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Molecular Pharmacology, Vol 11, 280-286, Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics

Structurally Specific Effects of Some Steroid Anesthetics on Spin-Labeled Liposomes

DAVID K. LAWRENCE 1 and EDWARD W. GILL 1

1 University Department of Pharmacology, South Parks Road, Oxford, England

The effects of a range of steroids related to a potent intravenous anesthetic, 3agr-hydroxy-5agr-pregnane-11,20-dione, on the molecular mobility and local polarity of ultrasonically dispersed vesicles of lecithin and cholesterol (liposomes) were investigated using a nitroxide-labeled dipalmitoyllecithin as a molecular probe. The anesthetics 3agr-hydroxy-5agr-pregnane-11,20-dione, 3agr-hydroxy-5agr-pregnan-20-one, butobarbitone, and octanol were found to cause fluidization of the lipid bilayer at concentrations approximating those attained during anesthesia in vivo, and the magnitude of the effect was linearly related to the drug concentration. When allowance was made for differences in molecular volume, it was found that these four molecules produced a degree of fluidization approximately the same as that found previously to be produced by halothane, at a given partial volume of drug in the liposomes. On the other hand, the steroids 3beta-hydroxy-5agr-pregnane-11,20-dione, 3beta-hydroxy-5agr-pregnan-20-one, 3agr-hydroxy-5agr-pregn-16-ene-11, 20-dione, and 3agr,11agr-dihydroxy-20,20-ethylenedioxy-5agr-pregnane, which are inactive as anesthetics, produced much less disordering of the lipid bilayer. The correlation of anesthetic potency with ability to disorder spin-labeled liposomes suggests the use of this technique for drug screening. The especially large difference between the effects of the 3agr- and 3beta-hydroxy isomers of 5agr-pregnane-11,20-dione showed that phospholipid/ cholesterol bilayers are capable of a high degree of structural discrimination, and lends support to the hypothesis that the lipid phase of nerve cell membranes is the site of action of all general anesthetics.

Submitted on August 23, 1974




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