Hypothesis: volatile anesthetics produce immobility by acting on two sites approximately five carbon atoms apart.

All series of volatile and gaseous compounds contain members that can produce anesthesia, as defined by the minimum alveolar anesthetic concentration (MAC) required to produce immobility in response to a noxious stimulus. For unhalogenated n-alkanes, cycloalkanes, aromatic compounds, and n-alkanols, potency (1 MAC) increases by two-to threefold with each carbon addition in the series (e.g., ethanol is twice as potent as methanol). Total fluorination (perfluorination) of n-alkanes essentially eliminates anesthetic potency: only CF 4 is anesthetic (MAC = 66.5 atm), which indicates that fluorine atoms do not directly influence sites of anesthetic action. Fluorine may enhance the anesthetic action of other moieties, such as the hydrogen atom in CHF 3 (MAC = 1.60 atm), but, consistent with the notion that the fluorine atoms do not directly influence sites of anesthetic action, adding -(CF 2 ) n moieties does not further increase potency (e.g., CHF 2 -CF 3 MAC = 1.51 atm). Similarly, adding -(CF 2 ) n moieties to perfluorinated alkanols (CH 2 OH-[CF 2 ] n F) does not increase potency. However, adding a second terminal hydrogen atom (e.g., CHF 2 -CHF 2 or CH 2 OH-CHF 2 ) produces series in which the addition of each -CF 2 - spacer in the middle of the molecule increases potency two- to threefold, as in each unhalogenated series. This parallel stops at four or five carbon atom chain lengths. Further increases in chain length (i.e., to CHF 2 [CF 2 ] 4 CHF 2 or CHF 2 [CF 2 ] 5 CH 2 OH) decrease or abolish potency (i.e., a discontinuity arises). This leads to our hypothesis that the anesthetic moieties (-CHF 2 and -CH 2 OH) interact with two distinct, spatially separate, sites. Both sites must be influenced concurrently to produce a maximal anesthetic (immobility) effect. We propose that the maximal potency (i.e., for CHF 2 [CF 2 ] 2 CHF 2 and CHF 2 [CF 2 ] 3 CH 2 OH) results when the spacing between the anesthetic moieties most closely matches the distance between the two sites of action. This reasoning suggests that a distance equivalent to a four or five carbon atom chain, approximately 5 A, separates the two sites. Implications : Volatile anesthetics may produce immobility by a concurrent action on two sites five carbon atom lengths apart.