Hypothesis: Volatile anesthetics produce immobility by acting on two sites approximately five carbon atoms apart
Hypothesis: Volatile anesthetics produce immobility by acting on two sites approximately five carbon atoms apart
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DOI：
10.1097/00000539-199906000-00036
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发表时间：
1999-06-01
影响因子：
5.7
通讯作者：
Trudell, JR
中科院分区：
文献类型：
--
作者：
Eger, EI;Halsey, MJ;Trudell, JR
所有系列的挥发性和气态化合物均含有可产生麻醉作用的成分，麻醉作用是根据有害刺激产生不动所需的最低肺泡麻醉浓度 (MAC) 定义的。对于未卤化的正烷烃、环烷烃、芳香族化合物和正烷醇，随着系列中每个碳的添加，效力 (1 MAC) 增加两到三倍（例如，乙醇的效力是甲醇的两倍）。正烷烃的全氟化（全氟化）基本上消除了麻醉效力：只有 CF 具有麻醉作用（MAC = 66.5 atm），这表明氟原子不会直接影响麻醉作用位点。氟可能增强其他部分的麻醉作用，例如 CHF3 中的氢原子 (MAC = 1.60 atm)，但是，与氟原子不直接影响麻醉作用位点的概念一致，添加 -(CF2)(n) 部分不会进一步增加效力（例如，CHF2-CF3 MAC = 1.51 atm）。同样，向全氟化烷醇 (CH2OH-[CF2](n)F) 添加 -(CF2)(n) 部分不会增加效力。然而，添加第二个末端氢原子（例如 CHF2-CHF2 或 CH2OH-CHF2）会产生系列，其中在分子中间添加每个 -CF2-“间隔基”可将效力增加两到三倍，与每个非卤化系列中一样。该平行线在四个或五个碳原子链长度处停止。链长度的进一步增加（即，增加至 CHF2[CF2](4)CHF2 或 CHF2[CF2](5)CH2OH) 会降低或消除效力（即，出现不连续性）。这导致我们假设麻醉部分（-CHF2 和 -CH2OH）与两个不同的、空间上分离的位点相互作用。两个部位必须同时受到影响才能产生最大的麻醉（不动）效果。我们认为，当麻醉部分之间的间距与两个作用位点之间的距离最接近时，就会产生最大效力（即，对于 CHF2[CF2](2)CHF2 和 CHF2[CF2](3)CH2OH)。这一推理表明，两个位点之间的距离相当于 4 或 5 个碳原子链，大约 5 埃。影响：挥发性麻醉剂可能通过同时作用于相隔五个碳原子长度的两个位点而产生不动性。
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, 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](n)F) 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](4)CHF2 or CHF2[CF2](5)CH2OH) 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](2)CHF2 and CHF2[CF2](3)CH2OH) 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 Angstrom, separates the two sites. Implications: Volatile anesthetics may produce immobility by a concurrent action on two sites five carbon atom lengths apart.