Franks N P, Lieb W R
Proc Natl Acad Sci U S A. 1986 Jul;83(14):5116-20. doi: 10.1073/pnas.83.14.5116.
Alcohols act as anesthetics only up to a certain chain length, beyond which their biological activity disappears. Although the molecular nature of general anesthetic target sites remains unknown, presently available data support the hypothesis that this "cutoff" in anesthetic activity could be due to a corresponding cutoff in the absorption of long-chain alcohols into lipid-bilayer portions of nerve membranes. To test this hypothesis, we have developed an extremely sensitive biological assay, based on inhibition of the light-emitting firefly luciferase reaction, which is capable of measuring lipid-bilayer/buffer partition coefficients K for very lipid soluble compounds. Contrary to the hypothesis and reported data, we find a strictly linear increase in log(K) as the chain length increases [delta(delta G0)CH2 = - 3.63 kJ/mol] for the primary alcohols from decanol to pentadecanol, with no hint of a cutoff. The fact that alcohols continue to partition into lipid bilayers long after their biological activity has ceased is consistent with the view that the primary target sites in general anesthesia are proteins rather than the lipid-bilayer portions of nerve membranes.
醇类只有在一定链长范围内才具有麻醉作用，超过该链长其生物活性就会消失。尽管全身麻醉靶点的分子性质尚不清楚，但目前可得的数据支持这样一种假说，即麻醉活性的这种“截止点”可能是由于长链醇类进入神经膜脂质双层部分的吸收出现了相应的截止。为了验证这一假说，我们基于抑制发光萤火虫荧光素酶反应开发了一种极其灵敏的生物测定法，该方法能够测量非常脂溶性化合物的脂质双层/缓冲液分配系数K。与该假说和已报道的数据相反，我们发现从癸醇到十五烷醇的伯醇随着链长增加，log(K)呈严格的线性增加[δ(δG0)CH2 = - 3.63 kJ/mol]，没有任何截止的迹象。醇类在其生物活性停止很久之后仍继续分配到脂质双层中，这一事实与全身麻醉的主要靶点是蛋白质而非神经膜脂质双层部分的观点一致。
