Anaesthetic potencies of primary alkanols: implications for the molecular dimensions of the anaesthetic site

Abstract

1 We have redetermined the anaesthetic potencies (EC50 s) for a series of primary alkanols, to resolve uncertainties about the molecular dimensions of the anaesthetic site resulting from the use of data from different laboratories. 2 For each alkanol, concentration-response relationships for loss of righting reflex (LRR) were plotted for over one hundred tadpoles, and the median effective concentrations determined. Aqueous concentrations present during potency assays were determined independently, and for alkanols with chain length greater than nonanol, correction was made for depletion from the aqueous phase.3 The EC50 s were found to decrease logarithmically with increasing number of carbon atoms in the hydrocarbon chain of the alkanol (CN), such that, on average, each additional methylene group was associated with an approximately four fold increase in potency. 4 The relationship between log EC50 and CN was best described by the quadratic equation, log EC o = 0.022 (+0.0038) CN2 + 0.76 (±0.051) CN + 3.7 (±0.14) (r2 = 0.9951). 5A previously described correlation between the apparent changes in the free energy of binding of an additional methylene group both to luciferase and to the sites for LRR in tadpoles was not confirmed. 6 A cut-off in potency beyond dodecanol was established in experiments where tadpoles were maintained in supersaturated solutions of tridecanol for 20 h without demonstrable LRR. 7 These findings indicate that the soluble enzyme firefly luciferase does not adequately model the anaesthetic site. Specifically, there are discrepancies in the position of cut-off, and the apparent changes in the free energy of binding, per methylene group, of an alkanol to luciferase do not parallel that for tadpoles.

Enhancement of homomeric glycine receptor function by longchain alcohols and anaesthetics

“…Our 'cut-off' for the n-alcohols is very similar to that found for recombinant human GABAA receptors (cxlfll and alfily2L subunits) expressed in Xenopus oocytes (Dildy-Mayfield et al, 1996). Moreover, our result agree with in vivo studies performed in tadpoles, which demonstrate that n-alcohol potency increases as the carbon backbone increases, although for tadpoles dodecanol is more effective than would be predicted from the oocyte data (Alifimoff et al, 1989). The effects of decanol were also studied in mice by Dildy-Mayfield et al (1996).…”

“…The enhancement of glycine receptor function produced by the alcohols (ethanol-dodecanol), was compared at EC50 concentration of these alcohols for producing loss of righting reflex in tadpoles (Alifimoff et al, 1989) (Figure 3). In most experiments, Xenopus oocytes expressing the al glycine receptor subunits were pre-exposed to these alcohols for 2 min.…”

Slowly inactivating component of Na+ current in peri-somatic region of hippocampal CA1 pyramidal neurons

“…We have shown in earlier experiments that TTX fully blocks all I Na . Hexanol, one of the n-alcohols known to block I NaT (Horishita and Harris 2008;Shiraishi and Harris 2004) and to have anesthetic effects (Alifimoff et al 1989), was chosen because of its strong potency with relatively low concentration compared with other alcohols with a shorter carbon chain such as ethanol and butanol. Hexanol at 2.8 mM (a moderate anesthetic concentration) suppressed both I NaS and I NaT , but to different degrees.…”

Modulation of Human 5-Hydroxytryptamine Type 3AB Receptors by Volatile Anesthetics and n-Alcohols

“…MAC for chloroform was taken as 0.5% the average value of two studies in mice (Miller et al, 1973;Deady et al, 1981). The anesthetizing concentrations of n-alcohols were defined as the aqueous concentrations that cause loss of righting reflex in tadpoles (Alifimoff et al, 1989).…”