地佐环平 | 77086-21-6

• 物质功能分类: 生物化工 - 抑制剂 - 神经信号通路(Neuronal Signaling)
• 分子结构分类: 有机化合物 - 苯类化合物 - 二苯并环庚烯
• 中文名称: 地佐环平
• 英文名称: Dizocilpine
• 英文别名: 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine；(1S,9R)-1-methyl-16-azatetracyclo[7.6.1.02,7.010,15]hexadeca-2,4,6,10,12,14-hexaene
• CAS: 77086-21-6
• 化学式: C₁₆H₁₅N
• 分子量: 221.302
• InChiKey: LBOJYSIDWZQNJS-CVEARBPZSA-N

物化性质

• 熔点：
  68.5-69°
• 比旋光度：
  20589 +161.4° (c = 0.038 g/2 ml ethanol)
• 沸点：
  320.3±11.0 °C(Predicted)
• 密度：
  1.144±0.06 g/cm3(Predicted)
• 溶解度：
  溶于 DMSO > 10 mM
• 颜色/状态：
  White solid from cyclohexane
• 蒸汽压力：
  7.50X10-5 mm Hg at 25 °C (est)
• 旋光度：
  Specific optical rotation: +161.4 deg at 20 °C/589 ( c = 0.038 g/2 ml ethanol)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  17
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  12
• 氢给体数：
  1
• 氢受体数：
  1

ADMET

毒理性

• 相互作用

当前研究的目的是调查地佐匹克隆马来酸盐（MK-801），一种非竞争性NMDA谷氨酸受体拮抗剂，对长期大剂量地塞米松（DEX）治疗引起的神经毒性的影响。结果显示，DEX（每天120 mg/kg，连续7天）损害了长期记忆和运动协调能力，减少了体重，并导致小鼠的致死性。形态学和超微结构研究证实，单独长期使用DEX后，海马神经元尤其是CA3区域的神经元受损。受损的锥体神经元显示出核形状的显著变化和细胞质的浓缩。单独使用MK-801（在非毒性剂量0.3 mg/kg/天），既没有改变小鼠的行为，也没有改变海马神经元的形态。然而，它并没有阻止DEX的神经毒性作用。相反，它加剧了DEX诱导的神经毒性。

... The purpose of the present study was to investigate the effect of dizocilpine maleate (MK-801), non-competitive NMDA glutamate receptor antagonist, on neurotoxic effect of the prolonged treatment with the high dose of dexamethasone (DEX). The results showed that DEX (120 mg/kg/day for 7 days) impaired the long-term memory and the motor coordination, reduced the body weight and induced the lethality of mice. The morphological and ultrastructural study have confirmed damage to hippocampal neurons especially in the CA3 region after the prolonged treatment with DEX alone. Damaged pyramidal neurons showed robust changes in the shape of the nucleus and cytoplasm condensation. MK-801 alone (at non-toxic dose of 0.3 mg/kg/day), changed neither the behavior of mice nor morphology of the hippocampal neurons. However, it did not prevent the neurotoxic effects of DEX. On the contrary, it intensified DEX-induced neurotoxicity.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在一项初步研究中，剂量为2.5毫克/千克的甲基苯丙胺（METH），而不是1.0毫克/千克，导致了伏隔核（NAc）中谷氨酸水平的延迟增加。假设重复增加的谷氨酸水平会导致对选择性的非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂地佐环平（MK-801）的行为敏化，并且蛋白激酶C（PKC）的激活在这种敏化中扮演着重要角色。本研究旨在确认较高剂量METH（2.5毫克/千克）引起的谷氨酸水平的延迟增加，并检查PKC抑制剂staurosporine对较高剂量METH诱导的地佐环平敏化的影响。2.5毫克/千克的METH，而不是1.0毫克/千克，导致了谷氨酸水平的延迟增加。单次注射METH（2.5毫克/千克）时，staurosporine的急性给药并不影响其运动活动。重复给予METH（2.5毫克/千克，每隔一天一次，共五次）发展了对地佐环平（0.2毫克/千克）引起的运动诱导效果的行为敏化，地佐环平是一种选择性的非竞争性NMDA受体拮抗剂。在每次METH处理后120分钟给予staurosporine（0.1毫克/千克）可以抑制对地佐环平行为敏化的发生。这些结果表明，谷氨酸水平的增加和PKC的激活参与了较高剂量METH诱导的对地佐环平行为敏化的延迟诱导突触和细胞可塑性的形成。

...In /a/ preliminary study, methamphetamine (METH) at 2.5 mg/kg, but not at 1.0 mg/kg, induced a delayed increase in glutamate levels in the nucleus accumbens (NAc). /It was hypothesized/ that repeated increases in glutamate levels produces behavioral sensitization to a selective uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801), and that an activation of protein kinase C (PKC) plays an important role for this sensitization. ... This study was conducted to confirm delayed increases in glutamate levels induced by a higher dose of METH (2.5 mg/kg), and to examine the effect of straurosporine, a PKC inhibitor, on the higher dose of METH-induced sensitization to dizocilpine. ... METH at 2.5 mg/kg, but not at 1.0 mg/kg, induced delayed increases in glutamate levels. The acute administration of staurosporine did not affect the locomotor activity by a single injection of METH (2.5 mg/kg). Repeated METH administrations (2.5 mg/kg, once in every other day, for five times) developed behavioral sensitization to the locomotion-inducing effect of dizocilpine (0.2 mg/kg), a selective uncompetitive NMDA receptor antagonist. Staurosporine (0.1 mg/kg), given 120 min later for every METH treatment, inhibited the development of behavioral sensitization to dizocilpine. ... These results suggest the involvement of increased glutamate levels and an activation of PKC in delayed-induced synaptic and cellular plasticity underlying the higher dose of METH-induced behavioral sensitization to dizocilpine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

当前研究旨在调查性别差异在双环己哌啶（MK-801）预处理与急性冷束缚应激（CRS）的交互作用对戊四唑（PTZ）诱导的瑞士白鼠癫痫发作中的重要性。本研究将CRS方案应用于小鼠，以探讨MK-801预处理（CRS前30分钟）与应激（随后注射PTZ）在癫痫易感性中的交互作用。为此，设立了6个组别：（1）PTZ对照组（仅接受PTZ）；（2）应激组（接受应激和PTZ）；（3）生理盐水组（接受生理盐水和PTZ）；（4）MK-801组（接受MK-801和PTZ）；（5）生理盐水+应激组（接受生理盐水、应激和PTZ）；（6）MK-801+应激组（接受MK-801、应激和PTZ）。MK-801（0.125、0.25、0.50 mg/kg）预处理显著增强了应激在PTZ诱导（65 mg/kg）的癫痫发作中的保护作用，在两性中通过延长肌阵挛和阵挛抽搐的发作时间。与所有组别（即PTZ对照组、应激组、生理盐水组、MK-801组、生理盐水+应激组和MK-801+应激组）中的雌性小鼠相比，雄性小鼠在肌阵挛（雄性，66.7-295.5秒；雌性，54.0-247.5秒；P < 0.05）和阵挛抽搐（雄性，123.5-789.8秒；雌性，94.5-757.2秒；P < 0.05）的发作时间上有显著延迟。本研究在小鼠中的发现表明性激素参与了MK-801预处理与急性CRS在PTZ诱导的癫痫发作中的交互作用。

... The present study was designed to investigate the importance of sex differences in the interaction between dizocilpine (MK-801) pretreatment and acute cold-restraint stress (CRS) in pentylenetetrazole (PTZ)-induced seizures in Swiss albino mice. ... A CRS protocol was applied to mice to investigate the interaction between MK-801 pretreatment (30 min before CRS) and stress (followed by PTZ injection) in epilepsy susceptibility. For this purpose, 6 groups were designated: (1) PTZ control group (received only PTZ); (2) stress group (received stress and PTZ); (3) saline group (received saline and PTZ); (4) MK-801 group (received MK-801 and PTZ); (5) saline + stress group (received saline, stress, and PTZ); and (6) MK-801 + stress group (received MK-801, stress, and PTZ). ... Pretreatment with MK-801 (0.125, 0.25, 0.50 mg/kg) significantly potentiated the protective effect of stress in PTZ-induced (65 mg/kg) seizures in both sexes by prolonging the onset of myoclonic jerks and clonic convulsions. Male mice had a significantly greater delay in the onset of myoclonic jerks (males, 66.7-295.5 sec; females, 54.0-247.5 sec; P < 0.05) and clonic convulsions (males, 123.5-789.8 sec; females, 94.5-757.2 sec; P < 0.05) compared with female mice in all groups (ie, PTZ control, stress, saline, MK-801, saline + stress, and MK-801 + stress groups). ... The findings of this study in mice suggest the involvement of sex hormones in the interaction between MK-801 pretreatment and acute CRS in PTZ-induced seizures.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

青春期的雄性Wistar大鼠每天接触12小时的乙醇蒸汽，持续5周。在停止接触乙醇8周后，评估了MK-801（0.0至0.1毫克/千克，腹膜内注射）对脑电图（EEG）和听觉事件相关电位（ERPs）的影响。青春期乙醇暴露减少了前额叶皮层在4至6赫兹频段的EEG变异性，但对皮层和海马的EEG功率和ERPs没有影响。MK-801显著降低了青春期乙醇暴露后顶叶皮层（4至6赫兹、6至8赫兹、8至16赫兹、16至32赫兹）和海马（16至32赫兹）的EEG功率，以及顶叶皮层（6至8赫兹、16至32赫兹）的EEG变异性。MK-801在对照组中显著降低了海马的EEG变异性（4至6赫兹、8至16赫兹、16至32赫兹），但在乙醇暴露的大鼠中没有降低。与对照组相比，MK-801降低了乙醇暴露大鼠对罕见音调的前额P1 ERP振幅和潜伏期。相比之下，MK-801显著降低了对照组的P3 ERP振幅和潜伏期，但在乙醇暴露的大鼠中没有降低。结论是，在青春期乙醇暴露后经过一段长时间的戒断期，MK-801对海马EEG变异性以及P3 ERP振幅和潜伏期的影响显著减弱。然而，MK-801对皮层和海马EEG功率的抑制作用在青春期接触乙醇的大鼠中增强了。总的来说，这些数据表明青春期乙醇暴露后NMDA系统发生了长期的变化。

... Adolescent male Wistar rats were exposed to EtOH vapor for 12 hr/d for 5 weeks. The effects of MK-801(0.0 to 0.1 mg/kg, intraperitoneally) on the electroencephalogram (EEG) and auditory event-related potentials (ERPs) were assessed after 8 weeks of abstinence from EtOH. ... Adolescent EtOH exposure reduced EEG variability in the frontal cortex in the 4 to 6 Hz band but had no effect on cortical and hippocampal EEG power and ERPs. ... MK-801 significantly reduced EEG power in the parietal cortex (4 to 6 Hz, 6 to 8 Hz, 8 to 16 Hz, 16 to 32 Hz) and hippocampus (16 to 32 Hz) and EEG variability in the parietal cortex (6 to 8 Hz, 16 to 32 Hz) following adolescent EtOH exposure. MK-801 produced a significant decrease in hippocampal EEG variability (4 to 6 Hz, 8 to 16 Hz, 16 to 32 Hz) in control, but not in EtOH-exposed rats. MK-801 reduced frontal P1 ERP amplitude and latency in response to the rare tone in EtOH-exposed rats compared to controls. In contrast, MK-801 significantly reduced P3 ERP amplitude and latency in control, but not in EtOH-exposed rats. /It was concluded that/ the effects of MK-801 on hippocampal EEG variability and P3 ERP amplitude and latency are significantly attenuated after a prolonged withdrawal period following adolescent EtOH exposure. However, the inhibitory effects of MK-801 on cortical and hippocampal EEG power were enhanced in rats exposed to EtOH during adolescence. Taken together, these data suggest protracted changes in NMDA systems following adolescent EtOH exposure.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果患者呕吐，让患者向前倾或将其置于左侧（如果可能的话，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗救助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2925290090

制备方法与用途

生物活性

Dizocilpine (MK-801)，一种有效的抗惊厥剂，是一种选择性非竞争性 NMDA 受体拮抗剂，Kd 为 37.2 nM。它通过与 NMDA 相关离子通道内的一个位点结合而起作用，从而阻止 Ca2+ 的流动。

靶点

• Ki: 37.2 nM (NMDA 受体，在大鼠脑膜中)

体外研究

Dizocilpine (MK-801) 逐步抑制由 NMDA 引起的电流。当 Mg2+ (10 mM) 存在时，即使 Dizocilpine 持续作用于存在 NMDA 的环境中，它也能防止阻断 N-Me-D-Asp 引起的电流。Dizocilpine 还能阻止 NMDA 诱发单通道活动在外膜斑块中。

此外，Dizocilpine (MK-801；<500 μM) 抑制 LPS 刺激下 BV-2 细胞中微胶质细胞的激活和 Cox-2 蛋白表达增加。在 BV-2 细胞中，Dizocilpine (<500 μM) 减少 TNF-α 释放，EC50 值为 400 μM。

体内研究

1. 在每次甲基苯丙胺 (METH) 注射前给予 Dizocilpine (MK 801) (1 mg/kg)，可减少小鼠纹状体中多巴胺 (DA) 贫乏的程度达 55%。
2. Dizocilpine (MK 801) (1 mg/kg) 还能减弱 METH 对小鼠纹状体内微胶质细胞激活的影响。
3. Dizocilpine ((+)-MK 801) (0.05, 0.2 mg/kg, 腹腔注射) 能减轻随后的可卡因诱发复吸现象，而不干扰大鼠的行为表现。在窝内进行两次复现会话前给予 Dizocilpine (MK 801) (0.2 mg/kg, 腹腔注射)，则不会抑制后续可卡因诱发复吸。
4. 在腹腔注射 Dizocilpine (0.03, 0.1, 0.3 和 1 mg/kg) 后，小鼠的活动量在 0.3 和 1 mg/kg 时显著增加，而在 0.03 和 0.1 mg/kg 时则无明显变化。

反应信息

• 作为反应物：
  描述：

  地佐环平 在 palladium on activated charcoal 盐酸 、 硫酸 、 氢气 、 硝酸 、 碳酸氢钠 、 溶剂黄146 作用下， 以 乙醚 、 氯仿 、 乙酸乙酯 为溶剂， 25.0 ℃ 、310.27 kPa 条件下， 反应 157.17h， 生成 (+)-2-isothiocyanato-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine hydrochloride
  参考文献：
  名称：

  Synthesis and binding properties of MK-801 isothiocyanates; (+)-3-isothiocyanato-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrochloride: a new, potent and selective electrophilic affinity ligand for the NMDA receptor-coupled phencyclidine binding site

  摘要：

  Three new site-directed irreversible (wash-resistant) ligands for the high-affinity phencyclidine (PCP) binding site associated with the N-methyl-D-aspartate (NMDA) receptor were synthesized and their binding characteristics were studied. (+)-3- And (+)-2-isothiocyanato-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrochloride ((+)-8a,b.HCl) were prepared in four steps from the corresponding nitro derivatives (+)-4a,b, which were obtained by nitration of (+)-3 (MK-801). In the same way the optical antipode (-)-8a.HCl was synthesized from (-)-3. At a concentration of 100 nM, the 3-isothiocyanate derivative (+)-8a irreversibly labeled approximately 50% of the (+)-[H-3]-3 binding sites, compared to 20 muM needed for its optical antipode (-)-8a and the 2-isothiocyanate(+)-8b. The apparent K(i) values for reversible inhibition of (+)-[H-3]-3 binding by (+)- and (-)-8a and (+)-8b were 37, 838, and 843 nM, respectively. In contrast, metaphit (1b) and etoxadrol m-isothiocyanate (2b), two previously reported irreversible ligands for the PCP binding site, label about 50% of the (+)-[H-3]-3 binding sites at 100 muM and 250 nM, respectively, with apparent K(i) values for reversible inhibition of 535 and 94 nM. Compound (+)-8a is also a selective affinity ligand, displaying little or no irreversible in vitro affinity at 100 muM for opioid, benzodiazepine, muscarinic, and dopamine receptors. At a 25 muM concentration, (+)-8a caused an irreversible 52% reduction of binding to sigma1-receptors. Compound (+)-8a is the most potent known electrophilic affinity label for the PCP binding site. Its potency and selectivity should enable it to be a valuable tool for the elucidation of the structure and function of the NMDA receptor-associated PCP binding site in the mammalian central nervous system.

  DOI：

  10.1021/jm00069a008
• 作为产物：
  描述：

  (5S,10R)-(+)-5-(bromomethyl)-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine 在 三乙基硼氢化锂 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 以85%的产率得到地佐环平
  参考文献：
  名称：

  通过电子调节的双功能催化剂催化的Reissert型反应，对四级立体中心进行对映选择性构建：各种生物学上有意义的化合物的有效合成。

  摘要：

  DOI：

  10.1021/ja016935c

文献信息

• COMPOSITIONS AND METHODS FOR TREATING NEURODEGENERATIVE DISEASE
  申请人：COGNITION THERAPEUTICS, INC.

  公开号：US20170197977A9

  公开（公告）日：2017-07-13

  This invention relates to novel diarylamino compounds that bind to the sigma-2 receptor, to pharmaceutical compositions comprising such compounds, and to methods for inhibiting or restoring synapse loss in neuronal cells, modulating a membrane trafficking change in neuronal cells, and treating cognitive decline and neurodegenerative diseases and disorders therewith.

  这项发明涉及与sigma-2受体结合的新型二芳胺化合物，包括这种化合物的药物组合物，以及用于抑制或恢复神经元细胞中突触丢失，调节神经元细胞中膜运输变化，并用于治疗认知衰退和神经退行性疾病和障碍的方法。
• NICOTINIC RECEPTOR NON-COMPETITIVE MODULATORS
  申请人：Targacept, Inc.

  公开号：US20140288185A1

  公开（公告）日：2014-09-25

  The present invention relates to compounds that modulate nicotinic receptors as non-competitive antagonists, methods for their synthesis, methods for use, and their pharmaceutical compositions.

  本发明涉及调节尼古丁受体作为非竞争性拮抗剂的化合物，其合成方法，使用方法以及它们的药物组成。
• 2-phenyl-3,3,3-trifluoro-2-hydroxy-propionic acid derivatives
  申请人：Malherbe Parichehr

  公开号：US20070027204A1

  公开（公告）日：2007-02-01

  The present invention relates to compounds of formula I: wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the specification and claims, which compounds are active on the GABA B receptor and are useful in the control or prevention of CNS illnesses, especially of illnesses and disorders comprising anxiety, depression, epilepsy, schizophrenia, and cognitive disorders.

  本发明涉及以下式I的化合物： 其中R1、R2、R3、R4、R5和R6如规范和声明中定义的那样，这些化合物对GABA B 受体具有活性，并且在控制或预防中枢神经系统疾病，特别是包括焦虑、抑郁症、癫痫、精神分裂症和认知障碍的疾病和疾病中是有用的。
• Novel Bicyclic Pyridinones
  申请人：Pettersson Martin Youngjin

  公开号：US20120252758A1

  公开（公告）日：2012-10-04

  Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I as defined herein. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  所述化合物及其药用可接受的盐被披露，其中所述化合物具有如本文所定义的Formula I的结构。相应的药物组合物、治疗方法、合成方法和中间体也被披露。
• Piperidinylamino-thieno[2,3-D] pyrimidine compounds
  申请人：Dhanoa S. Dale

  公开号：US20050222176A1

  公开（公告）日：2005-10-06

  The invention relates to 5-HT receptor modulators, particularly 5-HT 2B antagonists. Novel piperidinylamino-thieno [2,3-d] pyrimidine compounds represented by Formula I, II and III, and uses thereof for treating conditions including pulmonary arterial hypertension, congestive heart failure, and hypertension.

  这项发明涉及5-HT受体调节剂，特别是5-HT 2B 拮抗剂。公式I、II和III所代表的新型哌啶基氨基噻吩[2,3-d]嘧啶化合物，以及它们用于治疗包括肺动脉高压、充血性心力衰竭和高血压等疾病的用途。