芹菜甲素的药理作用

本文以合成的dl-芹菜甲素为代表,观察芹菜甲素的系统药理作用。在小于TD₅₀剂量下,芹菜甲素能对抗ⅳ戊四唑所致的全身强直性惊厥,但不能防止EEG癫痫样放电,芹菜甲素对抗脑室注射谷氨酸诱发惊厥、ACh诱发震颤和ip震颤素震颤。芹菜有较强的解除ACh和BaCl₂离体回肠痉挛作用。芹菜甲素对动物呼吸、循环和泌尿系统无明显作用。局部和全身给药也不影响瞳孔和对光反射。     

高纯度单体制备及结构鉴定芹菜籽中3种苯酞成分

目的 分离和鉴定芹菜籽中苯酞类化合物。方法 采用硅胶柱色谱、制备薄层色谱方法分离纯化苯酞类化学成分,用波谱分析技术鉴定化合物结构。结果 从芹菜籽中分离制备得到3种主要的苯酞类化合物,分别鉴定为芹菜甲素、芹菜乙素和新蛇床内酯。结论 采用该法制备的样品纯度大于98%,可作为对照品使用。     

丁基苯酞及其光学异构体的抗惊厥作用

ｌ－丁基苯酞是从芹菜籽中分离出的有效成分。ｄｌ－丁基苯酞（ｄｌ－３－ｎ－ｂｕｔｙｌｐｐｈｔｈａｌｉｄｅ），简称ＮＢＰ，又名芹菜甲素，是我所人工合成的消旋体〔１〕。于澍仁等〔２〕研究表明ｌ－ＮＢＰ和ｄｌ－ＮＢＰ对最大电休克，最小电休克、戊四唑惊厥和原发...     

芹菜素联合抗生素的抗耐甲氧西林金黄色葡萄球菌作用

目的:进一步研究芹菜素的抗耐甲氧西林金黄色葡萄球菌(MRSA)菌株作用,并与抗生素进行联合抗菌试验观察是否存在协同作用。方法:利用琼脂扩散法,头孢西丁纸片法和微量棋盘稀释法等药敏试验方法测定芹菜素的抗菌效果。结果:芹菜素对多株MRSA均有抑制作用,最小抑菌浓度(MIC)值为64～256μg.mL-1,与部分喹诺酮类、氨基糖苷类抗生素的联合抗菌指数(FICI值)为0.25～0.5。结论:芹菜素显示良好抗MRSA菌株活性,并与喹诺酮类和氨基糖苷类抗生素呈现明显协同作用。     

dl-3-正丁基苯酞对内皮素诱导脑缺血大鼠行为学的改善研究

目的探讨dl-3-正丁基苯酞对内皮素诱导脑缺血大鼠行为学的改善作用及其作用机制。方法采用向纹状体、皮层注射内皮素-1制作大鼠脑缺血模型。大鼠随机分为假手术组、模型组和dl-3-正丁基苯酞组。dl-3-正丁基苯酞组每日ig 70 mg/kg,起始于缺血后1周,持续给药2周。采用平衡木实验、粘性标签试验和圆筒试验评价神经功能恢复情况,应用免疫荧光技术观察海马齿状回新生神经细胞的情况。结果 dl-3-正丁基苯酞对脑缺血大鼠运功功能的恢复有明显的改善,明显促进海马齿状回的新生神经细胞增多,增加双皮质素(DCX)阳性细胞总树突长度。结论 dl-3-正丁基苯酞不仅能够对脑缺血后大鼠的运动功能有明显的改善,而且促进脑缺血后大鼠的神经再生,对脑缺血所致的神经细胞损坏的治疗提供参考。     

(E)-1(3H)-异苯并呋喃酮-Δ3-乙酰胺类化合物的合成及抗惊活性

目的设计合成了(E)-1(3H)-异苯并呋喃酮-Δ3-乙酰胺类化合物,寻找具有抗惊活性的化合物.方法以氯乙酸为起始原料,依次与氯化亚砜、胺、三苯膦反应制得季磷盐,再与邻苯二甲酸酐经Wittig反应制得目标化合物,硅胶柱色谱得纯品.通过最大电休克发作实验(MES),对目标化合物进行抗惊活性筛选.结果合成了9个新化合物,用IR和1H-NMR进行结构确证,其中3个化合物有良好的抗惊活性.结论 E型异构体具有抗惊活性.     

芫花主要黄酮成分对肝微粒体UGTs及UGT1A1活性的体外抑制作用

目的 考察芫花主要黄酮成分芫花素和芹菜素对尿苷二磷酸葡萄糖醛酸转移酶（UGTs）及UGT1A1活性的影响。方法 采用体外肝微粒体孵育模型,以4-硝基酚（4-nitrophenol,4-NP）为底物检测UGTs活性,胆红素为底物检测UGT1A1活性;利用UV及UPLC-MS/MS测定底物或代谢产物的含量。结果 对UGTs,在大鼠肝微粒体、小鼠肝微粒体以及人肝微粒体孵育体系中,芫花素和芹菜素均能不同程度地抑制UTGs活性;抑制强弱顺序：在大鼠肝微粒体温孵体系中,芫花素>芹菜素;在小鼠肝微粒体以及人肝微粒体温孵体系中,芹菜素>芫花素。对UGT1A1,在人肝微粒体孵育体系中,芫花素和芹菜素均表现为中等强度的竞争性抑制作用,抑制强弱顺序：芹菜素（IC₅₀=12.40 μmol·L^-1）>芫花素（IC₅₀=23.21 μmol·L^-1）。结论 芫花素和芹菜素对不同肝微粒体孵育体系中UGTs及UGT1A1均可产生显著抑制作用且存在种属差异。芫花素及芹菜素可能存在基于UGT酶的药物相互作用。     

N-(1-乙氧羰基-3-苯氨甲酰基丙基)甘氨酰甘氨酸衍生物的合成

报道4个N-(1-[1-乙氧羰基-3-(对甲)苯氨甲酰基]丙基甘氨酰｝-N-取代甘氨酸(XI_1～4)和5个1-[1-乙(或甲)氧羰基-3-(对甲)苯氨甲酰基]丙基-4-取代-1,4-哌嗪-2,5-二酮(XII_1～5)共9个估计有血管紧张素转化酶抑制活性化合物的合成和鉴定。所有这些化合物及9个相应的酯(X_1～9)均未见文献报道。药理初试结果,化合物XII₂,XII₅,XI₄和XII₁均有较强降压活性。     

丁苯酞对神经系统保护作用研究进展

丁苯酞软胶囊（商品名恩必普,butylphthalide,NBP）又称丁基苯酞（dinbente）,是由中国医学科学院药物研究所与石药集团共同研制、生产的国家一类新药,是我国心、脑血管领域第一个拥有自主知识产权的国家一类新药.其主要成分为丁苯酞,化学名为dl-3-正丁基苯酞（3-n-butylphathlide）,分子式为C12H14O2,相对分子质量为190.24,是人工合成的消旋体,其左旋体存在于芹菜籽中,但含量极低.     

NLRP3基因敲除增强芹菜素对triton-WR 1339所致高脂血症的降血脂及抗炎作用研究

目的探讨NLRP3对芹菜素降血脂和抗炎作用的干预及调控机制。方法采用Triton-WR1339对野生型(widetype,WT)C57BL/6小鼠和NLRP3-/-小鼠致高脂血症,给药组连续5 d灌胃给予芹菜素6.25 mg·kg^-1,收集血样及肝脏,测定血清中TC、TG、HDL、LDL;肝脏进行HE染色分析;ELISA测定血清中IL^-1β、IL-6、MCP-1含量。RT-qPCR测定肝脏中NLRP3、IL-4、ASC、CD36、CYP7A1、FGF21的mRNA表达水平。结果与NLRP3-/-模型组相比较,芹菜素降低NLRP3-/-模型小鼠血清TC、TG、LDL-C、IL^-1B、IL-6、MCP-1含量,提高HDL-C含量(P<0.05),减少肝脏脂肪病变比例;芹菜素对WT模型小鼠未见此作用。芹菜素均能上调WT和NLRP3-/-模型小鼠CD36、vLDLR的表达,抑制ASC、IL-4表达(P<0.05)。芹菜素仅调控NLRP3-/-模型小鼠的FGF21、CYP7A1的表达(P<0.05),对WT模型小鼠无作用。结论NLRP3基因敲除增强低剂量芹菜素改善Triton-WR 1339所致的高脂血症及炎症等症状。NLRP3基因敲除增强芹菜素调控血脂作用的机制可能为:NLRP3炎症小体缺失,从而增强芹菜素对FGF21/CYP7A1信号通路的调控相关。     

Synthesis and anticonvulsant evaluation of 3-substituted-4-(4-hexyloxyphenyl)-4H-1,2,4-triazoles

A series of 3-substituted-4-(4-hexyloxyphenyl)-4H-1,2,4-triazole derivatives (3a-s) were synthesized as open-chain analogues of 7-hexyloxyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolines (1c) using 4-hexyloxyaniline, acyl hydrazines, and dimethoxy-N,N-dimethylmethanamine as the starting material. Their anticonvulsant activities were evaluated by the maximal electroshock test (MES test) and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). MES test showed that all open-chain compounds exhibited strong anticonvulsant activity and lower neurotoxicity, and that some possessed obviously stronger activity than compound 1c. Compound 3d, 3-propyl-4-(4-hexyloxyphenyl)-4H-1,2,4-triazole was found to be the most potent with an ED₅₀ value of 5.7 mg/kg and protective index (PI = TD₅₀/ED₅₀) value of 11.5, which was much greater than that of the prototype drug phenytoin (PI = 6.9).     

Isobolographic profile of interactions between tiagabine and gabapentin: a preclinical study<Superscript>A,B</Superscript>

Combining the use of some antiepileptic drugs (AEDs) in patients with epilepsy can result in interactions of a pharmacodynamic or pharmacokinetic character. To quantify the profile of interactions between tiagabine (TGB) and gabapentin (GBP), two novel AEDs influencing the GABAergic neurotransmitter system, an isobolographic analysis was performed in the maximal electroshock seizure threshold (MEST), pentylenetetrazole (PTZ)-induced seizure and chimney tests in mice. TGB and GBP injected alone dose-dependently raised the electroconvulsive threshold in mice, which allowed the evaluation of TID₂₀ (the dose increasing the threshold by 20% compared with controls) in the MEST-test. TID₂₀ values for TGB and GBP alone were 4.3 mg/kg and 70 mg/kg, respectively. On the basis of isobolographic calculations, TGB was also co-administered with GBP at three fixed ratios (1:3, 1:1 and 3:1) of their respective TID₂₀ doses. The isobolographic analysis showed that all three combinations of TGB with GBP exerted supra-additive (synergistic) interactions in the MEST-test in mice. Likewise, TGB and GBP injected alone suppressed the clonic phase of PTZ-induced seizures, with (effective) doses protecting 50% of the animals tested against clonic convulsions (ED₅₀) for TGB and GBP of 0.9 and 199.3 mg/kg, respectively. Moreover, the two-drug combinations at the same fixed ratios of 1:3, 1:1 and 3:1 in PTZ-induced seizures also showed a tendency towards supra-additive (synergistic) interactions. The adverse (neurotoxic) effects produced by TGB and GBP alone or in combinations at the same fixed ratios of 1:3, 1:1 and 3:1 were evaluated in the chimney test. The (toxic) doses evoking motor impairment in 50% of animals tested (TD₅₀) for TGB and GBP alone were 13.6 and 979.6 mg/kg, respectively. The isobolographic analysis showed the interactions between the AEDs to be additive in this test. From a preclinical point of view, the interactions observed experimentally showed that the combination of TGB and GBP, due to a synergistic anti-seizure activity of the drugs, might provide adequate seizure control in patients with refractory epilepsy.^AThe results of the MEST-test in this study were presented at the 3rd Forum of European Neuroscience, Paris, France, 13–17 July, 2002 (abstract 559).^BThe results of the PTZ-test in this study were presented at the conference: Thirty years of cooperation between German and Polish pharmacologists—new perspectives in the Common Europe, Bialowieza, Poland, 18–21 September, 2003 (abstract: Pol J Pharmacol, 2003, 55:500–501).     

Synthesis and Anticonvulsant Activity of N‐(2‐Hydroxy‐ethyl)amide Derivatives

A series novel of N‐(2‐hydroxyethyl)amide derivatives was synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test, and their neurotoxicity was evaluated by the rotarod test (Tox). The maximal electroshock test showed that N‐(2‐hydroxyethyl)decanamide 1g , N‐(2‐hydroxyethyl)palmitamide 1l , and N‐(2‐hydroxyeth‐yl)stearamide 1n were found to show a better anticonvulsant activity and also had lower toxicity than the marked anti‐epileptic drug valproate. In the anti‐MES potency test, these compounds exhibited median effective doses (ED₅₀) of 22.0, 23.3, 20.5 mg/kg, respectively, and median toxicity doses (TD₅₀) of 599.8, >1000, >1000 mg/kg, respectively, resulting in a protective index (PI) of 27.5, >42.9, >48.8, respectively. This is a much better protective index than that of the marked anti‐epileptic drug valproate (PI = 1.6). To further investigate the effects of the anticonvulsant activity in several different models, compounds 1g , 1l , and 1n were tested having evoked convulsions with chemical substances, including pentylenetetrazloe, isoniazide, 3‐mercaptopropionic acid, bicuculline, thiosemicarbazide, and strychnine.     

Synthesis and Evaluation of Antidepressant-like Activity of Some 4-Substituted 1-(2-methoxyphenyl)Piperazine Derivatives

A series of new derivatives of N-(2-methoxyphenyl)piperazine have been synthesized for their affinity toward serotonergic receptors and for their potential antidepressant-like activity. They have been evaluated toward receptors 5-HT_1A, 5-HT₆, and 5-HT₇, as well as in vivo in the tail suspension, locomotor activity, and motor co-ordination tests. All the tested compounds proved very good affinities toward 5-HT_1A and 5-HT₇ receptors. The most promising compound was 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride, exhibiting affinity toward receptors K_i <1 nm (5-HT_1A) and K_i = 34 nm (5-HT₇). Antidepressant-like activity (tail suspension test) was observed at 2.5 mg/kg b.w. (mice, i.p.), and the effect was stronger than that observed for imipramine (5 mg/kg b.w.). Sedative activity was observed at ED₅₀ (locomotor test, mice, i.p.) = 17.5 mg/kg b.w. and neurotoxicity was observed at TD₅₀ (rotarod, mice, i.p.) = 53.2 mg/kg b.w.     

Synthesis and Anticonvulsant Activity of Ethyl 2,2‐dimethyl‐1‐(2‐substitutedhydrazinecarboxamido) Cyclopropanecarboxylate Derivatives

In this study on the development of new anticonvulsants, fourteen ethyl 2,2‐dimethyl‐1‐(2‐substitutedhydrazinecarboxamido) cyclopropanecarboxylate derivatives were synthesized and tested for anticonvulsant activity using the maximal electroshock, subcutaneous pentylenetetrazole screens, which are the most widely employed seizure models for early identification of candidate anticonvulsants. Their neurotoxicity was determined applying the rotorod test. Two compounds 6f and 6k showed promising anticonvulsant activities in both models employed for anticonvulsant evaluation. The most active compound 6k showed the maximal electroshock‐induced seizures with ED₅₀ value of 9.2 mg/kg and TD₅₀ value of 387.5 mg/kg after intraperitoneally injection to mice, which provided compound 6k with a protective index (TD₅₀/ED₅₀) of 42.1 in the maximal electroshock test.     

Synthesis and Anticonvulsant Activity of New N‐(Alkyl/Sub‐stituted aryl)‐N′‐[4‐(5‐cyclohexylamino)‐1,3,4‐thiadiazole‐2‐yl)phenyl]thioureas

A series of novel thiourea derivatives carrying the 5‐cylohexylamino‐1,3,4‐thiadiazole moiety was synthesized and their anticonvulsant activity was evaluated. Structures of the synthesized compounds have been confirmed by IR, ¹H‐NMR, and elemental analysis. All of the compounds were administered at a dose of 50 mg/kg. Some of the active compounds have different effects in pentylenetetrazole (PTZ) and maximal electroshock (MES) tests, indicating the therapeutical potential in petit mal seizures, but not in grand mal seizures. Compounds 10 , 11 , 13 , and 14 carrying 2‐methylphenyl, 4‐chlorophenyl, allyl, and 4‐methylphenyl on the thiourea pharmacophore, increased the survival rate in the PTZ model. The ED₅₀ values of the active compounds 10 , 11 , 13 , and 14 were found 68.42, 43.75, 18.75 and 25 mg/kg, respectively.     

芹菜甲素保护脑细胞的作用

以每周定时im马桑内酯0.9～1.5mg/kg三个月为实验性癫痫慢性发作模型。ig芹菜甲素700mg/kg能明显降低大鼠癲痫发作的程度和次数,延长潜伏期。脑形态学结果表明,芹菜甲素对大脑顶叶皮层细胞、胶质细胞和小脑蚓部蒲肯野细胞有一定的保护作用。同时观察的安定1.5～5mg/kg则无此作用。     

Evaluation of the anticonvulsant activity of 6-(4-chlorophenyoxy)-tetrazolo[5,1-a]phthalazine in various experimental seizure models in mice

This study investigated the anticonvulsant activity of a new phthalazine tetrazole derivative, QUAN-0808 (6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine), in the mouse maximal electroshock (MES) seizure model. The neurotoxicity of QUAN-0808 was investigated using the rotarod neurotoxicity test in mice. QUAN-0808 exhibited higher activity (median effective dose, ED₅₀ = 6.8 mg/ kg) and lower neurotoxicity (median toxic dose, TD₅₀ = 456.4 mg/kg), resulting in a higher protective index (PI = 67.1) compared with carbamazepine (PI = 6.4). In addition, QUAN-0808 exhibited significant oral anticonvulsant activity (ED₅₀ = 24 mg/kg) against MES-induced seizure with low neurotoxicity (TD₅₀ > 4500 mg/kg) in mice, resulting in a PI value of more than 187.5. QUAN-0808 was also tested in chemically induced animal models of seizure (pentylenetetrazole [PTZ], isoniazid [ISO], thiosemicarbazide [THIO] and 3-mercaptopropionic acid [3-MP]) to further investigate the anticonvulsant activity; QUAN-0808 produced significant anticonvulsant activity against seizures induced by ISO, THIO and 3-MP.     

Synthesis and Anticonvulsant Activity of 5‐Phenyl‐[1,2,4]‐triazolo[4,3‐a]quinolines

A series of novel 5‐phenyl‐[1,2,4]‐triazolo[4,3‐a]quinoline derivatives was synthesized by the cyclization of 2‐chloro‐4‐phenyl‐1,2‐dihydronaphthalene with formohydrazide. The starting material 2‐chloro‐4‐phenyl‐1,2‐dihydronaphthalene was synthesized from ethyl‐3‐oxo‐3‐phenylpropanoate and substituted aniline. Their anticonvulsant activities were evaluated by the maximal electroshock (MES) test and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). The maximal electroshock test showed that 7‐hexyloxy‐5‐phenyl‐[1,2,4]‐triazolo[4,3‐a]quinoline 4f was found to be the most potent compound with an ED₅₀ value of 6.5 mg/kg and a protective index (PI = ED₅₀ / TD₅₀) value of 35.1, which was much higher than the PI of the reference drug phenytoin.