BACKGROUND & AIMS: :Previous studies on the anticonvulsant activity of N-Cbz-alpha-aminoglutarimides have shown that the derivatives of N-Cbz-alpha-amino-N-alkoxy glutarimide have significant anticonvulsant activity. In addition, their anticonvulsant activities are dependent on the presence of N-alkoxy groups. Based on these results, a series of N-Cbz-alpha-amino-glutarimidooxy carboxylates derivatives (3a-e) were synthesized in moderate yield using a known synthetic procedure. Their anticonvulsant activities were evaluated using the maximal electroshock seizure (MES) test, the pentylene tetrazole induced seizure (PTZ) test, and the strychinine (Str) threshold test with the ultimate aim of developing more active anticonvulsants. None of the compounds (3a-e) tested showed anticonvulsant activity in the MES and PTZ test. However, all the compounds tested exhibited significant anticonvulsant activity in the Str. test. The most active compound in the Str. test was the methyl ester of N-Cbz-alpha-amino-glutarimidooxy acetic acid 3a (ED50 = 42.9 mg/kg).

背景与目标： : 先前对N-Cbz-α-氨基戊二酰亚胺的抗惊厥活性的研究表明，N-Cbz-α-氨基-N-烷氧基戊二酰亚胺的衍生物具有显着的抗惊厥活性。此外，它们的抗惊厥活性取决于N-烷氧基的存在。基于这些结果，使用已知的合成方法以中等收率合成了一系列N-Cbz-α-氨基-戊二酰氧基羧酸盐衍生物 (3a-e)。使用最大电击癫痫发作 (MES) 测试，戊烯四唑诱发的癫痫发作 (PTZ) 测试和士冬氨酸 (Str) 阈值测试评估了其抗惊厥活性，最终目的是开发更活跃的抗惊厥药。在MES和PTZ测试中，测试的化合物 (3a-e) 均未显示抗惊厥活性。但是，所有测试的化合物在Str中均显示出显着的抗惊厥活性。测试。在Str.测试中最具活性的化合物是N-Cbz-α-氨基-戊二酰基氧乙酸3a的甲酯 (ED50 = 42.9 mg/kg)。

BACKGROUND & AIMS: :Animals will respond with stress-like behavioral and biochemical changes when exposed to a neutral stimulus that had previously been paired with a stressful stimulus. This phenomenon is generally known as aversive conditioning or conditioned fear. We tested the effect of prior exposure to cocaine on rats subjected to an aversive conditioning paradigm. Rats were given repeated doses of cocaine to develop a reverse tolerance or sensitization to the locomotor stimulant properties of cocaine. We blocked this sensitization to cocaine in one cocaine-exposed group by co-administering an antagonist of the strychinine-insensitive glycine site of the N-methyl-D-aspartate receptor complex, R-(+)-HA-966, which prevented the development of locomotor sensitization to cocaine. After about three weeks, we examined the effect of cocaine sensitization and the prevention of sensitization by R-(+)-HA-966 on aversive conditioning. Rats were exposed to 10 tones (neutral stimuli) paired with footshock (stressful stimuli) over 30 min for the conditioning session. The following day, rts were returned to the cages, received 10 tones only over 30 min and were killed. No drugs were given to any rat before either session and control rats received the tones without footshock in both sessions. Prior exposure to cocaine caused an attenuation of the behavioral effects of aversive conditioning, namely the amount of time spent immobilized and the number of fecal boli expelled. Additionally, the elevated metabolic activity of dopamine in the medial prefrontal cortex, nucleus accumbens and ventral tegmental area associated with aversive conditioning was diminished in rats pre-exposed to cocaine. The behavioral and biochemical effects of pre-exposure to cocaine were reversed in rats that receive R-(+)-HA-966 co-treatment with the five day cocaine sensitization regimen. These data suggest that prior behavioral sensitization to cocaine diminishes the stressful effect of conditioned fear and that these effects are reversed when sensitization is prevented with R-(+)-HA-966.

背景与目标： : 当暴露于先前与压力刺激配对的中性刺激时，动物会做出类似压力的行为和生化变化。这种现象通常被称为厌恶条件或条件恐惧。我们测试了先前暴露于可卡因对遭受厌恶条件范例的大鼠的影响。给大鼠重复剂量的可卡因，以对可卡因的运动刺激特性产生反向耐受性或敏感性。我们通过共同施用N-甲基-D-天冬氨酸受体复合物R-(+)-HA-966的马胆酸对甘氨酸不敏感的甘氨酸位点的拮抗剂，在一个可卡因暴露组中阻止了对可卡因的这种敏化，这阻止了对可卡因的运动敏化。大约三周后，我们检查了可卡因致敏作用以及R-()-HA-966对厌恶性条件的预防致敏作用。在30分钟内，将大鼠暴露于10个音调 (中性刺激) 与脚休克 (压力刺激) 配对以进行调理。第二天，rts被送回笼子，仅在30分钟内收到10个音调，并被杀死。在任何一个疗程之前都没有给任何大鼠服用药物，并且对照组大鼠在两个疗程中都接受了没有脚电击的音调。先前暴露于可卡因会导致厌恶性条件的行为影响减弱，即固定时间和排出粪便的数量。此外，在暴露于可卡因的大鼠中，与厌恶性条件相关的内侧前额叶皮层，伏隔核和腹侧被盖区中多巴胺的代谢活性升高。在接受R-()-HA-966与5天可卡因致敏方案的联合治疗的大鼠中，预暴露于可卡因的行为和生化作用被逆转。这些数据表明，先前对可卡因的行为敏化会减少条件性恐惧的压力作用，并且当用R-()-HA-966阻止敏化时，这些作用会逆转。

BACKGROUND & AIMS: :Current evidence indicates that glutamate acting via the N-methyl-D-aspartate (NMDA) receptor/ion channel complex plays a major role in the neuronal degeneration associated with a variety of neurological disorders. In this report the role of glycine in NMDA neurotoxicity was examined. We demonstrate that NMDA-mediated neurotoxicity is markedly potentiated by glycine and other amino acids, e.g., D-serine. Putative glycine antagonists HA-966 and 7-chlorokynurenic acid were highly effective in preventing NMDA neurotoxicity, even in the absence of added glycine. The neuroprotective action of HA-966 and 7-chlorokynurenic acid, but not that of NMDA antagonists 3-(2-carboxypiperazine-4-yl)propylphosphonate and MK-801, could be reversed by glycine. These results indicate that glycine, operating through a strychinine-insensitive glycine site, plays a central permissive role in NMDA-mediated neurotoxicity.

背景与目标： : 目前的证据表明，通过N-甲基-D-天冬氨酸 (NMDA) 受体/离子通道复合物起作用的谷氨酸在与多种神经系统疾病相关的神经元变性中起主要作用。在本报告中，研究了甘氨酸在NMDA神经毒性中的作用。我们证明了NMDA介导的神经毒性被甘氨酸和其他氨基酸 (例如D-丝氨酸) 显着增强。假定的甘氨酸拮抗剂HA-966和7-氯核糖核酸在预防NMDA神经毒性方面非常有效，即使在没有添加甘氨酸的情况下也是如此。甘氨酸可以逆转HA-966和7-氯代尿酸的神经保护作用，而非NMDA拮抗剂3-(2-羧基哌嗪-4-基) 丙基膦酸盐和MK-801的神经保护作用。这些结果表明，甘氨酸通过对士林不敏感的甘氨酸位点起作用，在NMDA介导的神经毒性中起着中心许可作用。

BACKGROUND & AIMS: :Hoffmann (H) reflexes from foreleg flexor nerves were studied in cats. The right and left flexor nerves were stimulated and H reflexes were recorded from the same nerves. Paw preference was assessed by a food reaching test. Stimulation of the right median nerve elicited mono- and polysynaptic reflexes from the left ulnar nerve (crossed flexor nerve). Picrotoxin depressed, and strychnine increased H reflexes from both sides without affecting the spinal motor asymmetry. H reflexes were found to be larger on the left than the right side in right-preferent cats and vice versa in left-preferent cats. The right H-reflex recovery curve was higher than left in right-preferent cats. The inhibitory period of the recovery cycle disappeared after picrotoxin and changed to facilitation for the nonpreferred side. Strychinine caused bilateral, nearly-synchronous motoneuronal discharges from the right and left flexor nerves; the discharges originating from the left side preceded those from the right side in a right-preferent cat. These results indicate that spinal motor activity predominates on the nonpreferred side, which would be a prerequisite for postural adjustments during paw use in cats. This asymmetric motor organization in the forelegs of cats having quadrpedal locomotion seems to be similar to asymmetric motor organization in legs in humans.

背景与目标： : 在猫中研究了来自前肢屈肌神经的霍夫曼 (H) 反射。刺激左右屈肌神经，并记录同一神经的H反射。通过食物到达测试评估了爪子的偏好。右正中神经的刺激引起左尺神经 (交叉屈肌神经) 的单突触和多突触反射。苦味素抑制，士的宁增加两侧的H反射，而不影响脊柱运动不对称。在右偏爱的猫中，左侧的H反射比右侧大，反之亦然。右偏好猫的右H反射恢复曲线高于左。微毒素后，恢复周期的抑制期消失，并改变为非首选侧的促进作用。马钱子碱引起左右屈肌神经的双侧，几乎同步的运动神经元放电; 在右偏爱的猫中，来自左侧的放电先于右侧的放电。这些结果表明，脊柱运动活动在非首选侧占主导地位，这将是猫在使用爪子时进行姿势调整的先决条件。具有四足运动的猫前肢中的这种不对称运动组织似乎与人类腿部中的不对称运动组织相似。

BACKGROUND & AIMS: :GABA content of isolated, dark adapted frog retina was found to be 3.15 +/- 0.28 mM. After 30 minutes of exposure to intense light (200 lx), retinal GABA levels increased about 70%. Interestingly, incubation of dark adapted retina for 30 minutes with medium containing 0.4 mM taurine also led to a 70% increase in GABA levels. Since the light-induced elevation in GABA content was reduced over 50% by a simultaneous injection of 0.02 mM strychinine, it is likely that the light-induced GABA change is partly mediated by the release of taurine from the retina seen after light exposure. However, incubation of isolated retina with medium containing increasing concentrations of taurine (1, 2 and 20 mM), caused a progressive rise in 14C-GABA efflux from retina that was preloaded with 2.2 microM GABA and exposed to dim light (0.05 lx). It was also shown that taurine (1 and 5 mM) dramatically reduced 14C-aspartate efflux from retina preloaded with radioactive aspartate and exposed to dim light conditions. By comparison, intense light stimulation (40 lx) reduced basal 14C-aspartate efflux while dark exposure increased 14C-aspartate loss from the isolated retina. We found that taurine depressed the b-wave signal of frog retina, with the maximum effect occurring at a concentration of 1 mM. Addition of strychnine (0.4 mM) reversed the taurine effect on the b-wave, indicating that taurine receptors must be present in the inner retina. By contrast, taurine (0.1-20 mM) had no effect on the P111 component of the ERG initiated by either aspartate or cobalt. However, taurine exerted a modest depressant activity on P111 initiated by glutamate. The significance of these data relative to the putative neurotransmitter function of taurine in the inner retina is discussed.

背景与目标： : 发现孤立的深色适应青蛙视网膜的GABA含量为3.15/- 0.28 mM。暴露于强光 (200 lx) 30分钟后，视网膜GABA水平增加约70%。有趣的是，黑暗适应视网膜与含有0.4 mM牛磺酸的培养基孵育30分钟也导致GABA水平的70% 增加。由于通过同时注射0.02 mM的士冬氨酸，随着50% 的推移，光诱导的GABA含量升高降低，因此光诱导的GABA变化可能部分由暴露后从视网膜中释放的牛磺酸介导。然而，将分离的视网膜与含有浓度增加的牛磺酸 (1、2和20 mM) 的培养基一起孵育，导致来自预先装有2.2 microM GABA并暴露于暗光 (0.05 lx) 的视网膜的14C-GABA流出逐渐增加。还显示，牛磺酸 (1和5毫米) 显着减少了来自预先装有放射性天冬氨酸并暴露于昏暗光线条件下的视网膜的14c-天冬氨酸外排。相比之下，强光刺激 (40 lx) 减少了基底14c-天冬氨酸的流出，而黑暗暴露增加了离体视网膜14c-天冬氨酸的损失。我们发现牛磺酸抑制了青蛙视网膜的b波信号，最大的作用发生在1毫米的浓度下。添加士的宁 (0.4 mM) 逆转了牛磺酸对b波的作用，表明牛磺酸受体必须存在于内部视网膜中。相比之下，牛磺酸 (0.1-20 mM) 对由天冬氨酸或钴引发的ERG的P111组分没有影响。然而，牛磺酸对谷氨酸引发的P111具有适度的抑制活性。讨论了这些数据相对于牛磺酸在视网膜内的假定神经递质功能的重要性。

BACKGROUND & AIMS: :The crude drug, Chotoko (Uncariae Uncis cam Ramlus), the hooks of Uncaria spp. (Rubiaceae), has been claimed to possess sedative and anti-spasmodic actions, and is contained in a Chinese traditional preparation, Choto-san, as a main crude drug. Examinations were made on the anti-convulsion effects of Choto-san and Chotoko against some animal models of epilepsy conducted by the stimulation of drugs or electricity. Oral administration of the Choto-san extract to mice at the doses of 1.0 g/kg and 3.0 g/kg tended to inhibit the glutamate-induced convulsion in a dose-dependent manner, and the effect of the Chotoko extract at a 3.0 g/kg dose was significant, while both the extracts showed no activity against the picrotoxine-induced, strychinine-induced, and electroshock convulsions. The Choto-san preparation without Chotoko was inactive, and the activity of the Chotoko extract was more potent than that of the every crude drug comprising Choto-san, suggesting that Chotoko plays the most important role in the Choto-san prescription and contains some active compounds. Bioassay-guided fractionation of the Chotoko extract led to the location of the active components in the less polar alkaloids-containing fraction, from which three indole alkaloids, geissoschizine methylether (1), hirsuteine (2) and hirsutine (3), and an oxyindole alkaloid, isocorynoxeine (4) were isolated and identified. Oral administration of 1 and 2 to mice at the doses of 50, 100, and 200 mg/kg inhibited the glutamate-induced convulsion in a dose-dependent manner. The effect of 3, the dihydro derivative of 2, was less potent than those of 1 and 2. Compound 4 showed no activity at a 100 mg/kg dose compared with control. The above results support the Chinese herbal description of the anti-spasmodic action of Chotoko, and show that 1 and 2 contained in Chotoko must be mainly contributed to the activity. It is also suggested that Choto-san may be clinically available for treatment of epilepsy.

背景与目标： : 粗药，chootoko (Uncariae Uncis cam Ramlus)，钩藤属的钩。(茜草科)，据称具有镇静和抗痉挛作用，并作为主要生药包含在中国传统制剂Choto-san中。检查了Choto-san和Chotoko对通过药物或电刺激进行的某些癫痫动物模型的抗惊厥作用。以1.0g/kg和3.0g/kg的剂量对小鼠口服Choto-san提取物倾向于以剂量依赖性方式抑制谷氨酸引起的惊厥，并且以3.0g/kg的剂量对Chotoko提取物的作用是显着的，尽管两种提取物均对苦豆碱诱导的，马冬氨酸诱导的和电击惊厥均无活性。不含Chotoko的Choto-san制剂无活性，并且Chotoko提取物的活性比包含Choto-san的每种粗制药物的活性更有效，这表明Chotoko在Choto-san处方中起着最重要的作用，并且包含一些活性化合物。生物测定指导的Chotoko提取物的分馏导致活性成分在极性较小的含生物碱部分中的位置，其中三种吲哚生物碱，geissoschizine methylether (1)，hirsuteine (2) 和hirsutine (3)，以及一种氧吲哚生物碱，分离并鉴定了异糖苷 (4)。以50、100和200 mg/kg的剂量对小鼠口服1和2以剂量依赖性方式抑制谷氨酸诱导的惊厥。2的二氢衍生物3的作用不如1和2的作用。与对照相比，化合物4在100 mg/kg剂量下无活性。以上结果支持了中草药对Chotoko的抗痉挛作用的描述，并表明Chotoko中所含的1和2必须主要有助于该活性。还建议Choto-san在临床上可用于治疗癫痫。