• 主题
高级搜索  >
历史搜索 清空历史
首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >Enantiomers of HA-966 (3-amino-1-hydroxypyrrolid-2-one) exhibit distinct central nervous system effects: (+)-HA-966 is a selective glycine/N-methyl-D-aspartate receptor antagonist but (-)-HA-966 is a potent gamma-butyrolactone-like sedative.
【2h】

Enantiomers of HA-966 (3-amino-1-hydroxypyrrolid-2-one) exhibit distinct central nervous system effects: (+)-HA-966 is a selective glycine/N-methyl-D-aspartate receptor antagonist but (-)-HA-966 is a potent gamma-butyrolactone-like sedative.

机译：HA-966（3-氨基-1-羟基吡咯烷-2-酮）的对映异构体表现出独特的中枢神经系统作用：（+）-HA-966是选择性甘氨酸/ N-甲基-D-天冬氨酸受体拮抗剂但（- ）-HA-966是一种有效的类似γ-丁内酯的镇静剂。

代理获取
本网站仅为用户提供外文OA文献查询和代理获取服务，本网站没有原文。下单后我们将采用程序或人工为您竭诚获取高质量的原文，但由于OA文献来源多样且变更频繁，仍可能出现获取不到、文献不完整或与标题不符等情况，如果获取不到我们将提供退款服务。请知悉。
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The antagonist effect of (+/-)-3-amino-1-hydroxypyrrolid-2-one (HA-966) at the N-methyl-D-aspartate (NMDA) receptor occurs through a selective interaction with the glycine modulatory site within the receptor complex. When the enantiomers of (+/-)-HA-966 were resolved, the (R)-(+)-enantiomer was found to be a selective glycine/NMDA receptor antagonist, a property that accounts for its anticonvulsant activity in vivo. In contrast, the (S)-(-)-enantiomer was only weakly active as an NMDA-receptor antagonist, but nevertheless it possessed a marked sedative and muscle relaxant action in vivo. In radioligand binding experiments, (+)-HA-966 inhibited strychnine-insensitive [3H]glycine binding to rat cerebral cortex synaptic membranes with an IC50 of 12.5 microM, whereas (-)-HA-966 had an IC50 value of 339 microM. In electrophysiological experiments, (+)-HA-966 selectively antagonized NMDA receptor responses in rat cortical slices, whereas the (-)-enantiomer was much weaker. On cultured cortical neurones (+)-HA-966 inhibited glycine-potentiated NMDA responses with an IC50 = 13 microM compared with (-)-HA-966, which has an IC50 = 708 microM. In agreement with findings with racemic HA-966, even high concentrations of (+)-HA-966 did not completely inhibit NMDA responses, suggesting that (+)-HA-966 is a low-efficacy partial agonist. (+)-HA-966 produced parallel shifts to the right of the glycine concentration curve for potentiation of NMDA responses, resulting in an estimated pKb = 5.6. In mice, (+)-HA-966 antagonized sound and N-methyl-DL-aspartic acid (NMDLA)-induced seizures with ED50 values of 52.6 mg/kg of body weight (i.p.) and 900 mg/kg (i.v.), respectively. The coadministration of D-serine dose-dependently (10-100 micrograms into the cerebral ventricles per mouse) antagonized the anticonvulsant effect of a submaximal dose of (+)-HA-966 (100 micrograms administered directly into the cerebral ventricles) against NMDLA-induced seizures. The sedative/ataxic effect of racemic HA-966 was mainly attributable to the (-)-enantiomer, which was greater than 25-fold more potent than the (+)-enantiomer. It is suggested that, as in the case of the sedative gamma-butyrolactone, disruption of striatal dopaminergic mechanisms may be responsible for this action.
机译：（+/-）-3-氨基-1-羟基吡咯烷-2-酮（HA-966）对N-甲基-D-天冬氨酸（NMDA）受体的拮抗作用是通过与体内的甘氨酸调节位点选择性相互作用而发生的受体复合物。当解析（+/-）-HA-966的对映异构体时，发现（R）-（+）-对映异构体是选择性甘氨酸/ NMDA受体拮抗剂，这是其体内抗惊厥活性的特性。相反，（S）-（-）-对映体仅作为NMDA-受体拮抗剂具有弱活性，但在体内却具有明显的镇静和肌肉松弛作用。在放射性配体结合实验中，（+）-HA-966抑制了对士的宁不敏感的[3H]甘氨酸与大鼠大脑皮质突触膜的结合，IC50为12.5 microM，而（-）-HA-966的IC50值为339 microM。在电生理实验中，（+）-HA-966在大鼠皮质切片中选择性拮抗NMDA受体反应，而（-）-对映体弱得多。与（-）-HA-966（IC50 = 708 microM）相比，在培养的皮质神经元上，（+）-HA-966抑制了甘氨酸增强的NMDA反应，IC50 = 13 microM。与外消旋HA-966的发现一致，即使高浓度的（+）-HA-966也不能完全抑制NMDA反应，这表明（+）-HA-966是低效的部分激动剂。 （+）-HA-966在甘氨酸浓度曲线的右侧产生了平行移动，以增强NMDA响应，从而估计pKb = 5.6。在小鼠中，（+）-HA-966拮抗声音和N-甲基-DL-天冬氨酸（NMDLA）诱发的癫痫发作，ED50值为52.6 mg / kg体重（ip）和900 mg / kg（iv），分别。剂量依赖性D-丝氨酸的共同给药（每只小鼠10-100微克进入脑室）拮抗亚最大剂量的（+）-HA-966（直接向脑室直接给药100微克）对NMDLA-的抗惊厥作用诱发癫痫发作。外消旋HA-966的镇静/抗衰老作用主要归因于（-）-对映体，其效力比（+）-对映体强25倍以上。建议像镇静性γ-丁内酯一样，纹状体多巴胺能机制的破坏可能是这种作用的原因。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
代理获取

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号