title: Activation and modulation of recombinant glycine and GABAAreceptors by 4-halogenated analogues of propofol.
abstract: Glycine receptors are important players in pain perception and movement disorders and therefore important therapeutic targets. Glycine receptors can be modulated by the intravenous anaesthetic propofol (2,6-diisopropylphenol). However, the drug is more potent, by at least one order of magnitude, on GABAAreceptors. It has been proposed that halogenation of the propofol molecule generates compounds with selective enhancement of glycinergic modulatory properties.
  
  
  
  We synthesized 4-bromopropofol, 4-chloropropofol and 4-fluoropropofol. The direct activating and modulatory effects of these drugs and propofol were compared on recombinant rat glycine and human GABAAreceptors expressed in oocytes. Behavioural effects of the compounds were compared in the tadpole loss-of-righting assay.
  
  
  
  Concentration-response curves for potentiation of homomeric α1, α2 and α3 glycine receptors were shifted to lower drug concentrations, by 2-10-fold, for the halogenated compounds. Direct activation by all compounds was minimal with all subtypes of the glycine receptor. The four compounds were essentially equally potent modulators of the α1β3γ2L GABAAreceptor with EC50between 4 and 7 μM. The EC50for loss-of-righting in Xenopus tadpoles, a proxy for loss of consciousness and considered to be mediated by actions on GABAAreceptors, ranged from 0.35 to 0.87 μM.
  
  
  
  We confirm that halogenation of propofol more strongly affects modulation of homomeric glycine receptors than α1β3γ2L GABAAreceptors. However, the effective concentrations of all tested halogenated compounds remained lower for GABAAreceptors. We infer that 4-bromopropofol, 4-chloropropofol and 4-fluoropropofol are not selective homomeric glycine receptor modulators.
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Allison L
authors.initials: AL
authors.lastname: Germann
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Shin
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Brad D
authors.initials: BD
authors.lastname: Manion
authors.affiliation: Department of Life Sciences, Imperial College London, South Kensington, UK.|Department of Anaesthetics, Royal Berkshire NHS Foundation Trust, Reading, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Edge
authors.affiliation: Department of Life Sciences, Imperial College London, South Kensington, UK.
authors.forename: Edward H
authors.initials: EH
authors.lastname: Smith
authors.affiliation: Department of Life Sciences, Imperial College London, South Kensington, UK.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Franks
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA.|Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Alex S
authors.initials: AS
authors.lastname: Evers
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA. akk@morpheus.wustl.edu.|Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA. akk@morpheus.wustl.edu.
authors.forename: Gustav
authors.initials: G
authors.lastname: Akk
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015742:Propofol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D018009:Receptors, Glycine / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D011994:Recombinant Proteins; D015742:Propofol