Source:http://linkedlifedata.com/resource/pubmed/id/14614946
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
8
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| pubmed:dateCreated |
2003-11-17
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| pubmed:abstractText |
E-6375 (4-butoxy-2-[4-(2-cyanobenzoyl)-1-piperazinyl] pyrimidine hydrochloride) is a new intravenous general anaesthetic with an anaesthetic potency, in mice, comparable to propofol, or etomidate. Here, we examined the effect of E-6375 upon the GABAA receptor, a putative target of intravenous anaesthetic action. E-6375 reversibly enhanced GABA-evoked currents mediated by recombinant GABAA (alpha1beta2gamma2L) receptors expressed in Xenopus laevis oocytes, with little effect on NMDA- and kainate-evoked currents mediated by NR1a/NR2A and GluR1o/GluR2o glutamate receptors, respectively. E-6375 prolonged the decay of GABA-evoked miniature inhibitory postsynaptic currents recorded from rat Purkinje neurones demonstrating the anaesthetic also enhanced the activity of synaptic GABAA receptors. The GABA enhancing action of E-6375 on recombinant GABAA receptors was unaffected by the subtype of the alpha isoform (i.e. alphaxbeta2gamma2L; x=1-3) within the receptor, but was increased by the omission of the gamma2L subunit. Receptors incorporating beta2, or beta3, subunits were more sensitive to modulation by E-6375 than those containing the beta1 subunit. The selectivity of E-6375 was largely governed by the identity (serine or asparagine) of a single amino acid residue within the second transmembrane domain of the beta-subunit. The various in vivo actions of general anaesthetics may be mediated by GABAA receptor isoforms that have a differential distribution within the CNS. The identification of agents, such as E-6375, that discriminate between GABAA receptor subtypes may augur the development of general anaesthetics with an improved therapeutic profile.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Anesthetics, Intravenous,
http://linkedlifedata.com/resource/pubmed/chemical/GABA Modulators,
http://linkedlifedata.com/resource/pubmed/chemical/GABA-A Receptor Agonists,
http://linkedlifedata.com/resource/pubmed/chemical/Piperazines,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrimidines,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, GABA-A
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| pubmed:status |
MEDLINE
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| pubmed:month |
Dec
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| pubmed:issn |
0028-3908
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| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:volume |
45
|
| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
1029-40
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| pubmed:dateRevised |
2010-11-18
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| pubmed:meshHeading |
pubmed-meshheading:14614946-Amino Acid Sequence,
pubmed-meshheading:14614946-Anesthetics, Intravenous,
pubmed-meshheading:14614946-Animals,
pubmed-meshheading:14614946-Dose-Response Relationship, Drug,
pubmed-meshheading:14614946-Female,
pubmed-meshheading:14614946-GABA Modulators,
pubmed-meshheading:14614946-GABA-A Receptor Agonists,
pubmed-meshheading:14614946-Injections, Intravenous,
pubmed-meshheading:14614946-Male,
pubmed-meshheading:14614946-Mice,
pubmed-meshheading:14614946-Mice, Inbred ICR,
pubmed-meshheading:14614946-Molecular Sequence Data,
pubmed-meshheading:14614946-Oocytes,
pubmed-meshheading:14614946-Piperazines,
pubmed-meshheading:14614946-Purkinje Cells,
pubmed-meshheading:14614946-Pyrimidines,
pubmed-meshheading:14614946-Rats,
pubmed-meshheading:14614946-Rats, Mutant Strains,
pubmed-meshheading:14614946-Receptors, GABA-A,
pubmed-meshheading:14614946-Xenopus laevis
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| pubmed:year |
2003
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| pubmed:articleTitle |
GABAA receptor modulation by the novel intravenous general anaesthetic E-6375.
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| pubmed:affiliation |
Neuroscience Institute, Department of Pharmacology and Neuroscience, Ninewells Hospital and Medical School, The University of Dundee, Dundee DD1 9SY, UK.
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| pubmed:publicationType |
Journal Article
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