Activation and modulation of recombinant glycine and GABA_A receptors 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_A 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 GABA_A 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 GABA_A 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 GABA_A 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 GABA_A receptors. However, the effective concentrations of all tested halogenated compounds remained lower for GABA_A receptors. We infer that 4‐bromopropofol, 4‐chloropropofol and 4‐fluoropropofol are not selective homomeric glycine receptor modulators.

DOI: 10.1111/bph.13566

View this article

• Full article (html)
• Enhanced article (html)
• PDF
• References