General anesthetic potencies of a series of propofol analogs correlate with potency for potentiation of gamma-aminobutyric acid (GABA) current at the GABA(A) receptor but not with lipid solubility.
General anesthetic potencies of a series of propofol analogs correlate with potency for potentiation of gamma-aminobutyric acid (GABA) current at the GABA(A) receptor but not with lipid solubility.
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发表时间：
2001-04
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通讯作者：
M. Krasowski;A. Jenkins;P. Flood;Amiinah Y. Kung;A. Hopfinger;N. Harrison
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作者：
M. Krasowski;A. Jenkins;P. Flood;Amiinah Y. Kung;A. Hopfinger;N. Harrison
研究了27种全身麻醉剂异丙酚（2,6-二异丙基酚）类似物对非洲爪蟾蝌蚪的全身麻醉活性，以及增强亚极大GABA反应和/或直接激活重组GABA(A)受体的能力。14种异丙酚类似物使蝌蚪失去了翻正反射，而13种作为麻醉剂不起作用。这些化合物对GABA(A) α (1) β (2) γ (2s)受体的作用也具有相同的活性模式。与直接激活GABA(A) α (1) β (2) γ (2s)受体相比，在蝌蚪中作为全身麻醉剂的类似物的效力与GABA反应增强的相关性更好。计算出的类似物的辛醇/水分配系数并不能解释13种非麻醉类似物缺乏活性的原因，尽管这个物理化学参数确实与体内麻醉效力有一定的相关性。研究了一种非麻醉类似物2,6-二叔丁基苯酚的作用。2,6-二叔丁基酚对GABA(A)受体无活性，对蝌蚪没有麻醉作用，也不会拮抗异丙酚对GABA(A)受体或蝌蚪的任何作用。影响异丙酚类似物效价的关键因素似乎是芳香环上2号和6号位置上的烷基相对于1号位置上取代基的大小和形状。这些数据表明异丙酚在GABA(A)受体上的结合位点存在空间限制。
A series of 27 analogs of the general anesthetic propofol (2,6-diisopropylphenol) were examined for general anesthetic activity in Xenopus laevis tadpoles and for the ability to produce enhancement of submaximal GABA responses and/or direct activation at recombinant GABA(A) receptors. Fourteen of the propofol analogs produced loss of righting reflex in the tadpoles, whereas 13 were inactive as anesthetics. The same pattern of activity was noted with the actions of the compounds at the GABA(A) alpha(1)beta(2)gamma(2s) receptor. The potencies of the analogs as general anesthetics in tadpoles correlated better with potentiation of GABA responses than direct activation at the GABA(A) alpha(1)beta(2)gamma(2s) receptor. The calculated octanol/water partition coefficients for the analogs did not explain the lack of activity exhibited by the 13 nonanesthetic analogs, although this physicochemical parameter did correlate modestly with in vivo anesthetic potency. The actions of one nonanesthetic analog, 2,6-di-tert-butylphenol, were examined in detail. 2,6-Di-tert-butylphenol was inactive at GABA(A) receptors, did not function as an anesthetic in the tadpoles, and did not antagonize any of the actions of propofol at GABA(A) receptors or in tadpoles. A key influence on the potency of propofol analogs appears to be the size and shape of the alkyl groups at positions 2 and 6 of the aromatic ring relative to the substituent at position 1. These data suggest steric constraints for the binding site for propofol on the GABA(A) receptor.