Hypothesis

Autor: Andrew Pohorille, Donald D. Koblin, J. C. Sewell, Edmond I. Eger, R. A. Harris, Jim Sonner, Michael J. Halsey, James R. Trudell
Rok vydání: 1999
Předmět:
Zdroj: Anesthesia & Analgesia. 88:1395-1400
ISSN: 0003-2999
DOI: 10.1097/00000539-199906000-00036
Popis: 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.
Databáze: OpenAIRE
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