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Activation and modulation of recombinant glycine and GABAA receptors by 4-halogenated analogues of propofol.

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Title: Activation and modulation of recombinant glycine and GABAA receptors by 4-halogenated analogues of propofol.
Authors: Germann, Allison L, Shin, Daniel J, Manion, Brad D, Edge, Christopher J, Smith, Edward H, Franks, Nicholas P, Evers, Alex S, Akk, Gustav
Source: British Journal of Pharmacology; Nov2016, Vol. 173 Issue 21, p3110-3120, 11p, 2 Charts, 4 Graphs
Subject Terms: GLYCINE receptors, GABA receptors, PROPOFOL, PAIN perception, MOVEMENT disorder treatments, ANIMAL experimentation, ANURA, BIOCHEMISTRY, CELL receptors, DOSE-effect relationship in pharmacology, PHENOMENOLOGY, RECOMBINANT proteins, RESEARCH funding, VERTEBRATES, PHARMACODYNAMICS
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. [ABSTRACT FROM AUTHOR]
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  Data: Activation and modulation of recombinant glycine and GABA<subscript>A</subscript> receptors by 4-halogenated analogues of propofol.
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  Data: <searchLink fieldCode="AR" term="%22Germann%2C+Allison+L%22">Germann, Allison L</searchLink><br /><searchLink fieldCode="AR" term="%22Shin%2C+Daniel+J%22">Shin, Daniel J</searchLink><br /><searchLink fieldCode="AR" term="%22Manion%2C+Brad+D%22">Manion, Brad D</searchLink><br /><searchLink fieldCode="AR" term="%22Edge%2C+Christopher+J%22">Edge, Christopher J</searchLink><br /><searchLink fieldCode="AR" term="%22Smith%2C+Edward+H%22">Smith, Edward H</searchLink><br /><searchLink fieldCode="AR" term="%22Franks%2C+Nicholas+P%22">Franks, Nicholas P</searchLink><br /><searchLink fieldCode="AR" term="%22Evers%2C+Alex+S%22">Evers, Alex S</searchLink><br /><searchLink fieldCode="AR" term="%22Akk%2C+Gustav%22">Akk, Gustav</searchLink>
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  Data: British Journal of Pharmacology; Nov2016, Vol. 173 Issue 21, p3110-3120, 11p, 2 Charts, 4 Graphs
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  Data: <searchLink fieldCode="DE" term="%22GLYCINE+receptors%22">GLYCINE receptors</searchLink><br /><searchLink fieldCode="DE" term="%22GABA+receptors%22">GABA receptors</searchLink><br /><searchLink fieldCode="DE" term="%22PROPOFOL%22">PROPOFOL</searchLink><br /><searchLink fieldCode="DE" term="%22PAIN+perception%22">PAIN perception</searchLink><br /><searchLink fieldCode="DE" term="%22MOVEMENT+disorder+treatments%22">MOVEMENT disorder treatments</searchLink><br /><searchLink fieldCode="DE" term="%22ANIMAL+experimentation%22">ANIMAL experimentation</searchLink><br /><searchLink fieldCode="DE" term="%22ANURA%22">ANURA</searchLink><br /><searchLink fieldCode="DE" term="%22BIOCHEMISTRY%22">BIOCHEMISTRY</searchLink><br /><searchLink fieldCode="DE" term="%22CELL+receptors%22">CELL receptors</searchLink><br /><searchLink fieldCode="DE" term="%22DOSE-effect+relationship+in+pharmacology%22">DOSE-effect relationship in pharmacology</searchLink><br /><searchLink fieldCode="DE" term="%22PHENOMENOLOGY%22">PHENOMENOLOGY</searchLink><br /><searchLink fieldCode="DE" term="%22RECOMBINANT+proteins%22">RECOMBINANT proteins</searchLink><br /><searchLink fieldCode="DE" term="%22RESEARCH+funding%22">RESEARCH funding</searchLink><br /><searchLink fieldCode="DE" term="%22VERTEBRATES%22">VERTEBRATES</searchLink><br /><searchLink fieldCode="DE" term="%22PHARMACODYNAMICS%22">PHARMACODYNAMICS</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: <bold>Background and Purpose: </bold>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.<bold>Experimental Approach: </bold>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.<bold>Key Results: </bold>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.<bold>Conclusions and Implications: </bold>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. [ABSTRACT FROM AUTHOR]
– Name: Abstract
  Label:
  Group: Ab
  Data: <i>Copyright of British Journal of Pharmacology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1111/bph.13566
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        Text: English
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        PageCount: 11
        StartPage: 3110
    Subjects:
      – SubjectFull: GLYCINE receptors
        Type: general
      – SubjectFull: GABA receptors
        Type: general
      – SubjectFull: PROPOFOL
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      – SubjectFull: PAIN perception
        Type: general
      – SubjectFull: MOVEMENT disorder treatments
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      – SubjectFull: RESEARCH funding
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      – TitleFull: Activation and modulation of recombinant glycine and GABAA receptors by 4-halogenated analogues of propofol.
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              Text: Nov2016
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