Stereoselective Effects of Etomidate Optical Isomers on Gamma‐aminobutyric Acid Type A Receptors and Animals

@article{Tomlin1998StereoselectiveEO,
  title={Stereoselective Effects of Etomidate Optical Isomers on Gamma‐aminobutyric Acid Type A Receptors and Animals},
  author={Sarah L. Tomlin and Andrew Jenkins and William Robert Lieb and Nicholas P. Franks},
  journal={Anesthesiology},
  year={1998},
  volume={88},
  pages={708–717}
}
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… 
Preparation of barbiturate optical isomers and their effects on GABA(A) receptors.
TLDR
The rank order and degree of stereoselectivity that are observed for the enantiomers of hexobarbital, pentobar bital, and thiopental acting on the gamma-aminobutyric acid type A receptor are entirely consistent with this receptor playing a central role in the anesthetic actions of barbiturates.
Effects of thiopental and its optical isomers on nicotinic acetylcholine receptors.
TLDR
Both central neuronal and peripheral muscle nAChRs can be substantially inhibited by thiopental at surgical EC50 concentrations but with either no stereoselectivity or one opposite to that for general anesthesia.
Identification of Anesthetic Binding Sites on Human Serum Albumin Using a Novel Etomidate Photolabel*
TLDR
A novel analog of the general anesthetic etomidate in which the ethoxy group has been replaced by an azide group is synthesized, and which can be used as a photolabel to identify etomidates binding sites, and may prove to be a useful new photolab to identify anesthetic binding sites on the GABAA receptor or other putative targets.
Differential Potency of 2,6-Dimethylcyclohexanol Isomers for Positive Modulation of GABAA Receptor Currents
TLDR
The stereochemical configuration within the dimethylcyclohexanols is an important molecular feature in conferring positive modulation of GABAA receptor activity and for binding to the receptor, a consideration that needs to be taken into account when designing novel anesthetics with enhanced therapeutic indices.
Ecotoxicology of narcosis: stereoselectivity and potential target sites.
Lack of enantiomeric specificity in the effects of anesthetic steroids on lipid bilayers.
Cyclohexanol analogues are positive modulators of GABA(A) receptor currents and act as general anaesthetics in vivo.
Analogues of Etomidate: Modifications around Etomidate’s Chiral Carbon and the Impact on In Vitro and In Vivo Pharmacology
TLDR
Changing etomidate’s chiral center may be used as part of a strategy to design analogues with more desirable adrenocortical activities and/or subunit selectivities.
Etomidate and other non-barbiturates.
TLDR
The most relevant clinical and experimental pharmacological properties of these intravenous anesthetics, the molecular targets mediating other endpoints of the anesthetic state in vivo, and the work that led to the identification of the GABA(A) receptor as the key target for etomidate and aminosteroids are summarized.
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References

SHOWING 1-10 OF 45 REFERENCES
Enantioselectivity of steroid-induced gamma-aminobutyric acidA receptor modulation and anesthesia.
TLDR
It is shown that potentiation of GABA-mediated currents and gating of the GABA(A) channel by steroids, as well as steroid-induced anesthesia in tadpoles and mice, is enantioselective, with the (+)-enantiomers exhibiting significantly greater potency in all assays.
Subunit‐dependent interaction of the general anaesthetic etomidate with the γ‐aminobutyric acid type A receptor
TLDR
It is concluded that the subtype of β‐subunit influences the potency with which etomidate potentiates GABA‐evoked currents and that the β isoform is a crucial determinant of the GABA‐mimetic activity of this compound.
Stereospecific effects of inhalational general anesthetic optical isomers on nerve ion channels.
TLDR
Very pure optical isomers of the inhalational general anesthetic isoflurane exhibited clear stereoselectivity in their effects on particularly sensitive ion channels in identified molluscan central nervous system neurons.
Stereoselective and non‐stereoselective actions of isoflurane on the GABAA receptor
TLDR
The sustained residual current remaining after exposure of neurones to a desensitizing concentration of GABA was inhibited non‐stereoselectively, but only at high concentrations of isoflurane, and the inhibition was barely significant at the EC50 concentration for general anaesthesia.
Enhancement of homomeric glycine receptor function by longchain alcohols and anaesthetics
TLDR
The results suggest that the α subunits of strychnine‐sensitive glycine receptors contain sites of action for n‐alcohols, propofol, alphaxalone, pentobarbitone and volatile anaesthetics, but not for ketamine and etomidate.
Comparative pharmacology of the optical isomers of ketamine in mice.
Minimum Alveolar Anesthetic Concentration Values for the Enantiomers of Isoflurane Differ Minimally
TLDR
The results do not confirm the conclusion that interaction with a specific receptor is important to the mechanism of action of inhaled anesthetics, and the power to define a small significant difference is limited.
Interaction of i.v. anaesthetic agents with 5-HT3 receptors.
TLDR
With the exception of thiopentone these effects were outside the clinical range and suggest that anaesthetic agents are unlikely to interact directly with 5-HT3 receptors, and that other mechanism(s) must underlie the antiemetic effects of propofol.
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