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ANESTHETIC PHARMACOLOGY

2,6 Di-tert-butylphenol, a Nonanesthetic Propofol Analog, Modulates ₁ß Glycine Receptor Function in a Manner Distinct from Propofol

Jörg Ahrens, MD^*, Gertrud Haeseler, MD^*, Martin Leuwer, MD, Bahram Mohammadi, MD, Klaus Krampfl, MD, Reinhard Dengler, MD, and Johannes Bufler, MD

Departments of *Anaesthesiology and Neurology and Neurophysiology, Hannover Medical School, Hannover, Germany; and University Department of Anaesthesia, The University of Liverpool, Liverpool, United Kingdom

Gertrud Haeseler, MD, Department of Anaesthesiology, OE 8050, Hannover Medical School, D-30623 Hannover, Germany. Address e-mail to Haeseler.Gertrud{at}MH-Hannover.de

The anesthetic propofol (2,6 diisopropylphenol) mediates some of its effects by activating inhibitory chloride currents in the lower brainstem and spinal cord. The effects comprise direct activation of -aminobutyric acid-A and glycine receptors in the absence of the natural agonist, as well as potentiation of the effect of submaximal agonist concentrations. Replacement of propofol’s isopropyl groups by di-tert-butyl groups yields a compound without in vivo anesthetic effects. We have studied the effects of propofol and 2,6 di-tert-butylphenol on chloride inward currents via rat ₁ß glycine receptors heterologously expressed in human embryonic kidney cells. Propofol, but not 2,6 di-tert-butylphenol, directly activated glycine receptors; half-maximal current activation was observed with propofol 114 ± 27 µM. Both compounds potentiated the effect of a submaximal glycine concentration (10 µM) to a maximum value of 136% ± 71% (propofol) and 279% ± 109% (2,6 di-tert-butylphenol) of the response to glycine 10 µM. The 50% effective concentration for this effect was 12.5 ± 6.4 µM and 9.4 ± 10.2 µM for propofol and 2,6 di-tert-butylphenol, respectively. Propofol and its nonanesthetic structural analog do not differ in their ability to coactivate the glycine receptor but differ in their ability to directly activate the receptor in the absence of the natural agonist.

IMPLICATIONS: This in vitro study shows that, at the glycine receptor level, propofol does not differ from its nonanesthetic structural analog 2,6 di-tert-butylphenol in its ability to enhance the effect of small glycine concentrations but differs in its potential to directly activate chloride inward currents in the absence of the natural agonist.

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