Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Br J Pharmacol
2016 Nov 01;17321:3110-3120. doi: 10.1111/bph.13566.
Show Gene links
Show Anatomy links
Activation and modulation of recombinant glycine and GABAA receptors by 4-halogenated analogues of propofol.
Germann AL
,
Shin DJ
,
Manion BD
,
Edge CJ
,
Smith EH
,
Franks NP
,
Evers AS
,
Akk G
.
???displayArticle.abstract???
BACKGROUND AND PURPOSE: 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 GABAA receptors. It has been proposed that halogenation of the propofol molecule generates compounds with selective enhancement of glycinergic modulatory properties.
EXPERIMENTAL APPROACH: 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 GABAA receptors expressed in oocytes. Behavioural effects of the compounds were compared in the tadpole loss-of-righting assay.
KEY RESULTS: 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 GABAA receptor with EC50 between 4 and 7 μM. The EC50 for loss-of-righting in Xenopus tadpoles, a proxy for loss of consciousness and considered to be mediated by actions on GABAA receptors, ranged from 0.35 to 0.87 μM.
CONCLUSIONS AND IMPLICATIONS: We confirm that halogenation of propofol more strongly affects modulation of homomeric glycine receptors than α1β3γ2L GABAA receptors. However, the effective concentrations of all tested halogenated compounds remained lower for GABAA receptors. We infer that 4-bromopropofol, 4-chloropropofol and 4-fluoropropofol are not selective homomeric glycine receptor modulators.
Akk,
Mechanisms of neurosteroid interactions with GABA(A) receptors.
2007, Pubmed
Akk,
Mechanisms of neurosteroid interactions with GABA(A) receptors.
2007,
Pubmed
Alexander,
The Concise Guide to PHARMACOLOGY 2015/16: Ligand-gated ion channels.
2015,
Pubmed
Belelli,
The in vitro and in vivo enantioselectivity of etomidate implicates the GABAA receptor in general anaesthesia.
2003,
Pubmed
,
Xenbase
Bode,
The impact of human hyperekplexia mutations on glycine receptor structure and function.
2014,
Pubmed
Curtis,
Experimental design and analysis and their reporting: new guidance for publication in BJP.
2015,
Pubmed
de la Roche,
4-Chloropropofol enhances chloride currents in human hyperekplexic and artificial mutated glycine receptors.
2012,
Pubmed
Downie,
Effects of inhalational general anaesthetics on native glycine receptors in rat medullary neurones and recombinant glycine receptors in Xenopus oocytes.
1996,
Pubmed
,
Xenbase
Eckle,
4-bromopropofol decreases action potential generation in spinal neurons by inducing a glycine receptor-mediated tonic conductance.
2014,
Pubmed
Feng,
Multiple actions of propofol on alphabetagamma and alphabetadelta GABAA receptors.
2004,
Pubmed
Franks,
Selective actions of volatile general anaesthetics at molecular and cellular levels.
1993,
Pubmed
Franks,
General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal.
2008,
Pubmed
Germann,
Activation and modulation of recombinant glycine and GABAA receptors by 4-halogenated analogues of propofol.
2016,
Pubmed
,
Xenbase
Grudzinska,
The beta subunit determines the ligand binding properties of synaptic glycine receptors.
2005,
Pubmed
Haeseler,
Structural features of phenol derivatives determining potency for activation of chloride currents via alpha(1) homomeric and alpha(1)beta heteromeric glycine receptors.
2005,
Pubmed
Hales,
The actions of propofol on inhibitory amino acid receptors of bovine adrenomedullary chromaffin cells and rodent central neurones.
1991,
Pubmed
Harvey,
GlyR alpha3: an essential target for spinal PGE2-mediated inflammatory pain sensitization.
2004,
Pubmed
Haverkamp,
Diversity of glycine receptors in the mouse retina: localization of the alpha3 subunit.
2003,
Pubmed
Jurd,
General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit.
2003,
Pubmed
Kilkenny,
Animal research: reporting in vivo experiments: the ARRIVE guidelines.
2010,
Pubmed
Krasowski,
General anesthetic potencies of a series of propofol analogs correlate with potency for potentiation of gamma-aminobutyric acid (GABA) current at the GABA(A) receptor but not with lipid solubility.
2001,
Pubmed
,
Xenbase
Lingamaneni,
Anesthetic properties of 4-iodopropofol: implications for mechanisms of anesthesia.
2001,
Pubmed
,
Xenbase
Lynch,
Native glycine receptor subtypes and their physiological roles.
2009,
Pubmed
Lynch,
Molecular structure and function of the glycine receptor chloride channel.
2004,
Pubmed
Malosio,
Widespread expression of glycine receptor subunit mRNAs in the adult and developing rat brain.
1991,
Pubmed
Mascia,
A single amino acid determines differences in ethanol actions on strychnine-sensitive glycine receptors.
1996,
Pubmed
,
Xenbase
McGrath,
Implementing guidelines on reporting research using animals (ARRIVE etc.): new requirements for publication in BJP.
2015,
Pubmed
Meyer,
Identification of a gephyrin binding motif on the glycine receptor beta subunit.
1995,
Pubmed
Picard,
Inhibitors of acyl-CoA:cholesterol O-acyltransferase. 17. Structure-activity relationships of several series of compounds derived from N-chlorosulfonyl isocyanate.
1996,
Pubmed
Pistis,
The interaction of general anaesthetics with recombinant GABAA and glycine receptors expressed in Xenopus laevis oocytes: a comparative study.
1997,
Pubmed
,
Xenbase
Reith,
Development and role of GABA(A) receptor-mediated synaptic potentials during swimming in postembryonic Xenopus laevis tadpoles.
1999,
Pubmed
,
Xenbase
Reynolds,
Sedation and anesthesia mediated by distinct GABA(A) receptor isoforms.
2003,
Pubmed
Rudolph,
Molecular and neuronal substrates for general anaesthetics.
2004,
Pubmed
Schaefer,
Glycine receptor mouse mutants: model systems for human hyperekplexia.
2013,
Pubmed
Southan,
The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands.
2016,
Pubmed
Takahashi,
Functional correlation of fetal and adult forms of glycine receptors with developmental changes in inhibitory synaptic receptor channels.
1992,
Pubmed
,
Xenbase
Trapani,
Propofol analogues. Synthesis, relationships between structure and affinity at GABAA receptor in rat brain, and differential electrophysiological profile at recombinant human GABAA receptors.
1998,
Pubmed
,
Xenbase
Turecek,
Reciprocal developmental regulation of presynaptic ionotropic receptors.
2002,
Pubmed
Waud,
On biological assays involving quantal responses.
1972,
Pubmed
Zhang,
Alpha2 subunit specificity of cyclothiazide inhibition on glycine receptors.
2008,
Pubmed
