Wang G K
Department of Anesthesia Research Laboratories, Harvard Medical School, Boston, Massachusetts.
J Gen Physiol. 1990 Nov;96(5):1105-27. doi: 10.1085/jgp.96.5.1105.
Several local anesthetics (LA) have been previously shown to block muscle batrachotoxin (BTX)-activated Na+ channels in planar bilayers. The mean dwell time of different LA drugs, however, varies widely, from less than 10 ms to longer than several seconds. In this study, we have examined the structural determinants that govern the dwell time, the binding affinity, and the stereoselectivity of LA drugs using cocaine and bupivacaine homologues, RAC compounds, and their available stereoisomers. Our results from the structure-activity experiments reveal that (a) there are two apparent hydrophobic binding domains present in the LA binding site; one interacts with the aromatic moiety of the LA drugs, and the other interacts with the alkyl group attached to the tertiary amine of the LA drugs; (b) the LA mean dwell time and the binding affinity are largely determined by the hydrophobic interactions; (c) the LA binding site is highly stereoselective, with a difference in KD values over 50- and 6-fold for (+/-) cocaine and (+/-) bupivacaine, respectively; (d) the cocaine stereoselectivity is comparable among muscle, brain, and heart BTX-activated Na+ channels; and finally and most unexpectedly, (e) the stereoselectivity of LA drugs in BTX-activated Na+ channels appears greatly different from that reported in normal Na+ channels. Possible explanations for this difference are discussed.
先前已证明几种局部麻醉药（LA）可阻断平面双层中肌肉蛙毒素（BTX）激活的Na⁺通道。然而，不同LA药物的平均驻留时间差异很大，从不到10毫秒到超过几秒不等。在本研究中，我们使用可卡因和布比卡因同系物、RAC化合物及其可用的立体异构体，研究了决定LA药物驻留时间、结合亲和力和立体选择性的结构决定因素。我们结构活性实验的结果表明：（a）LA结合位点存在两个明显的疏水结合域；一个与LA药物的芳香部分相互作用，另一个与连接在LA药物叔胺上的烷基相互作用；（b）LA平均驻留时间和结合亲和力在很大程度上由疏水相互作用决定；（c）LA结合位点具有高度立体选择性，（±）可卡因和（±）布比卡因的KD值差异分别超过50倍和6倍；（d）可卡因在肌肉、脑和心脏BTX激活的Na⁺通道中的立体选择性相当；最后且最出乎意料的是，（e）LA药物在BTX激活的Na⁺通道中的立体选择性似乎与正常Na⁺通道中报道的有很大不同。本文讨论了这种差异的可能解释。
