NMDA Receptor

先前对Lanicemine和氯胺酮的研究表明，这两种化合物与NMDA通道孔内的位点结合具有低至中等亲和力，表现出很强的电压依赖性，并且缺乏NR2A和NR2B亚基选择性（表1）。然而，在稳态浓度下，氯胺酮在谷氨酸去除和重新施用后更容易被捕获在NMDA通道孔内（氯胺酮捕获率为86%，而Lanicemine的氯胺酮捕获率为54%）。在正常的锥体细胞驱动的突触传递条件下，低捕获理论上保留了使用依赖的通道块。因此，虽然NMDARs在中枢神经系统中普遍表达，但Lanicemine的低捕获特性可能会导致通道阻滞到大脑的那些元素，如皮质中间神经元，具有高水平的强亢活性。由于皮质中间神经元上NMDAR活性的选择性减少已被证明会增加自发性，因此高频（γ波段~ 40 Hz）脑电图（γ波段脑电图）可以作为NMDA通道阻滞剂，特别是Lanicemine的有用生物标志物。［１］

Lanicemine二盐酸盐在保持抗抑郁功效的同时几乎没有表现出拟精神病副作用[1]。除了激活负责产生伽马脑电图 (EEG) 的大脑回路外，二盐酸兰尼西明（3、10 或 30 mg/kg；腹腔注射）也会影响这些网络，而不会引起与氯胺酮相关的更广泛的系统级干扰[1]。

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通过定量脑电图（qEEG）客观调整低捕获NMDA通道阻滞剂AZD6765（拉尼西明）与氯胺酮的剂量匹配，我们证明了NMDA通道阻滞剂在产生抗抑郁疗效的同时，可不引发拟精神病和分离性副作用。此外，通过安慰剂对照数据，我们表明NMDA通道阻滞剂的抗抑郁反应可通过重复间歇给药得以维持。这些数据共同为开发基于谷氨酸能机制的新型难治性情绪障碍疗法提供了路径。[1]

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拉尼西明相对于氯胺酮在人体的EEG、生理及解离效应[1]
为验证氯胺酮与拉尼西明在临床前研究中观察到的差异化EEG/副作用特征是否适用于人类，我们在健康志愿者中开展了qEEG交叉研究。23名随机受试者中，14人接受75mg拉尼西明治疗，19人接受150mg拉尼西明，17人接受氯胺酮，15人接受安慰剂。研究因氯胺酮输注期间发生两起严重不良事件（体位性低血压所致晕厥）而提前终止。输注结束时，氯胺酮与拉尼西明均引起γ波段EEG显著增强，且150mg拉尼西明的基线校正γ-EEG与氯胺酮（0.5mg/kg）在统计学上无差异（图2左及右上）。此外，氯胺酮与150mg拉尼西明均显著降低前额叶θ-协调性（一种推定与早期抗抑郁治疗反应相关的EEG生物标志物）（图2左）。拉尼西明组未出现严重不良事件。

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Lanicemine/拉尼西明单次剂量（100mg）在难治性重度抑郁症（MDD）患者中的探索性安全性与疗效试验[1]
转化研究与前期临床前数据28表明，拉尼西明在75-150mg剂量范围内存在不引发拟精神病症状的治疗窗口。因此我们开展先导研究，评估该剂量范围（100mg）是否具备良好耐受性同时仍能产生抗抑郁信号。在IIA期单药治疗研究（研究1）中，34名难治性患者（平均HAM-D-17评分∼25；附表1）随机接受单次静脉输注拉尼西明100mg（n=16，男7/女9）或安慰剂（n=18，男7/女11）。

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拉尼西明/Lanicemine在中重度MDD且抗抑郁药治疗史不佳患者中的附加多剂量输注疗效试验[1]
基于研究1的探索性数据，我们设计了第二项II期研究（研究9），旨在评估3周内每周三次重复给药方案能否巩固并扩展单次给药观察到的治疗获益。在研究9中，我们考察了在现有抗抑郁治疗基础上联合拉尼西明重复给药对中重度MDD门诊患者（既往对多种抗抑郁药反应不佳）的症状改善作用。输注治疗3周后停止，并在后续5周未给药观察期内评估抗抑郁效应的持续性。

Animal/Disease Models: Male SD (Sprague-Dawley) rats[1]
Doses: 3, 10 or 30 mg/kg
Route of Administration: intraperitoneal (ip)
Experimental Results: Produced pronounced dose-dependent elevations in spontaneous gamma-band EEG, but only gamma changes for Ketamine were tightly coupled to increases in locomotor activity.

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Effects of ketamine and Lanicemine on EEG in rodent models [1]
Male Sprague-Dawley rats (n=6–9) were implanted with frontal and temporal skull screw electrodes for continuous EEG recording and trained to perform a single-tone operant discrimination task for food reward. EEG was recorded and behavioral performance was evaluated for a 30-min period before dosing and for three 30-min periods following dosing with intraperitoneal lanicemine (3, 10 or 30 mg kg−1), ketamine (1, 3, 10 or 30 mg kg−1) or vehicle control. EEG data acquired by Neuralynx were imported to NeuroExplorer Ver. 3.183 software suite. Consecutive 10-s epochs of EEG data from each channel were subjected to a fast Fourier transform, from which EEG power density was computed from 1 to 50 Hz.

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Lanicemine studies in human [1]
All studies in man were approved by the institutional review boards at each site and were conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. All participants provided written, informed consent before study entry and had the right to withdraw from the study at any time.

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EEG, physiological and dissociative effects of Lanicemine relative to ketamine in human (phase I, D2285M00008/NCT01130909) [1]
A phase I, randomized, double-blind, four-way, crossover study in healthy subjects was performed at a single center in France between May 2010 and January 2011 (D2285M00008/NCT01130909). Males aged 30–45 years, with body mass index 18–30 kg m−2 and non-smoking status for at least 4 weeks, without clinically relevant acute or chronic disease, received lanicemine 75 mg, lanicemine 150 mg, ketamine 0.5 mg kg−1 or placebo as single intravenous (i.v.) administrations. Washout was ⩾7 days between study periods.

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Single-dose (100 mg) exploratory safety and efficacy trial of Lanicemine in patients with treatment-resistant MDD (phase IIA, D6702C00001/NCT00491686) [1]
The phase IIA, double-blind, randomized study (D6702C00001/NCT00491686; study 1) was performed at five centers in the United States between July 2007 and November 2007. It consisted of a screening period (⩽30 days), one inpatient treatment period, and one follow-up visit 7–10 days after treatment. Outpatients (men and women) aged 21–65 years with DSM-IV-TR-diagnosed MDD, confirmed by the MINI, a history of poor response to ⩾2 antidepressants, and baseline Hamilton Rating Scale for Depression (HAM-D-17) score ⩾20 were eligible. Exclusion criteria included: current episode of depression ⩽12 weeks or ⩾5 years; history of DSM-IV Axis I disorder other than MDD or substantial Axis II disorder; use of mood stabilizers, other antipsychotic or psychoactive drugs within 7 days of day 1 or fluoxetine or monoamine oxidase inhibitors within 14 days of day 1 of the treatment period; and evidence of other clinically relevant disease.

Lanicemine 100 mg or placebo (0.9% saline) was administered as single i.v. infusions (30 ml volume over 60 min). The primary efficacy evaluation was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to 24 h post infusion. Secondary variables included: change in MADRS total score at other scheduled time points; Bond-Lader Visual Analogue Scale; Brief Psychiatric Rating Scale; and CogState (CogState, Melbourne, Australia). Safety evaluations included: adverse events, vital signs, physical examination, clinical laboratory evaluations and electrocardiograms.

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Adjunctive, multiple-infusion efficacy trial of Lanicemine in patients with moderate-to-severe MDD and a history of poor response to antidepressants (phase IIB, D6702C00009/NCT00781742) [1]
The phase IIB, double-blind, randomized, outpatient study (D6702C00009/NCT00781742; study 9) was performed at 30 centers in the United States between October 2008 and March 2010. It consisted of a screening period (⩽30 days), a 3-day placebo run-in (when patients received one single-blind placebo infusion (0.9% saline)), and a 3-week treatment period, followed by a 5-week treatment-free follow-up.

Patients were randomized in a 1:1:1 ratio to Lanicemine 100 mg, lanicemine 150 mg or placebo (three i.v. infusions per week) as adjunct to ongoing psychotropics that included at least one antidepressant. The predefined primary efficacy variable was change from randomization to week 3 in MADRS total score. Secondary variables included: MADRS score change at other scheduled assessments; remission (that is, MADRS score ⩽10); response (that is, ⩾50% reduction from baseline in MADRS score); Hamilton Rating Scale for Anxiety (HAM-A; anxiety); HAM-D-17 and QIDS-SR-16 (depressive symptoms); CGI-S and Clinical Global Impression of Improvement (CGI-I; global improvement); and Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q; quality of life). Efficacy evaluations were performed at weekly intervals from baseline (randomization) to week 8. Changes in QIDS-SR-16 score at day 1 and MADRS score at day 3 were also measured to assess onset of effect.

Change from baseline in MADRS total score and continuous secondary efficacy variables were compared between the two Laniceminegroups and placebo at week 3 with LOCF in the ITT analysis set, using an analysis of covariance model with baseline MADRS total score as a covariate, with treatment, MDD disease severity and comorbid generalized anxiety disorder status as fixed effects, and pooled center as a random effect. A logistic regression model including treatment and baseline in the model was used for categorical secondary efficacy variables.

An exploratory safety and efficacy trial of a single dose (100 mg) of lannicillin in patients with treatment-resistant major depressive disorder [1]
Translational studies and prior preclinical data suggest that lannicillin has a psychoactive therapeutic window in the human dose range of 75–150 mg. Therefore, we conducted a pilot study to determine whether this dose range (100 mg) is relatively well tolerated while still providing an antidepressant signal. In a phase IIA monotherapy study (Study 1), 34 patients with treatment-resistant depression (mean HAM-D-17 score of approximately 25; see Supplementary Table 1) were randomized to receive a single intravenous infusion of 100 mg lannicillin (n=16 (7 men; 9 women)) or placebo (n=18 (7 men; 11 women)).
Lannicillin 100 mg was generally well tolerated, with dizziness being the most common adverse event (Supplementary Table 2). Lannicilamine had no clinically significant effect on psychotic-like symptoms assessed by the Brief Psychiatric Rating Scale (BPRS) (1-hour mean ± standard error: 22.8 ± 1.1 in the lannicilamine group vs. 23.9 ± 1.2 in the placebo group; 4-hour mean ± standard error: 23.1 ± 1.2 in the lannicilamine group vs. 24.4 ± 1.5 in the placebo group), dissociative symptoms assessed by the CADSS (1-hour least squares mean (LSM) ± standard error: 0.6 (0.59) in the lannicilamine group vs. -0.8 (0.55) in the placebo group), or cognitive function assessed by the CogState (Supplementary Figures 1 and 2). No serious adverse events were reported during treatment. At the 24-hour time point, we did not observe a statistically significant difference in changes in MADRS scores between the lannicilamine and placebo groups. However, the placebo effect was significant at this point (e.g., a 14.2-point change in MADRS score), making the larger numerical change (2.44, P=0.472) between the lannicillin and placebo groups, though not statistically significant, difficult to interpret. Nevertheless, we observed statistically significant differences in MADRS scores between the lannicillin and placebo groups at 1 hour and 72 hours post-infusion (according to the presupposed criteria of this exploratory study) (P=0.183 and 0.089, respectively) (Supplementary Figure 3). Furthermore, changes in the Bond-Rad Visual Analogue Scale (VAS) for sadness/happiness at 4 hours also suggested an antidepressant-like effect (P=0.137). The antidepressant effect of lannicillin peaked at 72 hours (a 5.7-point reduction in MADRS score compared to the placebo group, P=0.089) and gradually subsided over 10–13 days after a single intravenous infusion, but remained on average 10 points lower than baseline.
Safety assessment included safety and tolerability evaluation, adverse events, pupil size and electronystagmography, and subjective separation effect assessed using the 27-item clinician-managed separation state scale (CADSS). Optokinetic parameters were measured using a Metrovision MON 2008H at 25 minutes after infusion initiation, and CADSS was assessed at pre-defined time points within 8 hours of infusion initiation.

[1]. Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacywith minimal psychotomimetic adverse effects. Mol Psychiatry. 2014 Sep;19(9):978-85.

Lannicilamine has been used in clinical trials for the treatment and basic science of depression, major depressive disorder, and treatment-resistant major depressive disorder. Interest in developing glutamatergic drugs, particularly NMDAR antagonists, for the treatment of severe mood disorders is rapidly growing. Here, we report that a low-capture NMDA channel blocker, lannicilamine (100 mg), has significant and durable antidepressant effects without the significant dissociative side effects observed with ketamine at this dose. Completed lannicilamine studies to date cover the largest cohort of patients with depression (n>120) treated with NMDA channel blockers to date, rigorously testing the hypothesis that NMDAR antagonists exert antidepressant efficacy independently of psychiatric side effects. Secondly, while data from Study 1 and Zarate et al. provide evidence supporting the antidepressant effect of a single dose of lannicilamine, a similar single-dose trend was not observed in Study 9. Given that Study 9 (unlike Study 1) was an adjunctive therapy study, and that most reports on ketamine to date have been monotherapy studies, the extent to which concomitant medication (i.e., benzodiazepines) alters the onset time of NMDA channel blocker antidepressant efficacy remains an open question. Preliminary reports on adjunctive therapy with ketamine and antidepressants also suggest a delayed onset of action. Finally, while Study 9 provides limited data on the efficacy and safety of repeated intermittent dosing, a better characterization and understanding of the long-term safety and efficacy profiles of NMDA channel blockers, including ranicillin, is crucial. These questions, along with other related issues, are being explored in ongoing research (e.g., Study 31: ClinicalTrials.gov registration number: NCT01482221). Ranicillin is a low-NMDA channel blocker that has shown antidepressant effects in patient studies and, at doses causing similar cortical activation changes, exhibits fewer dissociative and psychotic-like symptoms than ketamine. In clinical studies, lanicillin showed significant efficacy with no obvious clinical dissociation symptoms or psychotic-like side effects. These data are consistent with the pharmacological dissociation of efficacy and psychotic-like side effects observed in preclinical and phase I studies. Importantly, in a 3-week placebo-controlled phase IIB study of patients with moderate to severe depression, repeated infusions of lanicillin (100 or 150 mg every 3 days) maintained antidepressant efficacy without psychotic-like side effects. These results suggest that NMDA channel blockers can achieve antidepressant effects without obvious psychotic-like effects and can maintain efficacy with repeated administration. Ongoing clinical trials are exploring the potential antidepressant properties of lanicillin. [1]

C13H16CL2N2

271.19

270.069

C, 57.58; H, 5.95; Cl, 26.14; N, 10.33

153322-06-6

(Rac)-Lanicemine;61890-25-3;Lanicemine;153322-05-5

9795446

Off-white to light yellow solid powder

38.9

3

2

3

17

175

1

C1=CC=C(C=C1)[C@H](CC2=CC=CC=N2)N.Cl.Cl

KHJHFYAGQZYCLC-GXKRWWSZSA-N

InChI=1S/C13H14N2.2ClH/c14-13(11-6-2-1-3-7-11)10-12-8-4-5-9-15-12;;/h1-9,13H,10,14H2;2*1H/t13-;;/m0../s1

(1S)-1-phenyl-2-pyridin-2-ylethanamine;dihydrochloride

Lanicemine dihydrochloride; 153322-06-6; Lanicemine (dihydrochloride); AZD-6765 dihydrochloride; ARL-15896AR; FPL-15896AR; (1S)-1-phenyl-2-pyridin-2-ylethanamine;dihydrochloride; 59E712CNQR;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 240 mg/mL (884.99 mM)
H2O: ≥ 100 mg/mL (368.75 mM)

配方 1 中的溶解度: 6 mg/mL (22.12 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 悬浮液；超声助溶。
例如，若需制备1 mL的工作液，可将100 μL 60.0 mg/mL 澄清的 DMSO 储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入450 μL 生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 6 mg/mL (22.12 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 60.0 mg/mL 澄清 DMSO 储备液加入 900 μL 20% SBE-β-CD 生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 6 mg/mL (22.12 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 60.0 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

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配方 4 中的溶解度: 100 mg/mL (368.75 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
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7、 以上所有助溶剂都可在 Invivochem.cn网站购买。