Background Positive modulation of gamma-aminobutyric acid type A (GABAA) receptor function is recognized as an important component of the central nervous system depressant effects of many general anesthetics, including propofol. The role for GABAA receptors as an essential site in the anesthetic actions of propofol was recently challenged by a report that the propofol analog 4-iodopropofol (4-iodo-2,6-diisopropylphenol) potentiated and directly activated GABAA receptors, yet was devoid of sedative-anesthetic effects in rats after intraperitoneal injection. Given the important implications of these findings for theories of anesthesia, the authors compared the effects of 4-iodopropofol with those of propofol using established in vivo and in vitro assays of both GABAA receptor-dependent and -independent anesthetic actions. Methods The effects of propofol and 4-iodopropofol were analyzed on heterologously expressed recombinant human GABAA alpha1beta2gamma2 receptors, evoked population spike amplitudes in rat hippocampal slices, and glutamate release from rat cerebrocortical synaptosomes in vitro. Anesthetic potency was determined by loss of righting reflex in Xenopus laevis tadpoles, in mice after intraperitoneal injection, and in rats after intravenous injection. Results Like propofol, 4-iodopropofol enhanced GABA-induced currents in recombinant GABAA receptors, inhibited synaptic transmission in rat hippocampal slices, and inhibited sodium channel-mediated glutamate release from synaptosomes, but with reduced potency. After intraperitoneal injection, 4-iodopropofol did not produce anesthesia in mice, but it was not detected in serum or brain. However, 4-iodopropofol did produce anesthesia in tadpoles (EC50 = 2.5 +/- 0.5 microM) and in rats after intravenous injection (ED50 = 49 +/- 6.2 mg/kg). Conclusions Propofol and 4-iodopropofol produced similar actions on several previously identified cellular and molecular targets of general anesthetic action, and both compounds induced anesthesia in tadpoles and rats. The failure of 4-iodopropofol to induce anesthesia in rodents after intraperitoneal injection is attributed to a pharmacokinetic difference from propofol rather than to major pharmacodynamic differences.

1 Propofol (2,6 di-isopropylphenol), an intravenous general anaesthetic, blocks voltage-dependent Na+ channels (Na+ channels). In this study the interaction between propofol and Na+ channels was analysed by examining its effects on neurotoxin binding to various receptor sites of the Na+ channel in rat cerebrocortical synaptosomes.2 Propofol (10-200 mu M) exhibited concentration-dependent inhibition of equilibrium binding of [H-3]-batrachotoxinin-A 20-alpha-benzoate ([H-3]-BTX-B) to receptor site 2 of the Na+ channel (mean IC50=26 mu M; 6.5 mu M free). Scatchard analysis revealed that propofol significantly increased the K-D without affecting the B-max for [H-3]-BTX-B binding.3 Kinetic studies of [H-3]-BTX-B bindig in the presence of various concentrations (25-200 mu M) of propofol showed no significant changes in the association rate of [H-3]-BTX-B. However, propofol at 200 mu M significantly increased the rate of dissociation of [H-3]-BTX-B, consistent with an indirect allosteric competitive mechanism of inhibition.4 [H-3]-saxitoxin binding to receptor site 1 and [H-3]-brevetoxin-3 binding to receptor site 5 of the Na+ channel were not inhibited by propofol (10-200 mu M).5 Propofol (10-100 mu M) exhibited concentration-dependent inhibition of veratridine-evoked Na+ influx either in the absence or presence of scorpion toxin with IC50 values of 46 mu M (8.8 mu M free) and 44 mu M (8.5 mu M free), respectively.6 These results suggest that propofol inhibits voltage-dependent Na+ channels due to a preferential interaction with the inactivated state of the channel. Blockage of Na+ channels by propofol, which is known to inhibit glutamate release from synaptosomes, may contribute to its anaesthetic, anticonvulsant and neuroprotective properties.