γ-氨基丁酸（GABA）代谢酶抑制剂的研究
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摘要
γ-氨基丁酸(GABA)是哺乳动物中枢神经系统内的主要抑制性递质。GABA的降解主要由GABA转氨酶(GABA-T)催化,脱氨基生成琥珀酸半醛,再经琥珀酸半醛脱氢酶(SSADH)催化生成琥珀酸,进入三羧酸循环。增加脑内GABA浓度可以提高GABA能系统的神经抑制作用,进而可用于治疗多种神经系统疾病如癫痫、帕金森病、亨廷顿舞蹈症、Alzheimer病等,最近发现增加脑内GABA浓度还有阻断药物依赖的作用。一种增加GABA浓度的方法是设计可通过血脑屏障并选择性抑制GABA-T的化合物。因此GABA-T已经被确认为中枢神经系统药物的靶点。在本论文中,确定了对羟基苯甲醛可以作为设计GABA-T和SSADH抑制剂的先导化合物,合成并评价了两个对羟基苯甲醛类似物对GABA-T的不可逆抑制作用,研究了黄酮类化合物对这两个酶的抑制作用。另外还研究了豆腐果苷磷脂复合物的制备、理化性质及药代动力学。主要完成了以下研究工作:
(1)对羟基苯甲醛表现出对GABA-T强烈的竞争性抑制(IC50=16.5μmol/L),这种抑制作用与α-酮戊二酸呈竞争性,与GABA呈非竞争性。对羟基苯甲醛也以竞争性的方式强烈地抑制SSADH(IC50=24.7μmol/L)。这种抑制作用是由于对羟基苯甲醛与α-酮戊二酸及琥珀酸半醛的结构相似性和苯环的共轭作用导致的。初步的量子化学计算表明对羟基苯甲醛与α-酮戊二酸及琥珀酸半醛的结构相似性本质上是它们前线轨道的能量和形状的相似。这些结果表明这两个酶的活性位点可以接受苯环的存在,提示对羟基苯甲醛可以作为先导化合物设计结构新颖的GABA-T和SSADH抑制剂。
(2)考察了6类共17个对羟基苯甲醛类似物对GABA-T和SSADH的抑制作用,其中有8个对羟基苯甲醛类似物由本实验室合成。包括对羟基苯甲醛总计18个化合物对GABA-T和SSADH的IC50值显示出明显的构效关系。对于GABA-T的抑制,酚羟基及其对位的羰基或氨甲基是关键的。对于SSADH的抑制,酚羟基及其对位的羰基是非常重要的。4-丙烯酰苯酚对GABA-T和SSADH的IC50分别为5.48μmol/L和0.35μmol/L,4-β-氯丙酰苯酚对GABA-T和SSADH的IC50分别为3.99μmol/L和1.09μmol/L,均表现出极好的抑制活性。对羟基苯甲胺是一个强有力的GABA-T抑制剂(IC50= 15.4μmol/L),与GABA呈竞争性关系,而与α-酮戊二酸呈非竞争性关系。推测了一个统一的机制解释对羟基苯甲醛和对羟基苯甲胺对GABA-T的抑制。
(3) 4-丙烯酰苯酚以时间依赖的方式强烈的不可逆抑制GABA-T,其动力学参数为KI= 470μmol/L,kinact= 0.061 min-1,kinact/KI= 0.129 (mmol/L)-1min-1。加入α-酮戊二酸可以保护这种不可逆抑制作用,表明这种抑制作用是发生在GABA-T的活性部位。巯基乙醇也可以保护这种抑制作用。提出了一种Michael加成机制解释这种不可逆抑制作用。初步的量子化学计算结果也证实了Michael加成机制的合理性。这些结果为设计更有效的GABA-T抑制剂提供了新思路。
(4) 4-β-氯丙酰苯酚以时间依赖的方式强烈地不可逆抑制GABA-T,其动力学参数为KI= 24.3μmol/L,kinact= 0.0467 min-1,kinact/KI= 1.88 (mmol/L)-1min-1。加入α-酮戊二酸可以保护这种不可逆抑制作用,表明这种抑制作用是发生在GABA-T的活性部位。巯基乙醇和谷胱甘肽可以保护这种不可逆抑制作用。公认的GABA-T不可逆抑制机制不能解释这个化合物的不可逆抑制作用,因此提出了一种亲核取代机制解释这种不可逆抑制作用。虽然这个不可逆抑制机制需要进一步研究确证,但这些结果表明除了公认的两种机制还可以通过其他机制不可逆抑制GABA-T,这为设计新颖的GABA-T抑制剂提供了更广阔的空间。
(5)黄酮类化合物可以显著地以剂量依赖的方式抑制GABA-T和SSADH。黄酮类化合物对GABA-T和SSADH的抑制表现出不同的构效关系。在黄芩素、黄芩苷、野黄芩苷元、野黄芩苷、槲皮素、山奈酚和芦丁等7个黄酮类化合物中,黄芩素是GABA-T最有效的抑制剂(IC50=12.8μmol/L),野黄芩苷元是SSADH最有效的抑制剂(IC50=7.2μmol/L)。黄酮类化合物对GABA-T和SSADH的抑制是非竞争性的。这些结果提示黄酮类化合物对GABA-T和SSDAH的抑制作用可能是黄酮类化合物神经药理作用的部分原因。
(6)制备了豆腐果苷磷脂复合物,并通过正交设计考察了反应物初始浓度、投料比例和反应时间等因素对复合率的影响,表明最佳制备工艺是室温下以四氢呋喃为反应溶剂,豆腐果苷浓度为5 mg/mL,投料质量比例为1: 5,反应时间为2 h。X-射线衍射和差热扫描分析表明复合物呈现无定型特征,并改变了原药的相变特征;1H-NMR和IR显示了豆腐果苷的糖羟基和醛基参与复合物的结合。磷脂复合物可以明显改善豆腐果苷在水及正辛醇中的溶解性能。磷脂复合物可以显著地提高豆腐果苷在大鼠体内的生物利用度。磷脂复合物对药物吸收的改善作用与磷脂复合物不同于原药的理化性质及溶解性能有关。
本论文的研究结果对于设计结构新颖的GABA-T抑制剂具有重要意义,对于阐明黄酮类化合物的药理作用具有参考价值。豆腐果苷磷脂复合物的研究为其它天然药物的新制剂研究提供了新的思路。
γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system. GABA is metabolized by the successive action of GABA transaminase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH), to succinic acid, which is a substrate for the tricarboxylic acid cycle. An increase in the brain GABA concentration can enhance the inhibitory function of GABAergic system and have therapeutic applications in neurological disorders including epilepsy, Parkinson’s disease, Huntington’s chorea, and Alzheimer’s disease. Recently, it has been found that an increase in GABA also blocks the effects of drug addiction. An approach for increasing the brainGABA concentration would be to design a compound capable of permeating the blood-brain barrier that subsequently selectively inhibited GABA-T. Thus GABA-T has been validated as a target for neuroactive drugs.
In this dissertation, it was established that 4-hydroxybenzaldehyde may serve as a lead structure for GABA-T and SSADH inhibitors. Based on the results, both 4-hydroxybenzaldehyde analogues were synthesized and evaluated for irreversible inhibition of GABA-T. The inhibitory effect of flavonoids on GABA-T and SSADH was also investigated. Moreover, hilicid-phospholipid complex was prepared, and its physic-chemical properties and oral pharmacokinetics in rats were investigated. The main results are as follows:
(1) 4-Hydroxybenzaldehyde was shown to inhibit significantly GABA-T (IC50= 16.5μmol/L) in a competitive manner with respect toα-ketoglutarate but in a noncompetitive manner with respect to GABA. 4-Hydroxybenzaldehyde also exhibited a competitive inhibition of SSADH (IC50=24.7μmol/L). The inhibitory effects of 4-hydroxybenzaldehyde on both enzymes could result from the structural similarity between the molecule and the two enzymes’substrates, as well as the conjugative effect of benzene ring. Preliminary quantum chemical calculations suggested that the structural similarity of between 4-hydroxybenzaldehyde and the two substrates is due to the similarity of the energies and shapes of their molecular orbitals in nature. The results indicated that the presence of the benzene ring may be accepted by the active site of both enzymes, and 4-hydroxybenzaldehyde may be considered as a lead compound to design novel GABA-T and SSADH inhibitors.
(2) Six groups of 4-hydroxybenzaldehyde analogues were examined as inhibitors for GABA-T and SSADH. Among them, syntheses of eight compounds were achieved in this laboratory. Investigation of 18 compounds including 4-hydroxybenzaldehyde revealed the significant structure-activity relations with regard to both enzymes inhibition. A carbonyl group or an aminomethyl group, as well as a hydroxy group at the para position of the benzene ring are important for GABA-T inhibition. A carbonyl group and a hydroxy group at the para position of the benzene ring are important for SSADH inhibition. IC50 values of 4-Acryloylphenol (6) for GABA-T and SSADH are 5.48 and 0.35μmol/L, respectively, and IC50 values of 4-β-chloropropionylphenol (7) for GABA-T and SSADH are 3.99 and 1.09μmol/L, exhibiting more potent activity than that of 4-hydroxybenzaldehyde. 4-Hydroxybenzylamine potently inhibited GABA-T (IC50= 15.4μmol/L) in a competitive manner with respect to GABA but in a noncompetitive manner with respect toα-ketoglutarate. A possible mechanism was speculated to rationalize the inhibition of GABA-T by 4-hydroxybenzaldehyde and 4-hydroxybenzylamine.
(3) 4-Acryloylphenol was shown to inhibit irreversibly and potently the enzyme in a time-dependent manner with KI= 470μmol/L, kinact= 0.061 min-1 and kinact/KI= 0.129 (mmol/L)-1min-1. The inhibition was protected byα-ketoglutarate, indicating that it occurs at the active site of the enzyme.β-Mercaptoethanol also prevented the enzyme from irreversible inhibition. The possible mechanism involving a Michael addition was speculated to elucidate the inhibition. The rationality of the mechanism was supported by the preliminary quantum chemical calculations. The results suggested future directions for the design of more potent GABA-T inhibitors.
(4) 4-β-Chloropropionylphenol was shown to inhibit irreversibly and potently the enzyme in a time-dependent manner with KI= 24.3μmol/L, kinact= 0.0467 min-1, kinact/KI= 1.88 (mmol/L)-1min-1. The inhibition was protected byα-ketoglutarate, indicating that it is active site-directed.β-Mercaptoethanol and glutathione also prevented the enzyme from irreversible inhibition. Since the published mechanism can’t rationalize inactivation, a novel possible mechanism involving a nucleophilic substitution was speculated to rationalize the inactivation. Although the confirmation of the presumed mechanism requires further investigation, the results suggested that GABA-T could be inhibited irreversibly via a novel mechanism other than the two published mechanism, which give a new clue to design of more potent GABA-T inhibitors.
(5) A group of flavonoids including baicalein, baicalin, scutellarein, scutellarin, quercetin, kaempferol and rutin, significantly and dose-dependently inhibited GABA-T and SSADH in a noncompetitive manner. The different structure-activity relations were observed with respect to inhibition of GABA-T and SSADH. Among the seven flavonoids, baicalein was the most potent inhibitor for GABA-T (IC50= 12.8μmol/L), and scutellarein exhibited the best inhibitory effect on SSADH (IC50= 7.2μmol/L). The results suggested that the inhibition of both enzymes by flavonoids may contribute to the beneficial effect of flavonoids on the central nervous system.
(6) Helicid-phospholipid complex was prepare and the effect of such factors as the reactant concentrations, the ratio of reactants and the reactive time on the preparation was investigated via a orthogoral design, indicating the best conditions as follows: 5 mg/mL, 1: 5 and 2 h, respectively. X-ray diffraction spectra and DSC indicated that the complex exhibits an amorphous characteristic and change the transformation temperature of hilicid; 1H-NMR spectra and IR spectra suggested that hydroxy groups and aldehyde group of hilicid could interact with phospholipid. There is a great improvement in the solubility of hilicid-phospholipid complex both in water and in n-octanol. The complex significantly improved the relative bioavailability of helicid in rats. The improvement resulted from the particular physic-chemical and solubility properties of the hilicid-phospholipid complex.
The results of this dissertation could be significantly useful to design novel GABA-T inhibitors, and will facilitate to elucidate the neuropharmacological actions of flavonoids. The research of helicid-phospholipid complex led to a valuable direction in development of novel formulations of natural drugs.
(1)对羟基苯甲醛表现出对GABA-T强烈的竞争性抑制(IC50=16.5μmol/L),这种抑制作用与α-酮戊二酸呈竞争性,与GABA呈非竞争性。对羟基苯甲醛也以竞争性的方式强烈地抑制SSADH(IC50=24.7μmol/L)。这种抑制作用是由于对羟基苯甲醛与α-酮戊二酸及琥珀酸半醛的结构相似性和苯环的共轭作用导致的。初步的量子化学计算表明对羟基苯甲醛与α-酮戊二酸及琥珀酸半醛的结构相似性本质上是它们前线轨道的能量和形状的相似。这些结果表明这两个酶的活性位点可以接受苯环的存在,提示对羟基苯甲醛可以作为先导化合物设计结构新颖的GABA-T和SSADH抑制剂。
(2)考察了6类共17个对羟基苯甲醛类似物对GABA-T和SSADH的抑制作用,其中有8个对羟基苯甲醛类似物由本实验室合成。包括对羟基苯甲醛总计18个化合物对GABA-T和SSADH的IC50值显示出明显的构效关系。对于GABA-T的抑制,酚羟基及其对位的羰基或氨甲基是关键的。对于SSADH的抑制,酚羟基及其对位的羰基是非常重要的。4-丙烯酰苯酚对GABA-T和SSADH的IC50分别为5.48μmol/L和0.35μmol/L,4-β-氯丙酰苯酚对GABA-T和SSADH的IC50分别为3.99μmol/L和1.09μmol/L,均表现出极好的抑制活性。对羟基苯甲胺是一个强有力的GABA-T抑制剂(IC50= 15.4μmol/L),与GABA呈竞争性关系,而与α-酮戊二酸呈非竞争性关系。推测了一个统一的机制解释对羟基苯甲醛和对羟基苯甲胺对GABA-T的抑制。
(3) 4-丙烯酰苯酚以时间依赖的方式强烈的不可逆抑制GABA-T,其动力学参数为KI= 470μmol/L,kinact= 0.061 min-1,kinact/KI= 0.129 (mmol/L)-1min-1。加入α-酮戊二酸可以保护这种不可逆抑制作用,表明这种抑制作用是发生在GABA-T的活性部位。巯基乙醇也可以保护这种抑制作用。提出了一种Michael加成机制解释这种不可逆抑制作用。初步的量子化学计算结果也证实了Michael加成机制的合理性。这些结果为设计更有效的GABA-T抑制剂提供了新思路。
(4) 4-β-氯丙酰苯酚以时间依赖的方式强烈地不可逆抑制GABA-T,其动力学参数为KI= 24.3μmol/L,kinact= 0.0467 min-1,kinact/KI= 1.88 (mmol/L)-1min-1。加入α-酮戊二酸可以保护这种不可逆抑制作用,表明这种抑制作用是发生在GABA-T的活性部位。巯基乙醇和谷胱甘肽可以保护这种不可逆抑制作用。公认的GABA-T不可逆抑制机制不能解释这个化合物的不可逆抑制作用,因此提出了一种亲核取代机制解释这种不可逆抑制作用。虽然这个不可逆抑制机制需要进一步研究确证,但这些结果表明除了公认的两种机制还可以通过其他机制不可逆抑制GABA-T,这为设计新颖的GABA-T抑制剂提供了更广阔的空间。
(5)黄酮类化合物可以显著地以剂量依赖的方式抑制GABA-T和SSADH。黄酮类化合物对GABA-T和SSADH的抑制表现出不同的构效关系。在黄芩素、黄芩苷、野黄芩苷元、野黄芩苷、槲皮素、山奈酚和芦丁等7个黄酮类化合物中,黄芩素是GABA-T最有效的抑制剂(IC50=12.8μmol/L),野黄芩苷元是SSADH最有效的抑制剂(IC50=7.2μmol/L)。黄酮类化合物对GABA-T和SSADH的抑制是非竞争性的。这些结果提示黄酮类化合物对GABA-T和SSDAH的抑制作用可能是黄酮类化合物神经药理作用的部分原因。
(6)制备了豆腐果苷磷脂复合物,并通过正交设计考察了反应物初始浓度、投料比例和反应时间等因素对复合率的影响,表明最佳制备工艺是室温下以四氢呋喃为反应溶剂,豆腐果苷浓度为5 mg/mL,投料质量比例为1: 5,反应时间为2 h。X-射线衍射和差热扫描分析表明复合物呈现无定型特征,并改变了原药的相变特征;1H-NMR和IR显示了豆腐果苷的糖羟基和醛基参与复合物的结合。磷脂复合物可以明显改善豆腐果苷在水及正辛醇中的溶解性能。磷脂复合物可以显著地提高豆腐果苷在大鼠体内的生物利用度。磷脂复合物对药物吸收的改善作用与磷脂复合物不同于原药的理化性质及溶解性能有关。
本论文的研究结果对于设计结构新颖的GABA-T抑制剂具有重要意义,对于阐明黄酮类化合物的药理作用具有参考价值。豆腐果苷磷脂复合物的研究为其它天然药物的新制剂研究提供了新的思路。
γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system. GABA is metabolized by the successive action of GABA transaminase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH), to succinic acid, which is a substrate for the tricarboxylic acid cycle. An increase in the brain GABA concentration can enhance the inhibitory function of GABAergic system and have therapeutic applications in neurological disorders including epilepsy, Parkinson’s disease, Huntington’s chorea, and Alzheimer’s disease. Recently, it has been found that an increase in GABA also blocks the effects of drug addiction. An approach for increasing the brainGABA concentration would be to design a compound capable of permeating the blood-brain barrier that subsequently selectively inhibited GABA-T. Thus GABA-T has been validated as a target for neuroactive drugs.
In this dissertation, it was established that 4-hydroxybenzaldehyde may serve as a lead structure for GABA-T and SSADH inhibitors. Based on the results, both 4-hydroxybenzaldehyde analogues were synthesized and evaluated for irreversible inhibition of GABA-T. The inhibitory effect of flavonoids on GABA-T and SSADH was also investigated. Moreover, hilicid-phospholipid complex was prepared, and its physic-chemical properties and oral pharmacokinetics in rats were investigated. The main results are as follows:
(1) 4-Hydroxybenzaldehyde was shown to inhibit significantly GABA-T (IC50= 16.5μmol/L) in a competitive manner with respect toα-ketoglutarate but in a noncompetitive manner with respect to GABA. 4-Hydroxybenzaldehyde also exhibited a competitive inhibition of SSADH (IC50=24.7μmol/L). The inhibitory effects of 4-hydroxybenzaldehyde on both enzymes could result from the structural similarity between the molecule and the two enzymes’substrates, as well as the conjugative effect of benzene ring. Preliminary quantum chemical calculations suggested that the structural similarity of between 4-hydroxybenzaldehyde and the two substrates is due to the similarity of the energies and shapes of their molecular orbitals in nature. The results indicated that the presence of the benzene ring may be accepted by the active site of both enzymes, and 4-hydroxybenzaldehyde may be considered as a lead compound to design novel GABA-T and SSADH inhibitors.
(2) Six groups of 4-hydroxybenzaldehyde analogues were examined as inhibitors for GABA-T and SSADH. Among them, syntheses of eight compounds were achieved in this laboratory. Investigation of 18 compounds including 4-hydroxybenzaldehyde revealed the significant structure-activity relations with regard to both enzymes inhibition. A carbonyl group or an aminomethyl group, as well as a hydroxy group at the para position of the benzene ring are important for GABA-T inhibition. A carbonyl group and a hydroxy group at the para position of the benzene ring are important for SSADH inhibition. IC50 values of 4-Acryloylphenol (6) for GABA-T and SSADH are 5.48 and 0.35μmol/L, respectively, and IC50 values of 4-β-chloropropionylphenol (7) for GABA-T and SSADH are 3.99 and 1.09μmol/L, exhibiting more potent activity than that of 4-hydroxybenzaldehyde. 4-Hydroxybenzylamine potently inhibited GABA-T (IC50= 15.4μmol/L) in a competitive manner with respect to GABA but in a noncompetitive manner with respect toα-ketoglutarate. A possible mechanism was speculated to rationalize the inhibition of GABA-T by 4-hydroxybenzaldehyde and 4-hydroxybenzylamine.
(3) 4-Acryloylphenol was shown to inhibit irreversibly and potently the enzyme in a time-dependent manner with KI= 470μmol/L, kinact= 0.061 min-1 and kinact/KI= 0.129 (mmol/L)-1min-1. The inhibition was protected byα-ketoglutarate, indicating that it occurs at the active site of the enzyme.β-Mercaptoethanol also prevented the enzyme from irreversible inhibition. The possible mechanism involving a Michael addition was speculated to elucidate the inhibition. The rationality of the mechanism was supported by the preliminary quantum chemical calculations. The results suggested future directions for the design of more potent GABA-T inhibitors.
(4) 4-β-Chloropropionylphenol was shown to inhibit irreversibly and potently the enzyme in a time-dependent manner with KI= 24.3μmol/L, kinact= 0.0467 min-1, kinact/KI= 1.88 (mmol/L)-1min-1. The inhibition was protected byα-ketoglutarate, indicating that it is active site-directed.β-Mercaptoethanol and glutathione also prevented the enzyme from irreversible inhibition. Since the published mechanism can’t rationalize inactivation, a novel possible mechanism involving a nucleophilic substitution was speculated to rationalize the inactivation. Although the confirmation of the presumed mechanism requires further investigation, the results suggested that GABA-T could be inhibited irreversibly via a novel mechanism other than the two published mechanism, which give a new clue to design of more potent GABA-T inhibitors.
(5) A group of flavonoids including baicalein, baicalin, scutellarein, scutellarin, quercetin, kaempferol and rutin, significantly and dose-dependently inhibited GABA-T and SSADH in a noncompetitive manner. The different structure-activity relations were observed with respect to inhibition of GABA-T and SSADH. Among the seven flavonoids, baicalein was the most potent inhibitor for GABA-T (IC50= 12.8μmol/L), and scutellarein exhibited the best inhibitory effect on SSADH (IC50= 7.2μmol/L). The results suggested that the inhibition of both enzymes by flavonoids may contribute to the beneficial effect of flavonoids on the central nervous system.
(6) Helicid-phospholipid complex was prepare and the effect of such factors as the reactant concentrations, the ratio of reactants and the reactive time on the preparation was investigated via a orthogoral design, indicating the best conditions as follows: 5 mg/mL, 1: 5 and 2 h, respectively. X-ray diffraction spectra and DSC indicated that the complex exhibits an amorphous characteristic and change the transformation temperature of hilicid; 1H-NMR spectra and IR spectra suggested that hydroxy groups and aldehyde group of hilicid could interact with phospholipid. There is a great improvement in the solubility of hilicid-phospholipid complex both in water and in n-octanol. The complex significantly improved the relative bioavailability of helicid in rats. The improvement resulted from the particular physic-chemical and solubility properties of the hilicid-phospholipid complex.
The results of this dissertation could be significantly useful to design novel GABA-T inhibitors, and will facilitate to elucidate the neuropharmacological actions of flavonoids. The research of helicid-phospholipid complex led to a valuable direction in development of novel formulations of natural drugs.
引文
[1] 阎淑玲, 罗少华. 中枢神经系统治疗用药的现状与发展. 铁道医学, 1999, 27(2): 137-138.
[2] 海伦. 中枢神经系统疾病的治疗市场再认识. 中华医学信息导报, 2003, 18(14): 15.
[3] 颜廷仁, 端振英, 王永利. γ-氨基丁酸类似物的研究进展. 河北医科大学学报, 2004, 25(2): 109-111.
[4] 邹冈. 基础神经药理学. 北京: 科学出版社, 第 2 版, 1998: 135.
[5] 王尧, 杜子威. 神经生物化学与分子生物学. 北京: 人民卫生出版社, 第 1 版, 1997: 184.
[6] Tillakaratne NJK, Medina-Kauwe L, Gibson KM. Gamma-aminobutyric (GABA) metabolism in mammalian neural and nonneural tissues. Comp Biochem Physiol, 1995, 112A(2): 247-263.
[7] Sherif FM, Ahmed SS. Basic aspects of GABA-transaminase in neuropsychiatric disorders. Clin Biochem, 1995, 28(2): 145-154.
[8] Kushner SA, Dewey SL, Kornetsky C. The irreversible γ-aminobutyric acid (GABA) transaminase inhibitor γ-vinyl-GABA blocks cocaine self-administration in rats. J Pharmacol Exp Ther, 1999, 290(2): 797–802.
[9] Nanavati SM, Silverman RB. Design of potential anticonvulsant agents: mechanistic classification of GABA aminotransferase inactivators. J Med Chem, 1989, 32(11): 2413-2421.
[10] Lippert B, Metcalf BW, Jung MJ, et al. 4-amino-hex-5-enoic acid, a selective catalytic inhibitor of 4- aminobutyric-acid aminotransferase in mammalian brain. Eur J Biochem, 1977, 74(3): 441-445.
[11] Nanavati SM, Silverman RB. Mechanisms of inactivation of γ-aminobutyric acid aminotransferase by the antiepilepsy drug γ-vinyl GABA (vigabatrin). J Am Chem Soc, 1991, 113(24): 9341-9349.
[12] Burke JR, Silverman RB. Mechanism of inactivation of γ-aminobutyric acid aminotransferase by 4-amino-5-hexynoic acid (γ-ethynyl GABA). J Am Chem Soc,1991, 113(24): 9329-9340.
[13] Storici P, Biase DD, Bossa F, et al. Structures of γ-aminobutyric acid (GABA) aminotransferase, a pyridoxal 5’-phosphate, and [2Fe-2S] cluster-containing enzyme, complexed with γ-ethynyl-GABA and with the antiepilepsy drug vigabatrin. J Biol Chem, 2004, 279(1): 363–373.
[14] Rando RR, Bangerter FW. Reaction of the neurotoxin gabaculine with pyridoxal phosphate. J Am Chem Soc, 1977, 99(15): 5141-5145.
[15] Rando RR. Mechanism of the irreversible inhibition of -aminobutyric acid--ketoglutaric acid transaminase by the neurotoxin gabaculine. Biochemistry, 1977, 16(21): 4604-4610.
[16] Fu M, Silverman RB. Isolation and characterization of the product of inactivation of γ-aminobutyric acid aminotransferase by gabaculine. Bioorgan Med Chem, 1999, 7(8): 1581-1590.
[17] Silverman RB, Bichler KA, Leon AJ. Mechanisms of inactivation of γ-aminobutyric acid aminotransferase by 4-amino-5-fluoro-5-hexenoic acid. J Am Chem Soc, 1996, 118(6): 1241-1252.
[18] Silverman RB, Bichler KA, Leon AJ. Unusual Mechanistic Difference in the Inactivation of γ-Aminobutyric Acid Aminotransferase by (E)- and (Z)-4-Amino-6-fluoro-5-hexenoic Acid. J Am Chem Soc, 1996, 118(6): 1253-1261.
[19] Kolb M, Barth J, Heydt JG, et al. Synthesis and evaluation of mono-, di-, and trifluoroethenyl-GABA derivatives as GABA-T inhibitors. J Med Chem, 1987, 30(2): 267-272.
[20] Leon AJ, Silverman RB. Inactivation of γ-aminobutyric acid aminotransferase by (Z)-4-amino-6-fluoro-5-hexenoic acid: identification of an active site residue. Bioorg Med Chem Lett, 1996, 6(12): 1319-1322.
[21] Qiu J, Pingsterhaus JM, Silverman RB. Inhibition and substrate activity of conformationally rigid vigabatrin analogues with γ-aminobutyric acid aminotransferase. J Med Chem, 1999, 42(22): 4725-4728.
[22] Choi S, Silverman RB. Inactivation and inhibition of γ-aminobutyric acid aminotransferase by conformationally restricted vigabatrin analogues. J Med Chem, 2002, 45(20): 4531-4539.
[23] Choi S, Storici P, Schirmer T, Silverman RB. Design of a conformationally restricted analogue of the antiepilepsy drug vigabatrin that directs its mechanism of inactivation of γ-aminobutyric acid aminotransferase. J Am Chem Soc, 2002, 124(8): 1620-1624.
[24] Pan Y, Qiu J, Silverman RB. Design, synthesis, and biological activity of a difluoro-substituted, conformationally rigid vigabatrin analogue as a potent γ-aminobutyric acid aminotransferase inhibitor. J Med Chem, 2003, 46(25): 5292-5293.
[25] Silverman RB, Levy MA. Mechanism of inactivation of γ-aminobutyric acid-α-ketoglutaric acid aminotransferase by 4-amino-5-halopentanoic acids. Biochemistry, 1981, 20(5): 1197-1203.
[26] Silverman RB, Invergo BJ. Mechanism of inactivation of γ-aminobutyrate aminotransferase by 4-amino-5-fluoropentanoic acid. First example of an enamine mechanism for γ-amino acid with a partition ratio of 0. Biochemistry, 1986, 25(22): 6817-6820.
[27] Silverman RB, Roscher CLC. Mechanism-based inactivation of γ-aminobutyric acid aminotransferase by 3-amino-4-fluorobutanoic acid. Bioorgan Med Chem, 1996, 4(9): 1521-1535.
[28] Silverman RB, Levy MA. Syntheses of (S)-5-Substituted 4-aminopentanoic acids: a new class of γ-aminobutyric acid transaminase inactivators. J Org Chem, 1980, 45(5): 815-818.
[29] Silverman RB, Olson GT. 3-Substituted alanines inactivate γ-aminobutyric acid aminotransferase by the same mechanism as do 4-amino-5-halopentanoic acid analogues. Bioorg Med Chem Lett, 1996, 6(2): 143-146.
[30] Silverman RB, Nanavati SM. Selective inhibition of γ-aminobutyric acid aminotransferase by (3R, 4R), (3S, 4S) - and (3R, 4S), (3S, 4R) – 4 –amino – 5 - fluoro-3-p henylpentanoic acids. J Med Chem, 1990, 33(3): 931-936.
[31] Qiu J, Silverman RB. A new Class of conformationally rigid analogues of 4-amino-5-halopentanoic acids, potent inactivators of γ-aminobutyric acid aminotransferase. J Med Chem, 2000, 43(4): 706-720.
[32] Storici P, Qiu J, Schirmer T, et al. Mechanistic crystallography. Mechanism ofinactivation of γ-aminobutyric acid aminotransferase by (1R,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylic acid as elucidated by crystallography. Biochemistry, 2004, 43(44): 14057-14063.
[33] Silverman RB, George C. Inactivation of γ-aminobutyric acid aminotransferase by (Z)-4-amino-2-fluorobut-2-enoic acid. Biochemistry, 1988, 27(9): 3285-3289.
[34] Silverman RB, Durkee SC, Invergo BJ. 4-Amino-2-(substituted methyl)-2-butenoic acids: substrates and potent inhibitors of γ-aminobutyric acid aminotransferase. J Med Chem, 1986, 29(5): 764-770.
[35] Johnson TR, Silverman RB. Syntheses of (Z)-and (E)-4-amino-2-(trifluoromethyl) -2-butenoic acid and their inactivation of γ-aminobutyric acid aminotransferase. Bioorgan Med Chem, 1999, 7(8): 1625-1636.
[36] Fu M, Nikolic D, Breemen RBV, et al. Mechanism of inactivation of γ-aminobutyric acid aminotransferase by (S)-4-amino-4,5-dihydro-2- thiophene- carboxylic acid. J Am Chem Soc, 1999, 121(34): 7751-7759.
[37] Lightcap ES, Hopkins MH, Olson GT, et al. Time-Dependent Inhibition of γ-Aminobutyric Acid Aminotransferase, by 3-Hydroxybenzylhydrazine. Bioorgan Med Chem, 1995, 3(5): 579-585.
[38] Lightcap ES, Silverman RB. Slow-binding inhibition of γ-aminobutyric acid aminotransferase by hydrazine analogues. J Med Chem, 1996, 39(3): 686-694.
[39] Olson GT, Fu M, Lau S, et al. An aromatization mechanism of inactivation of γ-aminobutyric acid aminotransferase for the antibiotic L-cycloserine. J Am Chem Soc, 1998, 120(10): 2256-2267.
[40] Silverman RB, Olson GT. Inactivation of aminobutyric acid aminotransferase by L-3-chloroalanine hydroxamate. Bioorgan Med Chem, 1995, 3(1): 11-18.
[41] Lippert B, Metcalf BW, Resvick RJ. Enzyme-activated irreversible inhibition of rat and mouse brain 4-aminobutyric acid-alpha-ketoglutarate transaminase by 5-fluoro-4-oxo-pentanoic acid. Biochem Biophys Res Commun, 1982, 108(1): 146-152.
[42] Alston TA, Porter DJ, Wheeler DM, et al. Mechanism-based inactivation of GABA aminotransferase by 3,5-dioxocyclohexanecarboxylic acid. Biochem Pharmacol, 1982, 31(24): 4081-4084.
[43] Rey E, Pons G, Richard MO, et al. Pharmacokinetics of the individual enantiomers of vigabatrin (gamma-vinyl GABA) in epileptic children. Br J Clin Pharmacol, 1990, 30(2): 253-257.
[44] Jung MJ, Lippert B, Metcalf BW, et al. Gamma-vinyl GABA (4-amino-hex-5-enoic acid), a new selective irreversible inhibitor of GABA-T: effects on brain GABA metabolism in mice. J Neurochem, 1977, 29(5): 797-802.
[45] Mattson R, Petroff O, Rothman D, Behar K. Vigabatrin: effects on human brain GABA levels by nuclear magnetic resonance spectroscopy. Epilepsia, 1994, 35(suppl 5): S29-32.
[46] Grove J, Schechter P, Tell G, et al. Increased gamma-aminobutyric acid (GABA), homocarnosine, and β-alanine in cerebrospinal fluid of patients treated with gamma-vinyl-GABA (4-amino-hex-5-enoic acid). Life Sci, 1981, 28(21): 2431-2439.
[47] Schechter PJ, Hanke NF, Grove J, et al. Biochemical and clinical effects of gamma-vinyl GABA in patients with epilepsy. Neurology, 1984, 34(2): 182-186.
[48] Ben-Menachem E. Pharmacokinetic effects of vigabatrin on cerebrospinal fluid amino acids in human. Neurology, 1989, 30(suppl 3): S12-14.
[49] Pitkanen A, Halonen T, Ylinen A, et al. Somatostatin, beta-endorphin, and prolactin levels in human cerebrospinal fluid during the gamma-vinyl-GABA treatment of patients with complex partial epilepsy. Neuropeptides, 1987, 9(3): 185-195.
[50] Riekkinen P, Pitkanen A, Ylinen A, et al. Specificity of vigabatrin for the GABAergic system in human epilepsy. Epilspsia, 1989, 30(suppl 3): S518-522.
[51] Ben-Menachem E, Persson L, Manford J. Effect of long-term vigabatrin treatment on selected CSF neurotransmitter concentrations. J Child Neurol, 1991, 6(suppl 2): S11-16.
[52] Schechter PJ, Tranier Y, and Grove J. GABA-Biochemistry and CNS Functions. New York, Plenum Press, 1979: 43-57.
[53] Schechter PJ, Tranier Y, Jung MJ, et al. Audiogenic seizure protection by elevated brain GABA concentration in mice: effects of gamma-acetylenic gaba and gamma-vinyl GABA, two irreversible GABA-T inhibitors. Eur J Pharmacol, 1977, 45(4): 319-328.
[54] Meldrum B, Horton R. Blockade of epileptic responses in the photosensitive baboon, Papio papio, by two irreversible inhibitors of GABA-transaminase, gamma-acetylenic GABA (4-amino-hex-5-ynoic acid) and gamma-vinyl GABA (4-amino-hex-5-enoic acid). Psychopharmacology, 1978, 59(1): 47-50.
[55] Kalichman MW, Burnham WM, Livingston KE. Pharmacological investigation of gamma-aminobutyric acid (GABA) and fully-developed generalized seizures in the amygdala-kindled rat. Neuropharmacology, 1982, 21(2): 127-131.
[56] Miller JW, McKeon AC, Ferrendelli JA. Functional anatomy of pentylenetetrazol and electroshock seizures in the rat brainstem. Ann Neurol, 1987, 22(5): 615-621.
[57] Schechter PJ, Tranier Y. Effect of elevated brain GABA concentrations on the actions of bicuculline and picrotoxin in mice. Psychopharmacology, 1977, 54(2): 145-148.
[58] Loscher W, Schmidt D. Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations. Epilepsy Res, 1988, 2(3): 145-181.
[59] Ben-Menachem E, Persson L, Schechter PJ, et al. Effects of single doses of vigabatrin on CSF concentrations of GABA, homocarnosine, homovanillic acid and 5-hydroxyindoleacedic acid in patients with complex partial seizures. Epilepsy Res, 1988, 2(2): 96-101.
[60] Ben-Menachem E, Mumford J, Hamberger A. Effect of long-term vigabatrin therapy on GABA and other amino acid concentrations in the central nervous system: A case study. Epilepsy Res, 1993, 16(3): 241-243.
[61] Richens, A. 1991. Pharmacology and clinical pharmacology of vigabatrin. J Child Neurology, 1991, 6(Suppl 2): S7-10.
[62] Sivenius MRJ, Ylinen A, Murros K, et al. Double blind dose-reduction study of vigabatrin in complex partial epilepsy. Epilepsia, 1987, 28(6): 688-692.
[63] Bialer M, Johannessen SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs: a summary of the fourth Eilat conference (EILAT IV). Epilepsy Res, 1999, 34(1): 1-41.
[64] Marson AG, Kadir ZA, Hutton JL, et al. The new antiepileptic drugs: a systematic review of their efficacy and tolerability. Epilepsia, 1997, 38(8): 859-880.
[65] Dalla BB, Fontana E, Vigevano F, et al. Efficacy and tolerability of vigabatrin in children with refractory partial seizures: a single-blind, dose-increasing study. Epilepsia, 1995, 36(7): 687-691.
[66] Appleton RE, Peters AC, Mumford JP, et al. Randomised, placebo-controlled study of vigabatrin as first-line treatment of infantile spasms. Epilepsia, 1999, 40(11): 1627-1633.
[67] Hancock E, Osborne JP. Vigabatrin in the treatment of infantile spasms in tuberous sclerosis: literature review. J Child Neurol, 1999, 14(2): 71-74.
[68] Jambaque I, Chiron C, Dumas C, et al. Mental and behavioural outcome of infantile epilepsy treated by vigabatrin in tuberous sclerosis patients. Epilepsy Res, 2000, 38(2-3): 151-160.
[69] Chiron C, Dumas C, Jambaque I, et al. Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis. Epilepsy Res, 1997, 26(2): 389-395.
[70] Vigevano F, Cilio C. Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized prospective study. Epilepsia, 1997, 38(12): 1270-1274.
[71] Sabril IS Investigator and Peer Review Groups, Aicardi J, Mumford JP, et al. Vigabatrin as initial therapy for infantile spasms: a European retrospective survey. Epilepsia, 1996, 37(7): 638-642.
[72] Wallace SJ. Newer antiepileptic drugs: advantages and disadvantages. Brain Dev, 2001, 23(5): 277-283.
[73] Britton JW, So EL. New antiepileptic drugs: prospects for the future. J Epilepsy, 1995, 8(2): 267-281.
[74] Eke T, Talbot JF, Lawden MC. Severe persistent visual field constriction associated with vigabatrin. Br Med J, 1997, 314(7075): 180-181.
[75] Harding GF, Wild JM, Robertson KA, et al. Electro-oculography, electroretinography, visual evoked potentials and multifocal electroretinography in patients with vigabatrin-attributed visual field constriction. Epilepsia, 2000, 41(11): 1420-1431.
[76] Smithers JA, Lang JF, Okerholm RA. Quantitative analysis of vigabatrin in plasma and urine by reversed-phase high-performance liquid chromatography. JChromatogr, 1985, 341(1): 232-238.
[77] Hoke JF, Yuh L, Antony KK, et al. Pharmacokinetics of vigabatrin following single and multiple oral doses in normal volunteers. J Clin Pharmacol, 1993, 33(5): 458-462.
[78] Mumford J. A profile of vigabatrin. Br J Clin Pract, 1988, 42(suppl 6): 7-9.
[79] Haegele KD, Schechter PJ. Kinetics of the enantiomers of vigabatrin after an oral dose of the racemate or the active S-enantiomer. Clin Pharmacol Ther, 1986, 40(5): 581-586.
[80] Ben-Menachem E, Persson LI, Schechter PJ, et al. The effect of different vigabatrin treatment regimens on cerebrospinal fluid biochemistry and seizure control in epilepsy patients. Br J Clin Pharmacol, 1989, 27(suppl 1): 79S-85S.
[81] Haegele KD, Huebert ND, Ebel M, et al. Pharmacokinetics of vigabatrin: implications of creatinine clearance. Clin Pharmacol Ther, 1988, 44(5): 558-565.
[82] Richens A. Pharmacology and clinical Pharmacology of vigabatrin. J Child Neurol, 1991, 6(suppl 2): S7-10.
[83] Browne TR, Mattson RH, Penry JK, et al. Vigabatrin for refractory complex partial seizures: multicenter single- blind study with long-term follow-up. Neurology, 1987, 37(2): 184-189.
[84] Cocito L, Maffini M, Perfumo P, et al. Vigabatrin in complex partial seizures: a long-term study. Epilepsy Res, 1989, 3(2): 160-166.
[85] Rimmer E, Richens A. Interaction between vigabatrin and phenytoin. Br J Clin Pharmacol, 1989, 27(suppl 1): S27-33.
[86] 张宏杰, 周建军, 李新生. 天麻研究进展. 氨基酸和生物资源, 2003, 25(1): 17-20.
[87] 周俊, 杨雁宾, 杨崇仁. 天麻的化学研究-天麻化学成分的分离和鉴定. 化学学报, 1979, 37(3): 183-189.
[88] 冯孝章, 陈玉武, 杨峻山. 天麻化学成分的研究. 化学学报, 1979, 37(3): 176-182.
[89] 周俊, 浦湘渝, 杨雁宾. 新鲜天麻的几种酚性成分. 科学通报, 1981, 18: 1118-1120.
[90] Taguchi H, et a1. Studies on the constituents of Gastrodia elata Blume. ChemPharm Bul1, 1981, 29(1): 55-62.
[91] 黄胜阳, 石建功, 杨永春, 等. 藏药旺拉化学成分的研究. 中国中药杂志, 2002, 27(2): 118-120.
[92] 黄胜阳, 石建功, 杨永春, 等. 长苞凹舌兰化学成分研究. 药学学报, 2002, 37(3): 199-203.
[93] 郝小燕, 谭宁华, 周俊. 黔产天麻的化学成分. 云南植物研究, 2000, 22(1): 81-84.
[94] 李医明, 周卓轮, 洪水福. 珊瑚兰酚类化学成分的研究. 药学学报, l993, 28(10): 766-771.
[95] 肖永庆, 李丽, 游小琳. 天麻有效部位化学成分研究(Ⅰ). 中国中药杂志, 2002, 27(1): 35-36.
[96] Noda N, Kobayashi Y, Miyahara K, et al. 2,4-Bis(4-hydroxybenzyl) phenol from Gastrodia Elata. Phytochemistry, 1995, 39(5): 1247-1248.
[97] Xiao YQ, Li L, You XL, et al. A new compound from Gastrodia Elata Blume. J Asian Nat Prod Res, 2002, 4(1): 73–79.
[98] Lin JH, Liu YC, Hau JP, et al. Parishins b and c from rhizomes of Gastrodia Elata. Phytochemistry, 1995, 42(2): 549-551.
[99] Hayashi J, Sekinea T, Deguchia S, et al. Phenolic compounds from Gastrodia rhizome and relaxant effects of related compounds on isolated smooth muscle preparation. Phytochemistry, 2002, 59(5): 513–519.
[100] Andersson M, Bergendorff O, Nielsen M, et al. Inhibition of kainic acid binding to glutamate receptors by extracts of Gastrodia. Phytochemistry, 1995, 38(4): 835-836.
[101] 胡忠, 杨增明, 王均. 天麻球茎中一种抗真菌蛋白的分离和部分特性. 云南植物研究, 1988, 10(4): 373-380.
[102] 邓士贤, 莫云强. 天麻的药理研究(Ⅰ)天麻素及天麻甙元的镇静及抗惊厥作用. 云南植物研究, 1979, 1(2): 66-73.
[103] 钟裕国, 庞其捷, 张祖谦. 天麻甙元同系物与同型物的合成及其中枢镇静抗惊活性. 四川医学院学报, 1984, 15(3): 17-22.
[104] 尚伟芬, 于澍仁. 天麻药理作用研究进展. 中草药, 1997, 28(10): 629-632.
[105] 黄燕, 黄培新, 杨志敏. 中药益脑安治疗癫痫的实验研究. 广州中医药大学学报, 1998, 15(4): 267-269.
[106] Liu J, Mori A. Antioxidant and free radical scavenging activities of Gastrodia elata Bl. and Uncaria rhynchophylla (Miq.) Jacks. Neuropharmacology, 1992, 31(12): 1287-1298.
[107] Liu J, Mori A. Antioxidant and pro-oxidant activities of p-hydroxybenzyl alcohol and vanillin: effects on free radicals, brain peroxidation and degradation of benzoate, deoxyribose, amino acids and DNA. Neuropharmacology, 1993, 32(7): 659-669.
[108] Ha JH, Lee DU, Lee JT, et al. 4-Hydroxybenzaldehyde from Gastrodia elata B1. is active in the antioxidation and GABAergic neuromodulation of the rat brain. J Ethnopharmacol, 2000, 73(1-2): 329-333.
[109] Ha JH, Shin SM, Lee SK, et al. In vitro effects of hydroxybenzaldehydes from Gastrodia elata and their analogues on GABAergic neurotransmission, and a structure-activity correlation. Planta Med, 2001, 67(9): 877-880.
[110] An SJ, Park SK, Hwang IK, et al. Gastrodin decreases immunoreactivities of gamma-aminobutyric acid shunt enzymes in the hippocampus of seizure-sensitive gerbils. J Neurosci Res, 2003, 71(4): 534-543.
[111] 黄俊华, 王桂莲. 天麻注射液、去天麻甙部分和天麻甙药理作用的比较. 中国医学科学院学报, 1989, 11(2): 147-150.
[112] 熊健明, 莫云强, 梁斌, 陈植和, 邓士贤. 乙酰天麻素对小鼠和大鼠胎仔的影响. 中国药理学报, 1987, 8(1): 57-59.
[113] 杨世林, 兰进, 徐锦堂. 天麻的研究进展. 中草药, 2000, 31(1): 66-69.
[114] Yoon BH, Oh HR, Ahn JH, et al. Anxiolytic-like effects of Gastrodia elata and its phenolic constituents in mice. Biol Pharm Bull, 2006, 29(2): 261-265.
[115] 薛柳华, 唐一鹏. 天麻素对谷氨酸致培养皮层神经细胞损伤的保护作用. 北京中医药大学学报, 1999, 22(1): 39-40.
[116] Kim HJ, Moon KD, Oh SY, et al. Ether fraction of methanol extracts of Gastrodia elata, a traditional medicinal herb, protects against kainic acid-induced neuronal damage in the mouse hippocampus. Neurosci Lett, 2001, 314(1-2): 65-68.
[117] Hsieh CL, Chen CL, Tang NY, et al. Gastrodia elata BL mediates the suppression of nNOS and microglia activation to protect against neuronal damage in kainic acid-treated rats. Am J Chinese Med, 2005, 33(4): 599-611.
[118] Lee YS, Ha JH, Yong CS, et al. Inhibitory effects of constituents of Gastrodia elataBl. on glutamate-induced apoptosis in IMR-32 human neuroblastoma cells. Arch Pharm Res, 1999, 22(4): 404-409.
[119] Kim HJ, Moon KD, Lee DS, et al. Ethyl ether fraction of Gastrodia elata Blume protects amyloid β peptide-induced cell death. J Ethnopharmacol, 2003, 84(1): 95-98.
[120] Kim HJ, Lee SR, Moon KD. Ether fraction of methanol extracts of Gastrodia elata, medicinal herb protects against neuronal cell damage after transient global ischemia in gerbils. Phytother Res, 2003, 17(8): 909-912.
[121] Yu SJ, Kim JR, Lee CK, et al. Gastrodia elata blume and an active component, p-hydroxybenzyl alcohol reduce focal ischemic brain injury through antioxidant related gene expressions. Biol Pharm Bull, 2005, 28(6): 1016-1020.
[122] Hsieh MT, Peng WH, Wu CR, et al. The ameliorating effects of the cognitive-enhancing Chinese herbs on scopolamine-induced amnesia in rats. Phytother Res, 2000, 14(5): 375-377.
[123] Wu CR, Hsieh MT, Huang SC, et al. Effects of Gastrodia elata and its active constituents on scopolamine-induced amnesia in rats. Planta Med, 1996, 62(4): 317-321.
[124] Ho SC, Ho YF, Lai TH, et al. Traditional Chinese Herbs Against Hypertension Enhance the Effect of Memory Acquisition. Am J Chinese Med, 2005, 33(5): 787-795.
[125] Hsieh MT, Wu CR, Chen CF. Gastrodin and p-hydroxybenzyl alcohol facilitate memory consolidation and retrieval, but not acquisition, on the passive avoidance task in rats. J Ethnopharmacol, 1997, 56(1): 45-54.
[126] Wu CR, Hsieh MT, Liao J. p-Hydroxybenzyl alcohol attenuates learning deficits in the inhibitory avoidance task: involvement of serotonergic and dopaminergic systems. Chinese J Physiol, 1996, 39(4): 265-73.
[127] Hsieh MT, Wu CR, Hsieh CC. Ameliorating effect of p-hydroxybenzyl alcohol on cycloheximide-induced impairment of passive avoidance response in rats: Interactions with compounds acting at 5-HT 1A and 5-HT 2 receptors. Pharmacol Biochem Be, 1998, 60(2): 337–343.
[128] 高南南, 于澍仁. 天麻对D-半乳糖所致衰老小鼠的改善作用. 中草药, 1994,25(10): 521-523.
[129] 高南南, 于澍仁. 天麻对老龄大鼠学习记忆的改善作用. 中国中药杂志, 1995, 20(9): 562-563.
[130] 刘建新, 周天达. 天麻对大鼠大脑胶质细胞影响的实验研究. 中国中医基础医学杂志, 1997, 3(6): 23-25.
[131] 黄秀凤, 肖颐, 雷佩琳. 合成天麻素对体外培养乳鼠心肌细胞搏动及组织化学变化的影响. 中药通报, 1986, 11(5): 51-53.
[132] 黄俊华, 王桂莲. 天麻注射液及天麻甙药理作用的初步研究. 中国医学科学院学报, 1985, (5): 399-401.
[133] 赵国举, 任世兰, 吴绍光, 等. 天麻注射液对心血管作用的研究. 中成药研究, 1985, (6): 23-15.
[134] 任世兰, 于龙顺, 赵国举. 天麻对血管阻力和耐缺血缺氧能力的影响. 中草药, 1992, 23(6): 302.
[135] 王正荣, 罗红琳, 肖静, 等. 天麻素对动脉血管顺应性以及血流动力学的影响. 生物医学工程学杂志, 1994, 11(3): 197-.
[136] 陈植和, 张正仙, 王新华, 等. 乙酰天麻素对麻醉犬和兔的椎动脉和颈内动脉血流量的效应. 中国药理学报, 1987, 8(4): 321-325.
[137] 罗红琳, 袁淑兰. 天麻注射液对主动脉平滑肌细胞增殖的影响, 华西医科大学学报, 1997, 28(1): 62-65.
[138] 李晓莉, 张声华. 枸杞、人参、天麻、银杏叶耐缺氧效应的比较研究. 食品科学, 1999, 20(2): 18-20.
[139] 薛柳华, 唐一鹏. 天麻素对缺血再灌注神经细胞膜的保护作用. 北京中医药大学学报, 1998, 21(3): 18-21.
[140] 卫寄英, 刘桦, 吴芬芬, 等. 人工培育的一般天麻和增锌天麻对小鼠抗炎和免疫作用的观察. 南京铁道医学院学报, 1993, 12(4): 189-192.
[141] 于龙顺, 夏敬生. 天麻抗炎效应的研究. 中草药, 1989, 20(5):19-21.
[142] 莫云强, 邓士贤. 天麻的药理研究(Ⅱ)天麻素及天麻甙元对心脏及小肠的作用. 云南植物研究, 1980, 2(5): 230.
[143] 游金辉, 钟裕国. 3H-天麻甙元和3H-天麻素在小鼠体内的分布和代谢. 华西医科大学学报, 1994, 25(3): 325-328.
[144] 陆光伟, 邹元杰, 莫启忠. 3H-天麻素在大鼠体内的吸收、分布、代谢和排泄. 药学学报, 1985, 20(3): 167-172.
[145] 程刚, 郝秀华, 刘国良, 等. 天麻素在大鼠体内的药动学研究. 中国药学杂志, 2003, 38(2): 127-129.
[146] 刘克辛, 韩国柱, 张雅伦, 等. 天麻素在生物样品中的测定及其药物动力学. 中国药理学报, 1987, 8(5): 409-413.
[147] 谭天秩, 匡安仁. 3H-α-迭第二丁基对羟基苄醇在小鼠体内的分布. 华西医科大学学报, 1989, 20(1): 58-61.
[148] 刘桂艳, 王钢力, 马双成, 等. 山龙眼属药用植物有效成分研究概况. 中草药, 2004, 35(5): 593-595.
[149] 沙静姝, 毛洪奎. 豆腐果甙(昆明神衰果素). 药学通报, 1987, 22(1): 27.
[150] Chen W X, Luo S D, Breitmaier E. Helicid, β-allopyranoside from Helicid erratica Hook. Liebigs Ann Chem, 1981, 3(10): 1893-1895.
[151] Luo S D, Ruecker G. Structrue of helicidol, an additionalβ-allopyranoside from Helicia erratica. Planta Med, 1986, (5): 412.
[152] 赵劲萍, 潘维恩. 倮倮粟果化学成分的研究. 天然产物研究与开发, 1991, 3(3): 7-11.
[153] 赵劲萍, 潘维恩. 焰序山龙眼植物化学成分的研究. 天然产物研究与开发, 1992, 4(4): 35-40.
[154] Chen QX, Xie YG, Chai HX. Effect of helicid on convulsion induced by coriaria lactone in mice. West China J Pharm, 1986, 1(2): 91-95.
[155] Zhou X, Zhao TR, Nan GH. Influences of helicid on metabolism of four amino acids in the brain and synaptosomes in mice. Acta Pharmcol Sin, 1987, 8(5): 393-396.
[156] Zhou X, Cai XL, Zhao TR, et al. Studies of effects of helicid on glutamate decarboxylase and γ-aminobutyric acid transaminase in mouse brain by using isotope paper chromatography. Nuclear Tech, 1987, 10(7): 43.
[157] Chen ZX, Lou ZC. A preliminary study of the analgesic action of D fornyl-phenyl-β-D-allosupranoside. Acad J First Med Coll PLA, 1985, 5(3): 186-187.
[158] Clinical Research Coordinated Group. Treatment of neurasthenia with glycoside extracted from Semen Heliciae Erraticae. J Tradit Chin Med, 1985, 26(8): 47-48.
[159] Churchich JE, Moses U. 4-Aminobutyrate aminotransferase. The presence of nonequivalent binding sites. J Biol Chem, 1981, 256(3): 1101-1104.
[160] Nguyen E, Picklo Sr. MJ. Inhibition of succinic semialdehyde dehydrogenase activity by alkenal products of lipid peroxidation. Biochim Biophys Acta, 2003, 1637: 107–112.
[161] Chambliss KL, Gibson KM. Succinic semialdehyde dehydrogenase from mammalian brain: subunit analysis using polyclonal antiserum. Int J Biochem, 1992, 24(9): 1493-9.
[162] Manzocchi A, Biondi P, Secchi C, et al. Studies on analogues of succinic semialdehyde as substrates for succinate semialdehyde dehydrogenase from rat brain. J Neurochem, 1986, 46(6): 1895-1898.
[163] Murphy TC, Amarnath V, Gibson KM, et al. Oxidation of 4-hydroxy-2-nonenal by succinic semialdehyde dehydrogenase (ALDH5A). J Neurochem, 2003, 86(2): 298-305.
[164] Zhao SH, Miller AK, Berger J, et al. Synthesis of arylpiperazines via palladium- catalyzed aromatic amination reaction with unprotected piperazines. Tetrahedron Lett, 1996, 37(26): 4463-4466.
[165] 王葆仁. 有机合成反应. 北京: 科学出版社, 第 1 版, 1981: 646.
[166] 钱建华, 张宝砚, 刘琳, 等. 2-异丙基-1, 3-二氢-4(1H)异喹啉酮及其衍生物的合成. 有机化学, 2002, 22(8): 587-589.
[167] Wu YK, Ahlberg P. Intramolecularity and the function of the side arm base of simple models of traneaminases. J Org Chem, 1992, 57(23): 6324-6327.
[168] Rando RR, Bangerter FW. The irreversible inhibition of mouse brain gamma-aminobutyric acid (GABA)-alpha-ketoglutaric acid transaminase by gabaculine. J Am Chem Soc, 1976, 98(21): 6762-6764.
[169] Rando RR. The chemical labeling of glutamate decarboxylase in vivo. J Biol Chem, 1981, 256(3): 1111-1114.
[170] 张庆建, 赵毅民, 杨明, 等. 黄酮类化合物对中枢神经系统的作用. 中国中药杂志, 2001, 26(8): 511-514.
[171] 曹纬国, 刘志勤, 邵云, 等. 黄酮类化合物药理作用的研究进展. 西北植物学报, 2003, 23(12): 2241-2247.
[172] Carlo GD, Mascolo N, Izzo AA, et al. Flavoniods: old and new aspects of a class of natural therapeutic drugs. Life Sci, 1999, 65(4): 337-353.
[173] Harborne JB, Williams CA, Advances in flavonoid research since 1992. Phytochemistry, 2000, 55(6): 481-504.
[174] Goutman JD, Waxemberga MD, Do?ate-Oliverc F, et al. Flavonoid modulation of ionic currents mediated by GABAA and GABAC receptors. Eur J Pharmacol, 2003, 461(2-3): 79–87.
[175] Calapai G, Crupi A, Firenzuoli F, et al. Effects of Hypericum perforatum on levels of 5-hydroxytryptamine, noradrenaline and dopamine in the cortex, diencephalon and brainstem of the rat. J Pharm Pharmacol, 1999, 51(6): 723-728.
[176] 禹志领, 张广钦, 赵红旗, 等. 葛根总黄酮对小鼠记忆行为的影响. 中国药科大学学报, 1997, 28(6): 350-353.
[177] 郭胜民, 范晓雯, 何建伟, 等. 酸枣仁总黄酮的中枢抑制作用. 中药材, 1998, 21(11): 578-579.
[178] 崔志清, 王国祥, 王立斌. 雪莲黄酮甙A1对小鼠中枢神经系统的作用. 中草药, 1995, 26(5): 247-249.
[179] Hui KM, Huen MS, Wang HY, et al. Anxiolytic effect of wogonin, a benzodiazepine receptor ligand isolated from Scutellaria baicalensis Georgi. Biochem Pharmacol, 2002, 64(9): 1415-1424.
[180] Viola H, Wolfman C, Marder M, et al. 6-Chloro-3’-nitroflavone is a potent ligand for the benzodiazepine binding site of the GABA(A) receptor devoid of intrinsic activity. Pharmacol Biochem Be, 2000, 65(2): 313–320.
[181] Wolfman C, Viola H, Marder M, et al. Pharmacological characterization of 6-bromo-3’-nitroflavone, a synthetic flavonoid with high affinity for the benzodiazepine receptors. Pharmacol Biochem Be, 1998, 61(3): 239–246.
[182] Huen MSY, Leung JWC, Ng W, et al. 5,7-Dihydroxy-6-methoxyflavone, a benzodiazepine site ligand isolated from Scutellaria baicalensis Georgi, with selective antagonistic properties. Biochem Pharmacol, 2003, 66(1): 125–132.
[183] Marder M, Viola H, Wasowski C, et al. 6-Bromoflavone, a high-affinity ligand for the central benzodiazepine receptors is a member of a family of active flavonoids. Biochem Bioph Res Co, 1996, 223(2): 384–389.
[184] Marder M, Estiu G, Blanch LB, et al. Molecular modeling and QSAR analysis of the interaction of flavone derivatives with the benzodiazepine binding site of the GABAA receptor complex. Bioorgan Med Chem, 2001, 9(2): 323-335.
[185] Viola H, Marder M, Wasowski C, et al. 6,3’-Dibromoflavone and 6-nitro-3’-bromoflavone: new additions to the 6,3’-disubstituted flavone family of high-affinity ligands of the brain benzodiazepine binding site with agonistic properties. Biochem Bioph Res Co, 2000, 273(2): 694–698.
[186] Viola H, Marder M, Nunez J, et al. 6-Methyl-3’-bromoflavone, a high-affinity ligand for the benzodiazepine binding site of the GABA(A) receptor with some antagonistic properties. Biochem Bioph Res Co, 1999, 262(3): 643–646.
[187] Halonen T, Miettinen R, Toppinen A, et al. Vigabatrin protects against kainic acid-induced neuronal damage in the rat hippocampus. Neurosci Lett, 1995, 195(1): 13-16.
[188] Gabetta B, Bombardelli E, Pifferl G. Complexes of flavanolignanes with phospholipids, preparation thereof and associated pharmaceutical compositions. Eur Pat, Appl, 0209038, 1987.
[189] 吴建梅, 陈大为, 孙波, 等. 天然活性成分磷脂复合物药学研究概述. 中国药学杂志, 1998, 33(1): 9-11.
[190] 翟光喜,娄红祥,邹立家, 等. 药物磷脂复合物的研究进展. 中国药学杂志, 2001, 36(12): 800-803.
[191] 吴建梅, 陈大为, 刘艳丽. 黄芩苷磷脂复合物制备工艺的研究. 中国中药杂志, 2001, 26(3): 166-169.
[192] 吴建梅, 陈大为. 黄芩苷磷脂复合物理化性质的研究. 中国药学杂志, 2001, 36(3): 173-177.
[193] 凌沛学, 汤漩, 王凤山, 等. 药物与磷脂复合物研究近况. 中国药学杂志, 2005, 40(6): 401-402.
[194] Sarup A, Larsson OM, SchousboeA. GABA transporters and GABA-transaminase as drug targets. Curr Drug Targets, 2003, 2(4): 269-277.
[195] 唐胜平, 郑斯聚. 加巴喷丁的药理及其在镇痛中的应用. 实用疼痛学杂志, 2005, 1(3): 177-180.
[2] 海伦. 中枢神经系统疾病的治疗市场再认识. 中华医学信息导报, 2003, 18(14): 15.
[3] 颜廷仁, 端振英, 王永利. γ-氨基丁酸类似物的研究进展. 河北医科大学学报, 2004, 25(2): 109-111.
[4] 邹冈. 基础神经药理学. 北京: 科学出版社, 第 2 版, 1998: 135.
[5] 王尧, 杜子威. 神经生物化学与分子生物学. 北京: 人民卫生出版社, 第 1 版, 1997: 184.
[6] Tillakaratne NJK, Medina-Kauwe L, Gibson KM. Gamma-aminobutyric (GABA) metabolism in mammalian neural and nonneural tissues. Comp Biochem Physiol, 1995, 112A(2): 247-263.
[7] Sherif FM, Ahmed SS. Basic aspects of GABA-transaminase in neuropsychiatric disorders. Clin Biochem, 1995, 28(2): 145-154.
[8] Kushner SA, Dewey SL, Kornetsky C. The irreversible γ-aminobutyric acid (GABA) transaminase inhibitor γ-vinyl-GABA blocks cocaine self-administration in rats. J Pharmacol Exp Ther, 1999, 290(2): 797–802.
[9] Nanavati SM, Silverman RB. Design of potential anticonvulsant agents: mechanistic classification of GABA aminotransferase inactivators. J Med Chem, 1989, 32(11): 2413-2421.
[10] Lippert B, Metcalf BW, Jung MJ, et al. 4-amino-hex-5-enoic acid, a selective catalytic inhibitor of 4- aminobutyric-acid aminotransferase in mammalian brain. Eur J Biochem, 1977, 74(3): 441-445.
[11] Nanavati SM, Silverman RB. Mechanisms of inactivation of γ-aminobutyric acid aminotransferase by the antiepilepsy drug γ-vinyl GABA (vigabatrin). J Am Chem Soc, 1991, 113(24): 9341-9349.
[12] Burke JR, Silverman RB. Mechanism of inactivation of γ-aminobutyric acid aminotransferase by 4-amino-5-hexynoic acid (γ-ethynyl GABA). J Am Chem Soc,1991, 113(24): 9329-9340.
[13] Storici P, Biase DD, Bossa F, et al. Structures of γ-aminobutyric acid (GABA) aminotransferase, a pyridoxal 5’-phosphate, and [2Fe-2S] cluster-containing enzyme, complexed with γ-ethynyl-GABA and with the antiepilepsy drug vigabatrin. J Biol Chem, 2004, 279(1): 363–373.
[14] Rando RR, Bangerter FW. Reaction of the neurotoxin gabaculine with pyridoxal phosphate. J Am Chem Soc, 1977, 99(15): 5141-5145.
[15] Rando RR. Mechanism of the irreversible inhibition of -aminobutyric acid--ketoglutaric acid transaminase by the neurotoxin gabaculine. Biochemistry, 1977, 16(21): 4604-4610.
[16] Fu M, Silverman RB. Isolation and characterization of the product of inactivation of γ-aminobutyric acid aminotransferase by gabaculine. Bioorgan Med Chem, 1999, 7(8): 1581-1590.
[17] Silverman RB, Bichler KA, Leon AJ. Mechanisms of inactivation of γ-aminobutyric acid aminotransferase by 4-amino-5-fluoro-5-hexenoic acid. J Am Chem Soc, 1996, 118(6): 1241-1252.
[18] Silverman RB, Bichler KA, Leon AJ. Unusual Mechanistic Difference in the Inactivation of γ-Aminobutyric Acid Aminotransferase by (E)- and (Z)-4-Amino-6-fluoro-5-hexenoic Acid. J Am Chem Soc, 1996, 118(6): 1253-1261.
[19] Kolb M, Barth J, Heydt JG, et al. Synthesis and evaluation of mono-, di-, and trifluoroethenyl-GABA derivatives as GABA-T inhibitors. J Med Chem, 1987, 30(2): 267-272.
[20] Leon AJ, Silverman RB. Inactivation of γ-aminobutyric acid aminotransferase by (Z)-4-amino-6-fluoro-5-hexenoic acid: identification of an active site residue. Bioorg Med Chem Lett, 1996, 6(12): 1319-1322.
[21] Qiu J, Pingsterhaus JM, Silverman RB. Inhibition and substrate activity of conformationally rigid vigabatrin analogues with γ-aminobutyric acid aminotransferase. J Med Chem, 1999, 42(22): 4725-4728.
[22] Choi S, Silverman RB. Inactivation and inhibition of γ-aminobutyric acid aminotransferase by conformationally restricted vigabatrin analogues. J Med Chem, 2002, 45(20): 4531-4539.
[23] Choi S, Storici P, Schirmer T, Silverman RB. Design of a conformationally restricted analogue of the antiepilepsy drug vigabatrin that directs its mechanism of inactivation of γ-aminobutyric acid aminotransferase. J Am Chem Soc, 2002, 124(8): 1620-1624.
[24] Pan Y, Qiu J, Silverman RB. Design, synthesis, and biological activity of a difluoro-substituted, conformationally rigid vigabatrin analogue as a potent γ-aminobutyric acid aminotransferase inhibitor. J Med Chem, 2003, 46(25): 5292-5293.
[25] Silverman RB, Levy MA. Mechanism of inactivation of γ-aminobutyric acid-α-ketoglutaric acid aminotransferase by 4-amino-5-halopentanoic acids. Biochemistry, 1981, 20(5): 1197-1203.
[26] Silverman RB, Invergo BJ. Mechanism of inactivation of γ-aminobutyrate aminotransferase by 4-amino-5-fluoropentanoic acid. First example of an enamine mechanism for γ-amino acid with a partition ratio of 0. Biochemistry, 1986, 25(22): 6817-6820.
[27] Silverman RB, Roscher CLC. Mechanism-based inactivation of γ-aminobutyric acid aminotransferase by 3-amino-4-fluorobutanoic acid. Bioorgan Med Chem, 1996, 4(9): 1521-1535.
[28] Silverman RB, Levy MA. Syntheses of (S)-5-Substituted 4-aminopentanoic acids: a new class of γ-aminobutyric acid transaminase inactivators. J Org Chem, 1980, 45(5): 815-818.
[29] Silverman RB, Olson GT. 3-Substituted alanines inactivate γ-aminobutyric acid aminotransferase by the same mechanism as do 4-amino-5-halopentanoic acid analogues. Bioorg Med Chem Lett, 1996, 6(2): 143-146.
[30] Silverman RB, Nanavati SM. Selective inhibition of γ-aminobutyric acid aminotransferase by (3R, 4R), (3S, 4S) - and (3R, 4S), (3S, 4R) – 4 –amino – 5 - fluoro-3-p henylpentanoic acids. J Med Chem, 1990, 33(3): 931-936.
[31] Qiu J, Silverman RB. A new Class of conformationally rigid analogues of 4-amino-5-halopentanoic acids, potent inactivators of γ-aminobutyric acid aminotransferase. J Med Chem, 2000, 43(4): 706-720.
[32] Storici P, Qiu J, Schirmer T, et al. Mechanistic crystallography. Mechanism ofinactivation of γ-aminobutyric acid aminotransferase by (1R,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylic acid as elucidated by crystallography. Biochemistry, 2004, 43(44): 14057-14063.
[33] Silverman RB, George C. Inactivation of γ-aminobutyric acid aminotransferase by (Z)-4-amino-2-fluorobut-2-enoic acid. Biochemistry, 1988, 27(9): 3285-3289.
[34] Silverman RB, Durkee SC, Invergo BJ. 4-Amino-2-(substituted methyl)-2-butenoic acids: substrates and potent inhibitors of γ-aminobutyric acid aminotransferase. J Med Chem, 1986, 29(5): 764-770.
[35] Johnson TR, Silverman RB. Syntheses of (Z)-and (E)-4-amino-2-(trifluoromethyl) -2-butenoic acid and their inactivation of γ-aminobutyric acid aminotransferase. Bioorgan Med Chem, 1999, 7(8): 1625-1636.
[36] Fu M, Nikolic D, Breemen RBV, et al. Mechanism of inactivation of γ-aminobutyric acid aminotransferase by (S)-4-amino-4,5-dihydro-2- thiophene- carboxylic acid. J Am Chem Soc, 1999, 121(34): 7751-7759.
[37] Lightcap ES, Hopkins MH, Olson GT, et al. Time-Dependent Inhibition of γ-Aminobutyric Acid Aminotransferase, by 3-Hydroxybenzylhydrazine. Bioorgan Med Chem, 1995, 3(5): 579-585.
[38] Lightcap ES, Silverman RB. Slow-binding inhibition of γ-aminobutyric acid aminotransferase by hydrazine analogues. J Med Chem, 1996, 39(3): 686-694.
[39] Olson GT, Fu M, Lau S, et al. An aromatization mechanism of inactivation of γ-aminobutyric acid aminotransferase for the antibiotic L-cycloserine. J Am Chem Soc, 1998, 120(10): 2256-2267.
[40] Silverman RB, Olson GT. Inactivation of aminobutyric acid aminotransferase by L-3-chloroalanine hydroxamate. Bioorgan Med Chem, 1995, 3(1): 11-18.
[41] Lippert B, Metcalf BW, Resvick RJ. Enzyme-activated irreversible inhibition of rat and mouse brain 4-aminobutyric acid-alpha-ketoglutarate transaminase by 5-fluoro-4-oxo-pentanoic acid. Biochem Biophys Res Commun, 1982, 108(1): 146-152.
[42] Alston TA, Porter DJ, Wheeler DM, et al. Mechanism-based inactivation of GABA aminotransferase by 3,5-dioxocyclohexanecarboxylic acid. Biochem Pharmacol, 1982, 31(24): 4081-4084.
[43] Rey E, Pons G, Richard MO, et al. Pharmacokinetics of the individual enantiomers of vigabatrin (gamma-vinyl GABA) in epileptic children. Br J Clin Pharmacol, 1990, 30(2): 253-257.
[44] Jung MJ, Lippert B, Metcalf BW, et al. Gamma-vinyl GABA (4-amino-hex-5-enoic acid), a new selective irreversible inhibitor of GABA-T: effects on brain GABA metabolism in mice. J Neurochem, 1977, 29(5): 797-802.
[45] Mattson R, Petroff O, Rothman D, Behar K. Vigabatrin: effects on human brain GABA levels by nuclear magnetic resonance spectroscopy. Epilepsia, 1994, 35(suppl 5): S29-32.
[46] Grove J, Schechter P, Tell G, et al. Increased gamma-aminobutyric acid (GABA), homocarnosine, and β-alanine in cerebrospinal fluid of patients treated with gamma-vinyl-GABA (4-amino-hex-5-enoic acid). Life Sci, 1981, 28(21): 2431-2439.
[47] Schechter PJ, Hanke NF, Grove J, et al. Biochemical and clinical effects of gamma-vinyl GABA in patients with epilepsy. Neurology, 1984, 34(2): 182-186.
[48] Ben-Menachem E. Pharmacokinetic effects of vigabatrin on cerebrospinal fluid amino acids in human. Neurology, 1989, 30(suppl 3): S12-14.
[49] Pitkanen A, Halonen T, Ylinen A, et al. Somatostatin, beta-endorphin, and prolactin levels in human cerebrospinal fluid during the gamma-vinyl-GABA treatment of patients with complex partial epilepsy. Neuropeptides, 1987, 9(3): 185-195.
[50] Riekkinen P, Pitkanen A, Ylinen A, et al. Specificity of vigabatrin for the GABAergic system in human epilepsy. Epilspsia, 1989, 30(suppl 3): S518-522.
[51] Ben-Menachem E, Persson L, Manford J. Effect of long-term vigabatrin treatment on selected CSF neurotransmitter concentrations. J Child Neurol, 1991, 6(suppl 2): S11-16.
[52] Schechter PJ, Tranier Y, and Grove J. GABA-Biochemistry and CNS Functions. New York, Plenum Press, 1979: 43-57.
[53] Schechter PJ, Tranier Y, Jung MJ, et al. Audiogenic seizure protection by elevated brain GABA concentration in mice: effects of gamma-acetylenic gaba and gamma-vinyl GABA, two irreversible GABA-T inhibitors. Eur J Pharmacol, 1977, 45(4): 319-328.
[54] Meldrum B, Horton R. Blockade of epileptic responses in the photosensitive baboon, Papio papio, by two irreversible inhibitors of GABA-transaminase, gamma-acetylenic GABA (4-amino-hex-5-ynoic acid) and gamma-vinyl GABA (4-amino-hex-5-enoic acid). Psychopharmacology, 1978, 59(1): 47-50.
[55] Kalichman MW, Burnham WM, Livingston KE. Pharmacological investigation of gamma-aminobutyric acid (GABA) and fully-developed generalized seizures in the amygdala-kindled rat. Neuropharmacology, 1982, 21(2): 127-131.
[56] Miller JW, McKeon AC, Ferrendelli JA. Functional anatomy of pentylenetetrazol and electroshock seizures in the rat brainstem. Ann Neurol, 1987, 22(5): 615-621.
[57] Schechter PJ, Tranier Y. Effect of elevated brain GABA concentrations on the actions of bicuculline and picrotoxin in mice. Psychopharmacology, 1977, 54(2): 145-148.
[58] Loscher W, Schmidt D. Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations. Epilepsy Res, 1988, 2(3): 145-181.
[59] Ben-Menachem E, Persson L, Schechter PJ, et al. Effects of single doses of vigabatrin on CSF concentrations of GABA, homocarnosine, homovanillic acid and 5-hydroxyindoleacedic acid in patients with complex partial seizures. Epilepsy Res, 1988, 2(2): 96-101.
[60] Ben-Menachem E, Mumford J, Hamberger A. Effect of long-term vigabatrin therapy on GABA and other amino acid concentrations in the central nervous system: A case study. Epilepsy Res, 1993, 16(3): 241-243.
[61] Richens, A. 1991. Pharmacology and clinical pharmacology of vigabatrin. J Child Neurology, 1991, 6(Suppl 2): S7-10.
[62] Sivenius MRJ, Ylinen A, Murros K, et al. Double blind dose-reduction study of vigabatrin in complex partial epilepsy. Epilepsia, 1987, 28(6): 688-692.
[63] Bialer M, Johannessen SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs: a summary of the fourth Eilat conference (EILAT IV). Epilepsy Res, 1999, 34(1): 1-41.
[64] Marson AG, Kadir ZA, Hutton JL, et al. The new antiepileptic drugs: a systematic review of their efficacy and tolerability. Epilepsia, 1997, 38(8): 859-880.
[65] Dalla BB, Fontana E, Vigevano F, et al. Efficacy and tolerability of vigabatrin in children with refractory partial seizures: a single-blind, dose-increasing study. Epilepsia, 1995, 36(7): 687-691.
[66] Appleton RE, Peters AC, Mumford JP, et al. Randomised, placebo-controlled study of vigabatrin as first-line treatment of infantile spasms. Epilepsia, 1999, 40(11): 1627-1633.
[67] Hancock E, Osborne JP. Vigabatrin in the treatment of infantile spasms in tuberous sclerosis: literature review. J Child Neurol, 1999, 14(2): 71-74.
[68] Jambaque I, Chiron C, Dumas C, et al. Mental and behavioural outcome of infantile epilepsy treated by vigabatrin in tuberous sclerosis patients. Epilepsy Res, 2000, 38(2-3): 151-160.
[69] Chiron C, Dumas C, Jambaque I, et al. Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis. Epilepsy Res, 1997, 26(2): 389-395.
[70] Vigevano F, Cilio C. Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized prospective study. Epilepsia, 1997, 38(12): 1270-1274.
[71] Sabril IS Investigator and Peer Review Groups, Aicardi J, Mumford JP, et al. Vigabatrin as initial therapy for infantile spasms: a European retrospective survey. Epilepsia, 1996, 37(7): 638-642.
[72] Wallace SJ. Newer antiepileptic drugs: advantages and disadvantages. Brain Dev, 2001, 23(5): 277-283.
[73] Britton JW, So EL. New antiepileptic drugs: prospects for the future. J Epilepsy, 1995, 8(2): 267-281.
[74] Eke T, Talbot JF, Lawden MC. Severe persistent visual field constriction associated with vigabatrin. Br Med J, 1997, 314(7075): 180-181.
[75] Harding GF, Wild JM, Robertson KA, et al. Electro-oculography, electroretinography, visual evoked potentials and multifocal electroretinography in patients with vigabatrin-attributed visual field constriction. Epilepsia, 2000, 41(11): 1420-1431.
[76] Smithers JA, Lang JF, Okerholm RA. Quantitative analysis of vigabatrin in plasma and urine by reversed-phase high-performance liquid chromatography. JChromatogr, 1985, 341(1): 232-238.
[77] Hoke JF, Yuh L, Antony KK, et al. Pharmacokinetics of vigabatrin following single and multiple oral doses in normal volunteers. J Clin Pharmacol, 1993, 33(5): 458-462.
[78] Mumford J. A profile of vigabatrin. Br J Clin Pract, 1988, 42(suppl 6): 7-9.
[79] Haegele KD, Schechter PJ. Kinetics of the enantiomers of vigabatrin after an oral dose of the racemate or the active S-enantiomer. Clin Pharmacol Ther, 1986, 40(5): 581-586.
[80] Ben-Menachem E, Persson LI, Schechter PJ, et al. The effect of different vigabatrin treatment regimens on cerebrospinal fluid biochemistry and seizure control in epilepsy patients. Br J Clin Pharmacol, 1989, 27(suppl 1): 79S-85S.
[81] Haegele KD, Huebert ND, Ebel M, et al. Pharmacokinetics of vigabatrin: implications of creatinine clearance. Clin Pharmacol Ther, 1988, 44(5): 558-565.
[82] Richens A. Pharmacology and clinical Pharmacology of vigabatrin. J Child Neurol, 1991, 6(suppl 2): S7-10.
[83] Browne TR, Mattson RH, Penry JK, et al. Vigabatrin for refractory complex partial seizures: multicenter single- blind study with long-term follow-up. Neurology, 1987, 37(2): 184-189.
[84] Cocito L, Maffini M, Perfumo P, et al. Vigabatrin in complex partial seizures: a long-term study. Epilepsy Res, 1989, 3(2): 160-166.
[85] Rimmer E, Richens A. Interaction between vigabatrin and phenytoin. Br J Clin Pharmacol, 1989, 27(suppl 1): S27-33.
[86] 张宏杰, 周建军, 李新生. 天麻研究进展. 氨基酸和生物资源, 2003, 25(1): 17-20.
[87] 周俊, 杨雁宾, 杨崇仁. 天麻的化学研究-天麻化学成分的分离和鉴定. 化学学报, 1979, 37(3): 183-189.
[88] 冯孝章, 陈玉武, 杨峻山. 天麻化学成分的研究. 化学学报, 1979, 37(3): 176-182.
[89] 周俊, 浦湘渝, 杨雁宾. 新鲜天麻的几种酚性成分. 科学通报, 1981, 18: 1118-1120.
[90] Taguchi H, et a1. Studies on the constituents of Gastrodia elata Blume. ChemPharm Bul1, 1981, 29(1): 55-62.
[91] 黄胜阳, 石建功, 杨永春, 等. 藏药旺拉化学成分的研究. 中国中药杂志, 2002, 27(2): 118-120.
[92] 黄胜阳, 石建功, 杨永春, 等. 长苞凹舌兰化学成分研究. 药学学报, 2002, 37(3): 199-203.
[93] 郝小燕, 谭宁华, 周俊. 黔产天麻的化学成分. 云南植物研究, 2000, 22(1): 81-84.
[94] 李医明, 周卓轮, 洪水福. 珊瑚兰酚类化学成分的研究. 药学学报, l993, 28(10): 766-771.
[95] 肖永庆, 李丽, 游小琳. 天麻有效部位化学成分研究(Ⅰ). 中国中药杂志, 2002, 27(1): 35-36.
[96] Noda N, Kobayashi Y, Miyahara K, et al. 2,4-Bis(4-hydroxybenzyl) phenol from Gastrodia Elata. Phytochemistry, 1995, 39(5): 1247-1248.
[97] Xiao YQ, Li L, You XL, et al. A new compound from Gastrodia Elata Blume. J Asian Nat Prod Res, 2002, 4(1): 73–79.
[98] Lin JH, Liu YC, Hau JP, et al. Parishins b and c from rhizomes of Gastrodia Elata. Phytochemistry, 1995, 42(2): 549-551.
[99] Hayashi J, Sekinea T, Deguchia S, et al. Phenolic compounds from Gastrodia rhizome and relaxant effects of related compounds on isolated smooth muscle preparation. Phytochemistry, 2002, 59(5): 513–519.
[100] Andersson M, Bergendorff O, Nielsen M, et al. Inhibition of kainic acid binding to glutamate receptors by extracts of Gastrodia. Phytochemistry, 1995, 38(4): 835-836.
[101] 胡忠, 杨增明, 王均. 天麻球茎中一种抗真菌蛋白的分离和部分特性. 云南植物研究, 1988, 10(4): 373-380.
[102] 邓士贤, 莫云强. 天麻的药理研究(Ⅰ)天麻素及天麻甙元的镇静及抗惊厥作用. 云南植物研究, 1979, 1(2): 66-73.
[103] 钟裕国, 庞其捷, 张祖谦. 天麻甙元同系物与同型物的合成及其中枢镇静抗惊活性. 四川医学院学报, 1984, 15(3): 17-22.
[104] 尚伟芬, 于澍仁. 天麻药理作用研究进展. 中草药, 1997, 28(10): 629-632.
[105] 黄燕, 黄培新, 杨志敏. 中药益脑安治疗癫痫的实验研究. 广州中医药大学学报, 1998, 15(4): 267-269.
[106] Liu J, Mori A. Antioxidant and free radical scavenging activities of Gastrodia elata Bl. and Uncaria rhynchophylla (Miq.) Jacks. Neuropharmacology, 1992, 31(12): 1287-1298.
[107] Liu J, Mori A. Antioxidant and pro-oxidant activities of p-hydroxybenzyl alcohol and vanillin: effects on free radicals, brain peroxidation and degradation of benzoate, deoxyribose, amino acids and DNA. Neuropharmacology, 1993, 32(7): 659-669.
[108] Ha JH, Lee DU, Lee JT, et al. 4-Hydroxybenzaldehyde from Gastrodia elata B1. is active in the antioxidation and GABAergic neuromodulation of the rat brain. J Ethnopharmacol, 2000, 73(1-2): 329-333.
[109] Ha JH, Shin SM, Lee SK, et al. In vitro effects of hydroxybenzaldehydes from Gastrodia elata and their analogues on GABAergic neurotransmission, and a structure-activity correlation. Planta Med, 2001, 67(9): 877-880.
[110] An SJ, Park SK, Hwang IK, et al. Gastrodin decreases immunoreactivities of gamma-aminobutyric acid shunt enzymes in the hippocampus of seizure-sensitive gerbils. J Neurosci Res, 2003, 71(4): 534-543.
[111] 黄俊华, 王桂莲. 天麻注射液、去天麻甙部分和天麻甙药理作用的比较. 中国医学科学院学报, 1989, 11(2): 147-150.
[112] 熊健明, 莫云强, 梁斌, 陈植和, 邓士贤. 乙酰天麻素对小鼠和大鼠胎仔的影响. 中国药理学报, 1987, 8(1): 57-59.
[113] 杨世林, 兰进, 徐锦堂. 天麻的研究进展. 中草药, 2000, 31(1): 66-69.
[114] Yoon BH, Oh HR, Ahn JH, et al. Anxiolytic-like effects of Gastrodia elata and its phenolic constituents in mice. Biol Pharm Bull, 2006, 29(2): 261-265.
[115] 薛柳华, 唐一鹏. 天麻素对谷氨酸致培养皮层神经细胞损伤的保护作用. 北京中医药大学学报, 1999, 22(1): 39-40.
[116] Kim HJ, Moon KD, Oh SY, et al. Ether fraction of methanol extracts of Gastrodia elata, a traditional medicinal herb, protects against kainic acid-induced neuronal damage in the mouse hippocampus. Neurosci Lett, 2001, 314(1-2): 65-68.
[117] Hsieh CL, Chen CL, Tang NY, et al. Gastrodia elata BL mediates the suppression of nNOS and microglia activation to protect against neuronal damage in kainic acid-treated rats. Am J Chinese Med, 2005, 33(4): 599-611.
[118] Lee YS, Ha JH, Yong CS, et al. Inhibitory effects of constituents of Gastrodia elataBl. on glutamate-induced apoptosis in IMR-32 human neuroblastoma cells. Arch Pharm Res, 1999, 22(4): 404-409.
[119] Kim HJ, Moon KD, Lee DS, et al. Ethyl ether fraction of Gastrodia elata Blume protects amyloid β peptide-induced cell death. J Ethnopharmacol, 2003, 84(1): 95-98.
[120] Kim HJ, Lee SR, Moon KD. Ether fraction of methanol extracts of Gastrodia elata, medicinal herb protects against neuronal cell damage after transient global ischemia in gerbils. Phytother Res, 2003, 17(8): 909-912.
[121] Yu SJ, Kim JR, Lee CK, et al. Gastrodia elata blume and an active component, p-hydroxybenzyl alcohol reduce focal ischemic brain injury through antioxidant related gene expressions. Biol Pharm Bull, 2005, 28(6): 1016-1020.
[122] Hsieh MT, Peng WH, Wu CR, et al. The ameliorating effects of the cognitive-enhancing Chinese herbs on scopolamine-induced amnesia in rats. Phytother Res, 2000, 14(5): 375-377.
[123] Wu CR, Hsieh MT, Huang SC, et al. Effects of Gastrodia elata and its active constituents on scopolamine-induced amnesia in rats. Planta Med, 1996, 62(4): 317-321.
[124] Ho SC, Ho YF, Lai TH, et al. Traditional Chinese Herbs Against Hypertension Enhance the Effect of Memory Acquisition. Am J Chinese Med, 2005, 33(5): 787-795.
[125] Hsieh MT, Wu CR, Chen CF. Gastrodin and p-hydroxybenzyl alcohol facilitate memory consolidation and retrieval, but not acquisition, on the passive avoidance task in rats. J Ethnopharmacol, 1997, 56(1): 45-54.
[126] Wu CR, Hsieh MT, Liao J. p-Hydroxybenzyl alcohol attenuates learning deficits in the inhibitory avoidance task: involvement of serotonergic and dopaminergic systems. Chinese J Physiol, 1996, 39(4): 265-73.
[127] Hsieh MT, Wu CR, Hsieh CC. Ameliorating effect of p-hydroxybenzyl alcohol on cycloheximide-induced impairment of passive avoidance response in rats: Interactions with compounds acting at 5-HT 1A and 5-HT 2 receptors. Pharmacol Biochem Be, 1998, 60(2): 337–343.
[128] 高南南, 于澍仁. 天麻对D-半乳糖所致衰老小鼠的改善作用. 中草药, 1994,25(10): 521-523.
[129] 高南南, 于澍仁. 天麻对老龄大鼠学习记忆的改善作用. 中国中药杂志, 1995, 20(9): 562-563.
[130] 刘建新, 周天达. 天麻对大鼠大脑胶质细胞影响的实验研究. 中国中医基础医学杂志, 1997, 3(6): 23-25.
[131] 黄秀凤, 肖颐, 雷佩琳. 合成天麻素对体外培养乳鼠心肌细胞搏动及组织化学变化的影响. 中药通报, 1986, 11(5): 51-53.
[132] 黄俊华, 王桂莲. 天麻注射液及天麻甙药理作用的初步研究. 中国医学科学院学报, 1985, (5): 399-401.
[133] 赵国举, 任世兰, 吴绍光, 等. 天麻注射液对心血管作用的研究. 中成药研究, 1985, (6): 23-15.
[134] 任世兰, 于龙顺, 赵国举. 天麻对血管阻力和耐缺血缺氧能力的影响. 中草药, 1992, 23(6): 302.
[135] 王正荣, 罗红琳, 肖静, 等. 天麻素对动脉血管顺应性以及血流动力学的影响. 生物医学工程学杂志, 1994, 11(3): 197-.
[136] 陈植和, 张正仙, 王新华, 等. 乙酰天麻素对麻醉犬和兔的椎动脉和颈内动脉血流量的效应. 中国药理学报, 1987, 8(4): 321-325.
[137] 罗红琳, 袁淑兰. 天麻注射液对主动脉平滑肌细胞增殖的影响, 华西医科大学学报, 1997, 28(1): 62-65.
[138] 李晓莉, 张声华. 枸杞、人参、天麻、银杏叶耐缺氧效应的比较研究. 食品科学, 1999, 20(2): 18-20.
[139] 薛柳华, 唐一鹏. 天麻素对缺血再灌注神经细胞膜的保护作用. 北京中医药大学学报, 1998, 21(3): 18-21.
[140] 卫寄英, 刘桦, 吴芬芬, 等. 人工培育的一般天麻和增锌天麻对小鼠抗炎和免疫作用的观察. 南京铁道医学院学报, 1993, 12(4): 189-192.
[141] 于龙顺, 夏敬生. 天麻抗炎效应的研究. 中草药, 1989, 20(5):19-21.
[142] 莫云强, 邓士贤. 天麻的药理研究(Ⅱ)天麻素及天麻甙元对心脏及小肠的作用. 云南植物研究, 1980, 2(5): 230.
[143] 游金辉, 钟裕国. 3H-天麻甙元和3H-天麻素在小鼠体内的分布和代谢. 华西医科大学学报, 1994, 25(3): 325-328.
[144] 陆光伟, 邹元杰, 莫启忠. 3H-天麻素在大鼠体内的吸收、分布、代谢和排泄. 药学学报, 1985, 20(3): 167-172.
[145] 程刚, 郝秀华, 刘国良, 等. 天麻素在大鼠体内的药动学研究. 中国药学杂志, 2003, 38(2): 127-129.
[146] 刘克辛, 韩国柱, 张雅伦, 等. 天麻素在生物样品中的测定及其药物动力学. 中国药理学报, 1987, 8(5): 409-413.
[147] 谭天秩, 匡安仁. 3H-α-迭第二丁基对羟基苄醇在小鼠体内的分布. 华西医科大学学报, 1989, 20(1): 58-61.
[148] 刘桂艳, 王钢力, 马双成, 等. 山龙眼属药用植物有效成分研究概况. 中草药, 2004, 35(5): 593-595.
[149] 沙静姝, 毛洪奎. 豆腐果甙(昆明神衰果素). 药学通报, 1987, 22(1): 27.
[150] Chen W X, Luo S D, Breitmaier E. Helicid, β-allopyranoside from Helicid erratica Hook. Liebigs Ann Chem, 1981, 3(10): 1893-1895.
[151] Luo S D, Ruecker G. Structrue of helicidol, an additionalβ-allopyranoside from Helicia erratica. Planta Med, 1986, (5): 412.
[152] 赵劲萍, 潘维恩. 倮倮粟果化学成分的研究. 天然产物研究与开发, 1991, 3(3): 7-11.
[153] 赵劲萍, 潘维恩. 焰序山龙眼植物化学成分的研究. 天然产物研究与开发, 1992, 4(4): 35-40.
[154] Chen QX, Xie YG, Chai HX. Effect of helicid on convulsion induced by coriaria lactone in mice. West China J Pharm, 1986, 1(2): 91-95.
[155] Zhou X, Zhao TR, Nan GH. Influences of helicid on metabolism of four amino acids in the brain and synaptosomes in mice. Acta Pharmcol Sin, 1987, 8(5): 393-396.
[156] Zhou X, Cai XL, Zhao TR, et al. Studies of effects of helicid on glutamate decarboxylase and γ-aminobutyric acid transaminase in mouse brain by using isotope paper chromatography. Nuclear Tech, 1987, 10(7): 43.
[157] Chen ZX, Lou ZC. A preliminary study of the analgesic action of D fornyl-phenyl-β-D-allosupranoside. Acad J First Med Coll PLA, 1985, 5(3): 186-187.
[158] Clinical Research Coordinated Group. Treatment of neurasthenia with glycoside extracted from Semen Heliciae Erraticae. J Tradit Chin Med, 1985, 26(8): 47-48.
[159] Churchich JE, Moses U. 4-Aminobutyrate aminotransferase. The presence of nonequivalent binding sites. J Biol Chem, 1981, 256(3): 1101-1104.
[160] Nguyen E, Picklo Sr. MJ. Inhibition of succinic semialdehyde dehydrogenase activity by alkenal products of lipid peroxidation. Biochim Biophys Acta, 2003, 1637: 107–112.
[161] Chambliss KL, Gibson KM. Succinic semialdehyde dehydrogenase from mammalian brain: subunit analysis using polyclonal antiserum. Int J Biochem, 1992, 24(9): 1493-9.
[162] Manzocchi A, Biondi P, Secchi C, et al. Studies on analogues of succinic semialdehyde as substrates for succinate semialdehyde dehydrogenase from rat brain. J Neurochem, 1986, 46(6): 1895-1898.
[163] Murphy TC, Amarnath V, Gibson KM, et al. Oxidation of 4-hydroxy-2-nonenal by succinic semialdehyde dehydrogenase (ALDH5A). J Neurochem, 2003, 86(2): 298-305.
[164] Zhao SH, Miller AK, Berger J, et al. Synthesis of arylpiperazines via palladium- catalyzed aromatic amination reaction with unprotected piperazines. Tetrahedron Lett, 1996, 37(26): 4463-4466.
[165] 王葆仁. 有机合成反应. 北京: 科学出版社, 第 1 版, 1981: 646.
[166] 钱建华, 张宝砚, 刘琳, 等. 2-异丙基-1, 3-二氢-4(1H)异喹啉酮及其衍生物的合成. 有机化学, 2002, 22(8): 587-589.
[167] Wu YK, Ahlberg P. Intramolecularity and the function of the side arm base of simple models of traneaminases. J Org Chem, 1992, 57(23): 6324-6327.
[168] Rando RR, Bangerter FW. The irreversible inhibition of mouse brain gamma-aminobutyric acid (GABA)-alpha-ketoglutaric acid transaminase by gabaculine. J Am Chem Soc, 1976, 98(21): 6762-6764.
[169] Rando RR. The chemical labeling of glutamate decarboxylase in vivo. J Biol Chem, 1981, 256(3): 1111-1114.
[170] 张庆建, 赵毅民, 杨明, 等. 黄酮类化合物对中枢神经系统的作用. 中国中药杂志, 2001, 26(8): 511-514.
[171] 曹纬国, 刘志勤, 邵云, 等. 黄酮类化合物药理作用的研究进展. 西北植物学报, 2003, 23(12): 2241-2247.
[172] Carlo GD, Mascolo N, Izzo AA, et al. Flavoniods: old and new aspects of a class of natural therapeutic drugs. Life Sci, 1999, 65(4): 337-353.
[173] Harborne JB, Williams CA, Advances in flavonoid research since 1992. Phytochemistry, 2000, 55(6): 481-504.
[174] Goutman JD, Waxemberga MD, Do?ate-Oliverc F, et al. Flavonoid modulation of ionic currents mediated by GABAA and GABAC receptors. Eur J Pharmacol, 2003, 461(2-3): 79–87.
[175] Calapai G, Crupi A, Firenzuoli F, et al. Effects of Hypericum perforatum on levels of 5-hydroxytryptamine, noradrenaline and dopamine in the cortex, diencephalon and brainstem of the rat. J Pharm Pharmacol, 1999, 51(6): 723-728.
[176] 禹志领, 张广钦, 赵红旗, 等. 葛根总黄酮对小鼠记忆行为的影响. 中国药科大学学报, 1997, 28(6): 350-353.
[177] 郭胜民, 范晓雯, 何建伟, 等. 酸枣仁总黄酮的中枢抑制作用. 中药材, 1998, 21(11): 578-579.
[178] 崔志清, 王国祥, 王立斌. 雪莲黄酮甙A1对小鼠中枢神经系统的作用. 中草药, 1995, 26(5): 247-249.
[179] Hui KM, Huen MS, Wang HY, et al. Anxiolytic effect of wogonin, a benzodiazepine receptor ligand isolated from Scutellaria baicalensis Georgi. Biochem Pharmacol, 2002, 64(9): 1415-1424.
[180] Viola H, Wolfman C, Marder M, et al. 6-Chloro-3’-nitroflavone is a potent ligand for the benzodiazepine binding site of the GABA(A) receptor devoid of intrinsic activity. Pharmacol Biochem Be, 2000, 65(2): 313–320.
[181] Wolfman C, Viola H, Marder M, et al. Pharmacological characterization of 6-bromo-3’-nitroflavone, a synthetic flavonoid with high affinity for the benzodiazepine receptors. Pharmacol Biochem Be, 1998, 61(3): 239–246.
[182] Huen MSY, Leung JWC, Ng W, et al. 5,7-Dihydroxy-6-methoxyflavone, a benzodiazepine site ligand isolated from Scutellaria baicalensis Georgi, with selective antagonistic properties. Biochem Pharmacol, 2003, 66(1): 125–132.
[183] Marder M, Viola H, Wasowski C, et al. 6-Bromoflavone, a high-affinity ligand for the central benzodiazepine receptors is a member of a family of active flavonoids. Biochem Bioph Res Co, 1996, 223(2): 384–389.
[184] Marder M, Estiu G, Blanch LB, et al. Molecular modeling and QSAR analysis of the interaction of flavone derivatives with the benzodiazepine binding site of the GABAA receptor complex. Bioorgan Med Chem, 2001, 9(2): 323-335.
[185] Viola H, Marder M, Wasowski C, et al. 6,3’-Dibromoflavone and 6-nitro-3’-bromoflavone: new additions to the 6,3’-disubstituted flavone family of high-affinity ligands of the brain benzodiazepine binding site with agonistic properties. Biochem Bioph Res Co, 2000, 273(2): 694–698.
[186] Viola H, Marder M, Nunez J, et al. 6-Methyl-3’-bromoflavone, a high-affinity ligand for the benzodiazepine binding site of the GABA(A) receptor with some antagonistic properties. Biochem Bioph Res Co, 1999, 262(3): 643–646.
[187] Halonen T, Miettinen R, Toppinen A, et al. Vigabatrin protects against kainic acid-induced neuronal damage in the rat hippocampus. Neurosci Lett, 1995, 195(1): 13-16.
[188] Gabetta B, Bombardelli E, Pifferl G. Complexes of flavanolignanes with phospholipids, preparation thereof and associated pharmaceutical compositions. Eur Pat, Appl, 0209038, 1987.
[189] 吴建梅, 陈大为, 孙波, 等. 天然活性成分磷脂复合物药学研究概述. 中国药学杂志, 1998, 33(1): 9-11.
[190] 翟光喜,娄红祥,邹立家, 等. 药物磷脂复合物的研究进展. 中国药学杂志, 2001, 36(12): 800-803.
[191] 吴建梅, 陈大为, 刘艳丽. 黄芩苷磷脂复合物制备工艺的研究. 中国中药杂志, 2001, 26(3): 166-169.
[192] 吴建梅, 陈大为. 黄芩苷磷脂复合物理化性质的研究. 中国药学杂志, 2001, 36(3): 173-177.
[193] 凌沛学, 汤漩, 王凤山, 等. 药物与磷脂复合物研究近况. 中国药学杂志, 2005, 40(6): 401-402.
[194] Sarup A, Larsson OM, SchousboeA. GABA transporters and GABA-transaminase as drug targets. Curr Drug Targets, 2003, 2(4): 269-277.
[195] 唐胜平, 郑斯聚. 加巴喷丁的药理及其在镇痛中的应用. 实用疼痛学杂志, 2005, 1(3): 177-180.