Molecular Pharmacology, Vol 19, 49-55, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Can the Lipid Theories of Anesthesia Account for the Cutoff in Anesthetic Potency in Homologous Series of Alcohols?

¹ Departments of Anesthesia and Pharmacology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114

The general anesthetic potency of several members of the homologous series of saturated and unsaturated aliphatic alcohols (C_n:0 and C_n:1) was determined in tadpoles, using the loss of righting reflex as the criterion of anesthesia. In the C_n:0 series, anesthetic potency increased with chain length and was maximal for dodecanol (ED₅₀ 5.4 x 10^-6 M). The cutoff in potency was between n = 12 and n = 14 such that n-tridecanol was a partial anesthetic, whereas n-tetradecanol and higher alcohols were totally inactive. However, for the unsaturated alcohols, the anesthetic cutoff point was shifted to a longer chain length, i.e., the ⁹-tetradecenols are full anesthetics whereas the ⁹-hexadecenols are partial anesthetics. In each case the cis- and trans-isomers were equipotent. In the C_n:0 series in egg lecithin (EPC)-cholesterol (2:1) vesicles spin-labeled with 5-doxyl palmitic acid, the increase in membrane disorder at a fixed alcohol to lipid ratio attenuated progressively, being zero at n = 20. This slow decline in disordering ability is not completely consistent with the sharp loss of potency at the cutoff, which is better explained by the limited membrane solubility of the higher alkanols. All of the unsaturated alcohols were more effective disorderers than their saturated analogues when compared at the same membrane concentration. The cis- and trans-isomers disordered EPC-cholesterol (1:1) bilayers approximately equally in accord with their equal anesthetic potencies; however, at low proportions of cholesterol to phospholipid, cis-isomers disordered more than trans-isomers. The alternative lipid model based on the lateral-phase separations in mixed DML-DPL bilayers was not supported by data for the cis- and trans-tetradecenols. Thus, 20 mole per cent in the lipid of the cis-isomer lowered the midpoint temperature of the two-phase region, whereas the trans-isomer raised this temperature.

Note:
ACKNOWLEDGMENTS We wish to thank Dr. J. Gergeley, Boston Biomedical Research Institute, for use of electron spin resonance equipment, and Larry Chang for technical assistance early in the project.

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