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Anesthetic potency and the perturbation of positive ion or proton acceptor sites in the nerve membrane
Author(s) -
Davies R. H.,
Bagnall R. D.,
Crooks B.,
Jones W. G. M.
Publication year - 2009
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.560300808
Subject(s) - chemistry , anesthetic , hydrogen bond , proton , dipole , computational chemistry , acceptor , molecule , ion , membrane , chemical physics , stereochemistry , organic chemistry , anesthesia , medicine , biochemistry , physics , quantum mechanics , condensed matter physics
Differences in the strengths of hydrogen bond proton donor interactions of volatile anesthetics estimated from anesthetic potency data in the mouse and from MAC* values in humans are reviewed in relation to proton donor interactions of halogenated hydrocarbons in ester solvents. The unusually strong interactions estimated from the mouse data arise from the unexpected low potencies of compounds fully halogenated or possessing a large dipole, which were previously used as a reference base line for estimating the hydrogen bond interactions. Since these compounds as a class are generally markedly sensitizing, the possibility that sensitization has a quantitative reverse influence on potency is explored. Substitution by fluorine in comparison with other halogens in halogenated hydrocarbons produces slightly weaker hydrogen bond proton donor capability and stronger local dipole effects. Sensitization effects with fluorine are generally greater than those with chlorine. Since hydrogen bond proton donor interactions exhibit a specific inhibitory effect in cardiac sensitization, the possibility exists that it is the free local dipoles or multipoles interacting with a positive field within the nerve membrane which create the excitatory effect. Here the bonded fraction of molecules unable to align their dipoles with the positive field is contrasted. A model of anesthetic action is developed as the perturbation of an ion channel. The action is treated as a concentration effect perturbing the field intensity of the local charge where the multipoles of the anesthetic molecule are approximated by a set of local dipoles. If the perturbation for deactivating the channel is directly related to the concentration of the anesthetic, then using data on n ‐pentane in voltage channel experiments, four barriers of similar energy are suggested in the inhibition of the ion movement by the anesthetic. Where the multipole effect is adequately represented by a gross dipole, the predicted quantitative effects on anesthetic potency by compounds of weak hydrogen bond proton donor ability and marked dipole such as CH 3 CF 2 Cl and CH 3 CFCl 2 are of the right order. Some simple predictions of the model are considered.