Department of Anaesthesia, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Anesth Analg. 2010 Feb 1;110(2):455-60. doi: 10.1213/ANE.0b013e3181c5f689. Epub 2009 Nov 16.
Volatile aromatic compounds such as benzene are general anesthetics that cause amnesia, hypnosis, and immobility in response to noxious stimuli when inhaled. Although these compounds are not used clinically, they are frequently found in commercial items such as solvents and household cleaning products and are abused as inhalant drugs. Volatile aromatic anesthetics are useful pharmacological tools for probing the relationship between chemical structure and drug activity at putative general anesthetic targets. Neuronal nicotinic acetylcholine (nACh) receptors are ligand-gated ion channels widely expressed in the brain, which are thought to play important roles in learning and memory. In this study, we tested the hypothesis that aromatic anesthetics reversibly inhibit alpha(4)beta(2) neuronal nACh receptor function and sought to determine the structural correlates of receptor inhibition.
Electrophysiological techniques were used to quantify the effects of 8 volatile aromatic anesthetics on currents elicited by 1 mM ACh and mediated by human alpha(4)beta(2) nACh receptors expressed in Xenopus oocytes.
All of the volatile aromatic anesthetics used in this study reversibly inhibited alpha(4)beta(2) nACh receptors with IC(50) values ranging from 0.00091 atm for 1,2-difluorobenzene to 0.045 atm for hexafluorobenzene. With the exception of hexafluorobenzene, all of the compounds had IC(50) values less than minimum alveolar concentration. Inhibitory potency correlated poorly with the cation-pi binding energies of the compounds (r(2) = 0.48, P = 0.059). However, there was a good correlation between inhibitory potency and the octanol/gas partition coefficient (r(2) = 0.87, P = 0.0008).
Volatile aromatic anesthetics potently and reversibly inhibit human alpha(4)beta(2) neuronal nACh receptors. This inhibition may play a role in producing amnesia. In contrast to N-methyl-d-aspartate receptors, the inhibitory potencies of aromatic anesthetics for alpha(4)beta(2) neuronal nACh receptors seem to be dependent on drug hydrophobicity rather than electrostatic properties. This implies that the volatile aromatic anesthetic binding site in the alpha(4)beta(2) neuronal nACh receptor is hydrophobic in character and differs from the nature of the binding site in N-methyl-D-aspartate receptors.
挥发性芳香族化合物如苯是全身麻醉剂，吸入时会对有害刺激产生健忘、催眠和不动反应。尽管这些化合物在临床上未被使用，但它们经常存在于溶剂和家用清洁产品等商业产品中，并被滥用为吸入性药物。挥发性芳香族麻醉剂是研究化学结构与假定全身麻醉靶点药物活性之间关系的有用药理学工具。神经元烟碱型乙酰胆碱（nACh）受体是广泛表达于脑内的配体门控离子通道，被认为在学习和记忆中发挥重要作用。在这项研究中，我们检验了芳香族麻醉剂可逆抑制α（4）β（2）神经元 nACh 受体功能的假说，并试图确定受体抑制的结构相关性。
使用电生理学技术来量化 8 种挥发性芳香族麻醉剂对在非洲爪蟾卵母细胞中表达的人α（4）β（2）nACh 受体所引发的 1mM ACh 电流的影响。
本研究中使用的所有挥发性芳香族麻醉剂均可逆地抑制α（4）β（2）nACh 受体，其 IC（50）值范围从 1，2-二氟苯的 0.00091atm 到六氟苯的 0.045atm。除六氟苯外，所有化合物的 IC（50）值均低于最小肺泡浓度。抑制效力与化合物的阳离子-π结合能相关性差（r（2）=0.48，P=0.059）。然而，抑制效力与辛醇/气体分配系数之间存在良好的相关性（r（2）=0.87，P=0.0008）。
挥发性芳香族麻醉剂可强烈和可逆地抑制人α（4）β（2）神经元 nACh 受体。这种抑制可能在产生健忘症中起作用。与 N-甲基-D-天冬氨酸受体不同，芳香族麻醉剂对α（4）β（2）神经元 nACh 受体的抑制效力似乎取决于药物疏水性而不是静电特性。这意味着α（4）β（2）神经元 nACh 受体中挥发性芳香族麻醉剂的结合位点具有疏水性特征，与 N-甲基-D-天冬氨酸受体结合位点的性质不同。
