GABAA receptor modulation by the novel intravenous general anaesthetic E-6375

D. Pau, D. Belelli, H. Callachan, D. R. Peden, J. I. Dunlop, J. A. Peters, X. Guitart, B. Gutierrez, J. J. Lambert

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

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 GABAA1β 2γ2L) 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 α isoform (i.e. αxβ2γ 2L; x=1-3) within the receptor, but was increased by the omission of the γ2L subunit. Receptors incorporating β2, or β3, subunits were more sensitive to modulation by E-6375 than those containing the β1 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 β-subunit. The various in vivo actions of general anaesthetics may be mediated by GABA A 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.

Original languageEnglish
Pages (from-to)1029-1040
Number of pages12
JournalNeuropharmacology
Volume45
Issue number8
DOIs
Publication statusPublished - Dec 2003

Keywords

  • AMPA receptor
  • E-6375 (4-butoxy-2-[4-(2-cyanobenzoyl)-1- piperazinyl] pyrimidine hydrochloride)
  • GABA receptor
  • General anaesthetic
  • Inhibitory synaptic transmission
  • NMDA receptor

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