognitive%20Impairment%20in%20a%20Mouse%20Model%20of%20Down%20Syndrome.pdf |pmid=17322876 |doi=10.1038/nn1860}}</ref> |
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Pentylenetetrazol has been used experimentally to study seizure phenomena and to identify pharmaceuticals that may control seizure susceptibility. 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 A receptor|GABA<sub>A</sub>]] receptor. Several classes of compounds can modulate the pentylenetetrazol discriminative stimulus, including [[5-HT1A|5-HT<sub>1A</sub>]], [[5-HT3|5-HT<sub>3</sub>]], [[NMDA]], [[glycine]], and [[L-type calcium channel]] [[ligands]].<ref>{{ cite journal |vauthors=Jung ME, Lal H, Gatch MB | title = The discriminative stimulus effects of pentylenetetrazol as a model of anxiety: recent developments | journal = Neurosci. Biobehav. Rev. | year = 2002 | volume = 26 | issue = 4 | pages = 429–39 | pmid = 12204190 | doi = 10.1016/S0149-7634(02)00010-6 | s2cid = 26055062 }}</ref> |
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==See also== |
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The finding of pentylenetetrazol's effectiveness in treating a mouse model of 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.<ref>Ruby et al.; Hippocampal-dependent learning requires a functional circadian system; Proceedings of the National Academy of Sciences of the United States of America, 2008, vol. 105, no. 40,15593-15598</ref> |
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* [[List of investigational sleep drugs]] |
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* [[GABAA receptor negative allosteric modulator|GABA<sub>A</sub> receptor negative allosteric modulator]] |
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==Alternatives== |
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* [[GABAA receptor#Ligands|GABA<sub>A</sub> receptor § Ligands]] |
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In 1939, pentylenetetrazol was replaced by [[electroconvulsive therapy]] as the preferred method for inducing seizures in England's mental hospitals. |
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==References== |
==References== |
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{{Reflist|30em}} |
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{{Respiratory stimulants}} |
{{Respiratory stimulants}} |
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{{GABA receptor modulators}} |
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{{GABAergics}} |
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{{Convulsants}} |
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[[Category:Antidepressants]]<!--Convulsive therapy--> |
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[[Category:Stimulants]] |
[[Category:Stimulants]] |
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[[Category: |
[[Category:GABAA receptor negative allosteric modulators]] |
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[[Category:Withdrawn drugs]] |
[[Category:Withdrawn drugs]] |
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[[Category:Respiratory agents]] |
[[Category:Respiratory agents]] |
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[[Category:Convulsants]] |
[[Category:Convulsants]] |
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[[Category:Tetrazoles]] |
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[[de:Pentetrazol]] |
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[[es:Pentilenotetrazol]] |
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[[ru:Пентилентетразол]] |