Raines D E, Korten S E, Hill A G, Miller K W
Department of Anesthesia, Massachusetts General Hospital, Boston.
Anesthesiology. 1993 May;78(5):918-27. doi: 10.1097/00000542-199305000-00017.
N-alkanols containing up to 12 carbons are anesthetic; however, those with more than 12 carbons are not. This phenomenon has been termed cutoff. Lipid disordering theories of anesthesia suggest that cutoff occurs because the alkyl chains of long-chain alcohols approach the length and shape of the lipids of neuronal membranes and, therefore, intercalate into membranes without perturbing them. Protein theories suggest that cutoff occurs because the size of long-chain alcohols exceeds that of a protein binding site having finite dimensions. These theories were tested with a new series of alcohols, the cycloalkanemethanols, c(CnH2n-1).CH2.OH.
Anesthetic potency was measured in Rana pipiens tadpoles using the reversible loss of righting reflexes as the endpoint. The change in order parameter induced by cycloalkanemethanols and n-alkanols in lipid bilayers made of egg phosphatidylcholine and cholesterol was measured with electron paramagnetic resonance spectroscopy.
On ascending the series from cyclopropanemethanol (EC50 = 54 +/- 3.2 mM) to cycloundecanemethanol (EC50 = 7.0 +/- 0.12 microM) anesthetic potencies first increased exponentially but then decreased sharply at cyclododecanemethanol (EC50 = 13 +/- 0.2 microM). Cyclotetradecanemethanol was found not to cause anesthesia in tadpoles, even after 48 h of exposure, although saturated solutions shifted the dose-response curve of octanol from 66 +/- 2.6 to 47 +/- 2.8 microM. A linear loss in the ability to disorder lipid bilayers was observed on ascending both alcohol series such that cyclotetradecanemethanol and n-tridecanol actually increased bilayer order.
Molecular length does not correlate with anesthetic cutoff in these two alcohol series. Cutoff is predicted by the ability of both series of alcohols to disorder lipid bilayers and correlates with their molecular volume.
含12个及以下碳原子的正链烷醇具有麻醉作用；然而，含碳数超过12个的正链烷醇则没有麻醉作用。这种现象被称为截止效应。麻醉的脂质紊乱理论表明，截止效应的发生是因为长链醇的烷基链接近神经元膜脂质的长度和形状，因此可以插入膜中而不干扰它们。蛋白质理论则认为，截止效应的发生是因为长链醇的大小超过了具有有限尺寸的蛋白质结合位点。我们用一系列新的醇类，即环烷甲醇，c(CnH2n-1).CH2.OH，对这些理论进行了验证。
以牛蛙蝌蚪的翻正反射可逆性丧失为终点，测定环烷甲醇和正链烷醇的麻醉效力。用电子顺磁共振光谱法测量环烷甲醇和正链烷醇在由鸡蛋磷脂酰胆碱和胆固醇制成的脂质双层中引起的序参数变化。
从环丙醇（EC50 = 54±3.2 mM）到环十一醇（EC50 = 7.0±0.12 μM），随着该系列的上升，麻醉效力首先呈指数增加，但在环十二醇（EC50 = 13±0.2 μM）时急剧下降。发现环十四醇即使在暴露48小时后也不会在蝌蚪中引起麻醉，尽管饱和溶液将辛醇的剂量反应曲线从66±2.6 μM移至47±2.8 μM。在两个醇系列上升时，均观察到脂质双层紊乱能力呈线性下降，以至于环十四醇和正十三醇实际上增加了双层的有序性。
在这两个醇系列中，分子长度与麻醉截止效应不相关。截止效应可由这两个系列的醇使脂质双层紊乱的能力预测，并且与它们的分子体积相关。
