NMDA Receptor

Previous studies with Lanicemine and ketamine demonstrated that both compounds bind with low-to-moderate affinity to sites within the NMDA channel pore, exhibit strong voltage dependence, and have similar lack of NR2A vs NR2B subunit selectivity (Table 1). However, at steady-state concentrations, ketamine had a greater propensity to be trapped within the NMDA channel pore following the removal and reapplication of glutamate (trapping: 86% with ketamine vs 54% with Lanicemine). Low trapping theoretically preserves use-dependent channel block under conditions of normal, pyramidal cell-driven, synaptic transmission. Thus, while NMDARs are ubiquitously expressed within the central nervous system, the low-trapping property of lanicemine may bias channel block to those elements of the brain, such as cortical interneurons, with high levels of tonic activity. Since selective reduction in NMDAR activity on cortical interneurons has been shown to increase spontaneous, high-frequency (gamma-band ∼40 Hz) EEG gamma-band EEG may serve as a useful biomarker for NMDA channel blockers in general and lanicemine in particular. [1]

Lanicemine dihydrochloride exhibits little psychotomimetic adverse effects while maintaining antidepressant efficacy[1]. In addition to activating the brain circuits responsible for producing gamma electroencephalograms (EEG), lanicemine dihydrochloride (3, 10, or 30 mg/kg; intraperitoneally) also affects these networks without causing the more widespread system-level disturbance that is associated with ketamine[1].

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Using quantitative electroencephalography (qEEG) to objectively align doses of a low-trapping NMDA channel blocker, AZD6765 (Lanicemine), to that of ketamine, we demonstrate the potential for NMDA channel blockers to produce antidepressant efficacy without psychotomimetic and dissociative side effects. Furthermore, using placebo-controlled data, we show that the antidepressant response to NMDA channel blockers can be maintained with repeated and intermittent drug administration. Together, these data provide a path for the development of novel glutamatergic-based therapeutics for treatment-refractory mood disorders. [1]

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EEG, physiological and dissociative effects of Lanicemine relative to ketamine in human [1]
To determine whether the differentiated EEG/side-effect profile seen preclinically with ketamine and lanicemine translates to humans, we conducted the qEEG crossover study in healthy volunteers. Out of 23 subjects randomized, 14 subjects were treated with lanicemine 75 mg, 19 with lanicemine 150 mg, 17 with ketamine and 15 with placebo. The study was stopped earlier than planned following two serious adverse events (syncope due to orthostatic hypotension) occurring during ketamine infusion. Significant increases in gamma-band EEG were observed at the stop of infusion for both ketamine and lanicemine, and baseline-corrected gamma-EEG following 150 mg lanicemine was statistically indistinguishable from ketamine (0.5 mg kg−1) (Figure 2, left and top right). In addition, both ketamine and the 150-mg dose of lanicemine produced significant reductions in prefrontal theta-cordance, a derived EEG biomarker putatively linked to early antidepressant treatment response (Figure 2, left) There were no serious adverse events associated with lanicemine.

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Single-dose (100 mg) exploratory safety and efficacy trial of Lanicemine in patients with treatment-resistant MDD [1]
Translational and previous preclinical data28 suggested a psychotomimetic-free therapeutic window for lanicemine in humans at doses of 75–150 mg. We therefore conducted a pilot study to determine whether a dose in this range (100 mg) might be relatively well tolerated and yet still provide an antidepressant signal. In a phase IIA monotherapy study (study 1), 34 treatment-resistant patients (mean HAM-D-17 score ∼25; Supplementary Table 1) were randomized to a single infusion of lanicemine 100 mg i.v. (n=16 (7, male; 9, female)) or placebo (n=18 (7, male; 11, female)).

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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 [1]
On the basis of the exploratory data from study 1, a second phase II study (study 9) was designed to determine whether repeated administration of lanicemine over 3 weeks at an interval of three infusions per week would consolidate and extend the therapeutic benefits observed from a single administration. In study 9, we examined the effect of augmenting patients' existing antidepressant therapies with repeated lanicemine administration on symptom improvement in outpatients with moderate-to-severe MDD with a history of poor response to multiple antidepressants. Infusions were stopped after 3 weeks to explore the durability of the antidepressant effect over a subsequent 5-week observation period in which drug was not administered.

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.

Single-dose (100 mg) exploratory safety and efficacy trial of Lanicemine in patients with treatment-resistant MDD [1]
Translational and previous preclinical data suggested a psychotomimetic-free therapeutic window for lanicemine in humans at doses of 75–150 mg. We therefore conducted a pilot study to determine whether a dose in this range (100 mg) might be relatively well tolerated and yet still provide an antidepressant signal. In a phase IIA monotherapy study (study 1), 34 treatment-resistant patients (mean HAM-D-17 score ∼25; Supplementary Table 1) were randomized to a single infusion of lanicemine 100 mg i.v. (n=16 (7, male; 9, female)) or placebo (n=18 (7, male; 11, female)).

Lanicemine 100 mg was generally well tolerated, with the most common adverse event being dizziness (Supplementary Table 2). Lanicemine produced no clinically meaningful effects on psychotomimetic symptoms measured by the Brief Psychiatric Rating Scale (mean±s.e. at 1 h: 22.8±1.1 for lanicemine vs 23.9±1.2 for placebo; at 4 h: 23.1±1.2 vs 24.4±1.5), dissociative symptoms measured by the CADSS (least squares mean (LSM)±s.e. change from baseline at 1 h: 0.6 (0.59) for lanicemine vs −0.8 (0.55) for placebo), or cognitive functions measured by CogState (Supplementary Figures 1 and 2).

There were no serious adverse events reported during treatment. At the 24-h time point, we failed to observe a statistically significant difference in the change in MADRS scores between Lanicemine vs placebo. However, this comparison was confounded by a strong placebo effect (for example, 14.2 MADRS score change) at this time point, rendering the meaningfulness of the non-statistically significant, numerically greater change for Lanicemine vs placebo (2.44, P=0.472) difficult to interpret. However, we observed statistically significant differences (according to prespecified criteria for this exploratory study) for lanicemine vs placebo in MADRS scores at 1 and 72 h after the infusion (P=0.183 and 0.089, respectively) (Supplementary Figure 3). An antidepressant-like effect was also indicated by changes in sad/happy Bond-Lader Visual Analogue Scale at 4 h (P=0.137). The trend for the antidepressant effect of lanicemine peaked at 72 h (MADRS score change vs placebo of −5.7 (P=0.089)) and had dissipated vs placebo by 10–13 days after the single i.v. infusion, while remaining on average 10 points below baseline measures.

Safety evaluations included safety and tolerability assessments, adverse events, pupil size and electronystagmography, and subjective dissociative effects measured by the 27-item Clinician Administered Dissociative States Scale (CADSS). Opticokinetic parameters were measured 25 min after start of infusion using Metrovision MON 2008H and CADSS was assessed at prespecified times up to 8 h after start of infusion.

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

Lanicemine has been used in trials studying the treatment and basic science of Depression, Major Depressive Disorder, and Treatment Resistant Major Depressive Disorder.

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There is a rapidly growing interest in the development of glutamatergic drugs, especially NMDAR antagonists, for the treatment of severe mood disorders.5 Here, we report robust and sustained antidepressant effects for a low-trapping NMDA channel blocker, Lanicemine (100 mg), at doses without the limiting prominent dissociative side effects observed with ketamine. Completed studies with lanicemine now encompass the largest pool of depressed patients (n>120) exposed to an NMDA channel blocker to date, and represent a stringent test of the hypothesis that NMDAR antagonists can deliver antidepressant efficacy independent of psychotomimetic side effects.

Second, while study 1 and published data by Zarate et al provide evidence supporting a single-dose antidepressant effect for Lanicemine, a similar single-dose trend was not as robustly observed in study 9. Given that study 9 (in contrast to study 1) was an adjunctive study and most reports to date with ketamine have also been monotherapy studies, an open question remains regarding the extent to which concomitant medications (that is, benzodiazepine administration) may alter the time course of antidepressant treatment effects for NMDA channel blockers. Preliminary reports on ketamine when used adjunctively with antidepressants also suggest a delayed onset of efficacy. Finally, while study 9 provides limited data regarding the efficacy and safety of repeated intermittent administrations, it will be critical to better characterize and understand the long-term safety and efficacy profile of NMDA channel blockers including lanicemine. These questions and others are currently being addressed in ongoing studies (for example, Study 31: ClinicalTrials.gov Identifier: NCT01482221).

Lanicemine, a low-trapping NMDA channel blocker, demonstrated antidepressant effects in patient studies, with fewer dissociative and psychotomimetic symptoms than ketamine at dose exposures that caused similar changes in cortical activation. In clinical studies, lanicemine produced robust and significant efficacy without clinically appreciable dissociative and psychotomimetic adverse effects. These data are consistent with the pharmacological separation of efficacy from psychotomimetic 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 MDD, repeated administration of lanicemine (100 or 150 mg per infusion) at 3-day intervals provided sustained antidepressant efficacy, without psychotomimetic effects. The results of these studies demonstrate that an NMDA channel blocker can achieve antidepressant responses in the absence of prominent psychotomimetic effects and are sustained with repeated dosing. The putative antidepressant characteristics of lanicemine are being explored in ongoing clinical trials. [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

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

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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)

Solubility in Formulation 1: 6 mg/mL (22.12 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 60.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 6 mg/mL (22.12 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 60.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 6 mg/mL (22.12 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 60.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (368.75 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)