Low‐Affinity NMDA Receptor Antagonists

Palmer, Gene C.; Miller, Jerry A.; Cregan, Edward F.; Gendron, Patricia; Peeling, James

doi:10.1111/j.1749-6632.1997.tb48432.x

Cited by 14 publications

(3 citation statements)

References 12 publications

(16 reference statements)

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“…Translational and previous preclinical data 28 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.…”

Section: Resultsmentioning

confidence: 97%

Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects

et al. 2013

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Ketamine, an N-methyl-D-aspartate receptor (NMDAR) channel blocker, has been found to induce rapid and robust antidepressant-like effects in rodent models and in treatment-refractory depressed patients. However, the marked acute psychological side effects of ketamine complicate the interpretation of both preclinical and clinical data. Moreover, the lack of controlled data demonstrating the ability of ketamine to sustain the antidepressant response with repeated administration leaves the potential clinical utility of this class of drugs in question. 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.

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Section: Resultsmentioning

confidence: 97%

Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects

et al. 2013

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“…Thus it is predicted that the greater the trapping blockade, the greater the risk of psychotomimetic effects. Indeed, ketamine, which induces psychotomimetic effects (17, 18), showed 86% trapping, whereas AZD6765, which has an improved therapeutic safety profile (19, 20), trapped at a much lower level (54% of its initial block). Like ketamine, AZD6765 is also considered a non-selective NMDA channel blocker (21).…”

Section: Introductionmentioning

confidence: 99%

A Randomized Trial of a Low-Trapping Nonselective N-Methyl-D-Aspartate Channel Blocker in Major Depression

Zarate

Mathews

Ibrahim

et al. 2013

Biological Psychiatry

211

174

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Background The high-affinity N-methyl-D-aspartate (NMDA) antagonist ketamine exerts rapid antidepressant effects, but has psychotomimetic properties. AZD6765 is a low-trapping NMDA channel blocker with low rates of associated psychotomimetic effects. This study investigated whether AZD6765 could produce rapid antidepressant effects in subjects with treatment-resistant major depressive disorder (MDD). Methods In this double-blind, randomized, crossover, placebo-controlled study, 22 subjects with DSM-IV treatment-resistant MDD received a single infusion of either AZD6765 (150 mg) or placebo on two test days one week apart. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS), which was used to rate overall depressive symptoms at baseline; at 60, 80, 110, and 230 minutes post-infusion; and on Days 1, 2, 3, and 7 post-infusion. Several secondary outcome measures were also used, including the Hamilton Depression Rating Scale (HDRS). Results Within 80 minutes, MADRS scores significantly improved in subjects receiving AZD6765 compared to placebo; this improvement remained significant only through 110 minutes (d=0.40). On the HDRS, a drug difference was found at 80 and 110 minutes and at Day 2 (d=0.49). Overall, 32% of subjects responded to AZD6765 and 15% responded to placebo at some point during the trial. No difference was observed between the groups with regard to psychotomimetic or dissociative adverse effects. Conclusions In patients with treatment-resistant MDD, a single intravenous dose of the low trapping NMDA channel blockerAZD6765 was associated with rapid but short-lived antidepressant effects; no psychotomimetic effects were observed.

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“…However, the therapeutic potential of MK‐801 is diminished by side remarkable psychotomimetic effects associated with its high affinity interaction with the intrachannel binding site (ICS) of the NMDA receptor 3. In contrast to MK‐801, the low affinity open channel blockers, such as amantadine, memantine, or ARL 15896, often show better therapeutic indices because of their rapid blocking kinetics and strong voltage dependency 4,5. The goal of the study reported here was to provide: (1) focused synthesis of flexible analogs of MK‐801, (2) a computational estimate of the binding of MK‐801 and its flexible analogs to the NMDA receptor by the molecular docking method, and (3) a study of neuroprotective and behavioral (in particular, cognition‐enhancing) properties of series of novel open chain MK‐801 analogs whose side effects were expected to be minimized due to less rigid interaction of ICS with flexible molecules relative to MK‐801.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective and Cognition‐Enhancing Properties of MK‐801 Flexible Analogs

Бачурин

Ткаченко

Baskin

et al. 2001

Annals of the New York Academy of Sciences

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Neuroprotective and biobehavioral properties of a series of novel open chain MK‐801 analogs, as well as their structure‐activity relationships have been investigated. Three groups of compounds were synthesized: monobenzylamino, benzhydrylamino, and dibenzylamino (DBA) analogs of MK‐801. It was revealed that DBA analogs exhibit pronounced glutamate‐induced calcium uptake blocking properties and anti‐NMDA activity. The hit compound of DBA series, NT‐1505, was investigated for its ability to improve cognition functions in animal model of Alzheimer's disease type dementia, simulated by treating animals with cholinotoxin AF64A. The results from an active avoidance test and a Morris water maze test showed that experimental animals, treated additionally with NT‐1505, exhibited much better learning ability and memory than the control group (AF64A treated) and close to that of the vehicle group of animals (treated with physiological solution). Study of NT‐1505 influence on locomotor activity revealed that it is characterized by a spectrum of behavioral activity radically different from that of MK‐801, and in contrast to the latter one does not produce any psychotomimetic side effects in the therapeutically significant dose interval. The computed docking of MK‐801 and its flexible analogs on the NMDA receptor elucidated the crucial role of the hydrogen bond formed between these compounds and the asparagine residue for magnesium binding in the NMDA receptor. It was suggested that strong hydrophobic interaction between MK‐801 and the hydrophobic pocket in the NMDA receptor‐channel complex determines much higher irreversibility of this adduct compared to the intermediates formed between this site and Mg ions or flexible DBA derivatives, which might explain the absence of PCP‐like side effects of the latter compounds.

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Low‐Affinity NMDA Receptor Antagonists

Cited by 14 publications

References 12 publications

Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects

Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects

A Randomized Trial of a Low-Trapping Nonselective N-Methyl-D-Aspartate Channel Blocker in Major Depression

Neuroprotective and Cognition‐Enhancing Properties of MK‐801 Flexible Analogs

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