Activation and modulation of recombinant glycine and GABAAreceptors by 4-halogenated analogues of propofol

Allison L. Germann, Daniel J. Shin, Brad D. Manion, Christopher J. Edge, Edward H. Smith, Nicholas P. Franks, Alex S. Evers, Gustav Akk

Research output: Contribution to journalArticle

12 Scopus citations

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 GABAAreceptors. 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 GABAAreceptors 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 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. Conclusions and Implications: 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.

Original languageEnglish
Pages (from-to)3110-3120
Number of pages11
JournalBritish Journal of Pharmacology
DOIs
StatePublished - Jan 1 2016

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