Stereoselective effects of etomidate optical isomers on gamma-aminobutyric acid type A receptors and animals

Anesthesiology. 1998 Mar;88(3):708-17. doi: 10.1097/00000542-199803000-00022.


Background: The intravenous anesthetic etomidate is optically active and exists in two mirror-image enantiomeric forms. However, although the R(+) isomer is used as a clinical anesthetic, quantitative information on the relative potencies of the R(+) and S(-) isomers is lacking. These data could be used to test the relevance of putative molecular targets.

Methods: The anesthetic concentrations for a half-maximal effect (EC50) needed to induce a loss of righting reflex in tadpoles (Rana temporaria) were determined for both etomidate enantiomers. The effects of the isomers on gamma-aminobutyric acid (GABA)-induced currents in stably transfected mouse fibroblast cells was also investigated using the patch-clamp technique. In addition, the effects of the isomers on a lipid chain-melting phase transition were determined.

Results: The EC50 concentrations for general anesthesia for the R(+) and S(-) isomers were 3.4 +/- 0.1 microM and 57 +/- 1 microM, with slopes of n = 1.9 +/- 0.1 and n = 2.9 +/- 0.2, respectively. The R(+) isomer was also much more effective than the S(-) isomer at potentiating GABA-induced currents, although the degree of stereoselectivity varied with anesthetic concentration. R(+) etomidate potentiated the GABA-induced currents by increasing the apparent affinity of GABA for its receptor. Both isomers were equally effective at disrupting lipid bilayers.

Conclusions: These data are consistent with the idea that the GABA(A) receptor plays a central role in the actions of etomidate. Etomidate exerts its effects on the receptor by binding directly to a specific site or sites on the protein and allosterically enhancing the apparent affinity of GABA for its receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1,2-Dipalmitoylphosphatidylcholine / pharmacology
  • Anesthetics, Intravenous / chemistry
  • Animals
  • Cell Line
  • Dose-Response Relationship, Drug
  • Etomidate / chemistry*
  • Etomidate / pharmacology
  • Ion Channel Gating / drug effects
  • Lipid Bilayers
  • Mice
  • Rana temporaria
  • Receptors, GABA-A / drug effects*
  • Stereoisomerism
  • gamma-Aminobutyric Acid / pharmacology


  • Anesthetics, Intravenous
  • Lipid Bilayers
  • Receptors, GABA-A
  • 1,2-Dipalmitoylphosphatidylcholine
  • gamma-Aminobutyric Acid
  • Etomidate