title: GABAA receptor modulation by the novel intravenous general anaesthetic E-6375.
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 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.
authors: Neuroscience Institute, Department of Pharmacology and Neuroscience, Ninewells Hospital and Medical School, The University of Dundee, Dundee DD1 9SY, UK.
authors: D
authors: D
authors: Pau
authors: D
authors: D
authors: Belelli
authors: H
authors: H
authors: Callachan
authors: D R
authors: DR
authors: Peden
authors: J I
authors: JI
authors: Dunlop
authors: J A
authors: JA
authors: Peters
authors: X
authors: X
authors: Guitart
authors: B
authors: B
authors: Gutierrez
authors: J J
authors: JJ
authors: Lambert
mesh_terms: D000595:Amino Acid Sequence; D018686:Anesthetics, Intravenous / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D018757:GABA Modulators / Q000737:chemistry / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D009865:Oocytes; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011922:Rats, Mutant Strains; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: C481380:4-butoxy-2-(4-(2-cyanobenzoyl)-1-piperazinyl) pyrimidine hydrochloride; D018686:Anesthetics, Intravenous; D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D010879:Piperazines; D011743:Pyrimidines; D011963:Receptors, GABA-A