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

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 GABA_Areceptors. 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 GABA_Areceptors 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 GABA_Areceptor 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 GABA_Areceptors, 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 GABA_Areceptors. However, the effective concentrations of all tested halogenated compounds remained lower for GABA_Areceptors. We infer that 4-bromopropofol, 4-chloropropofol and 4-fluoropropofol are not selective homomeric glycine receptor modulators.