GABAA receptor modulation by the novel intravenous general anaesthetic E-6375
| Autor: | Jeremy J. Lambert, Helen Callachan, Dianne R. Peden, X. Guitart, Delia Belelli, John A. Peters, James I. Dunlop, B. Gutierrez, D. Pau |
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| Rok vydání: | 2003 |
| Předmět: |
Male
Molecular Sequence Data AMPA receptor Neurotransmission Pharmacology Piperazines Rats Mutant Strains GABAA-rho receptor Mice Purkinje Cells Xenopus laevis Cellular and Molecular Neuroscience GABA receptor Animals Amino Acid Sequence GABA-A Receptor Agonists GABA Modulators General anaesthetic Receptor Mice Inbred ICR Dose-Response Relationship Drug GABAA receptor Chemistry Receptors GABA-A Rats Pyrimidines nervous system Injections Intravenous Oocytes NMDA receptor Female Anesthetics Intravenous |
| Zdroj: | Neuropharmacology. 45:1029-1040 |
| ISSN: | 0028-3908 |
| DOI: | 10.1016/s0028-3908(03)00299-5 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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