Ecotoxicology of narcosis: Stereoselectivity and potential target sites

• Published in: Chemosphere (Oxford) 2008-07, Vol.72 (9), p.1256-1259
• Main Author: Sandermann, Heinrich
• Format: Article
• Language: English
• Subjects: Amphibia. Reptilia; Anesthetics, Intravenous - chemistry; Anesthetics, Intravenous - toxicity; Animal, plant and microbial ecology; Animals; Applied ecology; Biological and medical sciences; Chemical Phenomena; Chemistry, Physical; Ecotoxicology, biological effects of pollution; Environmental Pollutants - chemistry; Environmental Pollutants - toxicity; Etomidate; Fundamental and applied biological sciences. Psychology; GABA A channel; General aspects; Larva; Lipid/protein interface; Propofol; Propofol - chemistry; Propofol - toxicity; Rana temporaria; Stereoisomerism; Stereoselectivity; Structure-Activity Relationship; Stupor - chemically induced; Tadpole narcosis; Vertebrates: general zoology, morphology, phylogeny, systematics, cytogenetics, geographical distribution; Xenopus laevis
• ISSN: 0045-6535; 1879-1298
• DOI: 10.1016/j.chemosphere.2008.05.002

The stereoselectivity of certain anesthetics is currently thought to be inconsistent with lipid theories of narcosis. The EC 50-values of etomidate enantiomers for tadpole narcosis are now examined as a function of octanol/water partition coefficients, and enhancement factors for predicted over experimental EC 50 values are determined from a calibration curve for non-selective narcosis. The unfavored S-(−)-enantiomers of etomidate and two analogues surprisingly still fulfill the Meyer–Overton rule. The R(+)-enantiomers of etomidate and four structural analogues are up to 34-fold more active than expected. The non-chiral anesthetic, propofol, is 8-fold more active than expected. It is concluded that there may be two pathways to tadpole narcosis: enhanced narcosis involving specific receptor binding sites and non-selective narcosis corresponding to the Meyer–Overton rule and operating on the lipid/protein interface.