title: Hypothesis: volatile anesthetics produce immobility by acting on two sites approximately five carbon atoms apart.
abstract: 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 CF4 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 CHF3 (MAC = 1.60 atm), but, consistent with the notion that the fluorine atoms do not directly influence sites of anesthetic action, adding -(CF2)n moieties does not further increase potency (e.g., CHF2-CF3 MAC = 1.51 atm). Similarly, adding -(CF2)n moieties to perfluorinated alkanols (CH2OH-[CF2]nF) does not increase potency. However, adding a second terminal hydrogen atom (e.g., CHF2-CHF2 or CH2OH-CHF2) produces series in which the addition of each -CF2- "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 CHF2[CF2]4CHF2 or CHF2[CF2]5CH2OH) decrease or abolish potency (i.e., a discontinuity arises). This leads to our hypothesis that the anesthetic moieties (-CHF2 and -CH2OH) 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 CHF2[CF2]2CHF2 and CHF2[CF2]3CH2OH) 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.
  
  
  CONCLUSIONS
  Volatile anesthetics may produce immobility by a concurrent action on two sites five carbon atom lengths apart.
authors.affiliation: Department of Anesthesia and Perioperative Medicine, University of California, San Francisco 94143-0464, USA. edmond_eger@quickmail.ucsf.edu
authors.forename: E I
authors.initials: EI
authors.lastname: Eger
authors.forename: M J
authors.initials: MJ
authors.lastname: Halsey
authors.forename: R A
authors.initials: RA
authors.lastname: Harris
authors.forename: D D
authors.initials: DD
authors.lastname: Koblin
authors.forename: A
authors.initials: A
authors.lastname: Pohorille
authors.forename: J C
authors.initials: JC
authors.lastname: Sewell
authors.forename: J M
authors.initials: JM
authors.lastname: Sonner
authors.forename: J R
authors.initials: JR
authors.lastname: Trudell
mesh_terms: D018685:Anesthetics, Inhalation / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D005740:Gases; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D018685:Anesthetics, Inhalation; D005740:Gases; D006845:Hydrocarbons, Fluorinated