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a drug used as a circulatory and respiratory stimulant; larger doses cause convulsions in shock therapy; Metrazol is a trademark (同)pentamethylenetetrazol, Metrazol

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/01/15 20:22:13」(JST)

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Pentylenetetrazol, also known as pentylenetetrazole, metrazol, pentetrazol (INN), pentamethylenetetrazol, Cardiazol or PTZ, was 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 seizures were difficult to avoid. Its approval by the FDA was revoked in 1982.^[1]

Mechanism

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 are effective anticonvulsants, such as the sedatives diazepam and phenobarbital, but presumably pentylenetetrazol has the opposite effect when it binds to the GABA-A receptor.^[2]

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, it was concluded that pentylenetetrazol acts at calcium channels, and it causes calcium channels to lose selectivity and conduct sodium ions as well.^[3]

Uses

Pentylenetetrazol has been used experimentally to study seizure phenomena 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.^[4]

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 antagonists in restoring the declarative memory deficits associated with the mouse model of human Down Syndrome. Ts65Dn mice injected with a 2-week regimen 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 regimen. 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.^[5]

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.^[6]

Alternatives

In 1939, pentylenetetrazol was replaced by electroconvulsive therapy as the preferred method for inducing seizures in England's mental hospitals. However, it wasn't disapproved of in the United States until 1982.

References

^ Minkel JR (February 25, 2007). "Drug May Counteract Down Syndrome". Scientific American. Retrieved 2007-03-20.
^ Squires RF, Saederup E, Crawley JN, Skolnick P, Paul SM (1984). "Convulsant potencies of tetrazoles are highly correlated with actions on GABA / benzodiazepine / picrotoxin receptor complexes in brain". Life Sci. 35 (14): 1439–44. doi:10.1016/0024-3205(84)90159-0. PMID 6090836.
^ Papp A, Fehér O, Erdélyi L (1987). "The ionic mechanism of the pentylenetetrazol convulsions". Acta Biol. Hung. 38 (3–4): 349–61. PMID 3503442.
^ Jung ME, Lal H, Gatch MB (2002). "The discriminative stimulus effects of pentylenetetrazol as a model of anxiety: recent developments". Neurosci. Biobehav. Rev. 26 (4): 429–39. doi:10.1016/S0149-7634(02)00010-6. PMID 12204190.
^ Fernandez F, Morishita W, Zuniga E, Nguyen J, Blank M, Malenka RC, Garner CC (2007). "Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome". Nat. Neurosci. 10 (4): 411–3. doi:10.1038/nn1860. PMID 17322876.
^ Ruby NF, Hwang CE, Wessells C, Fernandez F, Zhang P, Sapolsky R, Heller HC (2008). "Hippocampal-dependent learning requires a functional circadian system". PNAS USA 105 (40): 15593–8. doi:10.1073/pnas.0808259105. PMC 2563080. PMID 18832172.

UpToDate Contents

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1. ダウン症：マネージメント down syndrome management

English Journal

m-trifluoromethyl diphenyl diselenide attenuates glutaric acid-induced seizures and oxidative stress in rat pups: Involvement of the γ-aminobutyric acidergic system.

Magni DV, Brüning CA, Gai BM, Quines CB, Rosa SG, Fighera MR, Nogueira CW.SourceLaboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, Brasil. danielimagni@gmail.com.
Journal of neuroscience research.J Neurosci Res.2012 Sep;90(9):1723-31. doi: 10.1002/jnr.23070. Epub 2012 Apr 26.
Glutaric acidemia type I (GA-I) is an inherited metabolic disease characterized by accumulation of glutaric acid (GA) and seizures. The intrastriatal GA administration in rats has been used as an animal model to mimic seizures presented by glutaric acidemic patients. m-Trifluoromethyl diphenyl disel
PMID 22535575

Synthesis and Anticonvulsant Activity of O-alkylated Derivatives of 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone Oxime.

Bansal R, Chauhan P, Sharma R.SourceUniversity Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014, India.
Arzneimittel-Forschung.Arzneimittelforschung.2012 Jul 12. [Epub ahead of print]
In this study, O-alkylated derivatives of nafimidone oxime chemically, 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone oxime have been synthesized as potential anticonvulsant compounds. O-alkylation of the oxime using hydrochlorides of various dialkylaminoethyl chlorides, methyl chloroacetate and alkyl dih
PMID 22791243

Japanese Journal

Synthesis and Anticonvulsant Activity of Certain Substituted Furochromone, Benzofuran and Flavone Derivatives

Ragab Fatma Abdel-Fattah,El-Sayed Nehad Aboul Magd,Eissa Amal Abdel Haleem Mohamed,El Kerdawy Ahmed Mahmoud
CHEMICAL & PHARMACEUTICAL BULLETIN 58(9), 1148-1156, 2010
… All the newly synthesized compounds were tested for their anticonvulsant activity in both subcutaneous pentylenetetrazole induced seizures (scPTZ) and maximal electric shock induced seizures (MES) tests using valproic acid and phenytoin respectively as reference standards. …
NAID 130000324587

Anxiolytic and Antiseizure Effects of Sida tiagii Bhandri

Datusalia Ashok Kumar,Kalra Pankaj,Narasimhan Balasubramanian,Sharma Sunil,Goyal Ramesh Kumar
Journal of health science 54(5), 544-550, 2008-10-01
… The central nervous system (CNS) pharmacological effects of ethylacetate extract (EAS) of Sida tiagii Bhandri collected from northern province (Rajasthan) of India were assessed by elevated plus-maze, pentobarbitone induced sleeping time, spontaneous motor activity, pentylenetetrazole-induced seizure, forced swim test and rotarod tests. …
NAID 110006935580

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関連記事	「pentylenetetrazol」

「pentylenetetrazol」

Pentylenetetrazol
Systematic (IUPAC) name
	6,7,8,9-Tetrahydro-5H-tetrazolo(1,5-a)azepine
Clinical data
Legal status	?
Identifiers
CAS number	54-95-5
ATC code	R07AB03
PubChem	CID 5917
ChemSpider	5704
UNII	WM5Z385K7T
KEGG	D07409
ChEBI	CHEBI:34910
ChEMBL	CHEMBL116943
Chemical data
Formula	C6H10N4
Molecular mass	138.171 g/mol
	SMILES C12=NN=N[N]1CCCCC2;
	InChI InChI=1S/C6H10N4/c1-2-4-6-7-8-9-10(6)5-3-1/h1-5H2 ; Key:CWRVKFFCRWGWCS-UHFFFAOYSA-N ;
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[sciam-1] Minkel JR (February 25, 2007). "Drug May Counteract Down Syndrome". Scientific American. Retrieved 2007-03-20.

[2] Squires RF, Saederup E, Crawley JN, Skolnick P, Paul SM (1984). "Convulsant potencies of tetrazoles are highly correlated with actions on GABA / benzodiazepine / picrotoxin receptor complexes in brain". Life Sci. 35 (14): 1439–44. doi:10.1016/0024-3205(84)90159-0. PMID 6090836.

[3] Papp A, Fehér O, Erdélyi L (1987). "The ionic mechanism of the pentylenetetrazol convulsions". Acta Biol. Hung. 38 (3–4): 349–61. PMID 3503442.

[4] Jung ME, Lal H, Gatch MB (2002). "The discriminative stimulus effects of pentylenetetrazol as a model of anxiety: recent developments". Neurosci. Biobehav. Rev. 26 (4): 429–39. doi:10.1016/S0149-7634(02)00010-6. PMID 12204190.

[5] Fernandez F, Morishita W, Zuniga E, Nguyen J, Blank M, Malenka RC, Garner CC (2007). "Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome". Nat. Neurosci. 10 (4): 411–3. doi:10.1038/nn1860. PMID 17322876.

[6] Ruby NF, Hwang CE, Wessells C, Fernandez F, Zhang P, Sapolsky R, Heller HC (2008). "Hippocampal-dependent learning requires a functional circadian system". PNAS USA 105 (40): 15593–8. doi:10.1073/pnas.0808259105. PMC 2563080. PMID 18832172.

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