Uncompetitive NMDA Receptor Antagonist Research Articles

Effects of the N-Methyl-d-aspartate Receptor Antagonist Perzinfotel [EAA-090; [2-(8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic Acid] on Chemically Induced Thermal Hypersensitivity

Perzinfotel [EAA-090; [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic acid] is a selective, competitive N-methyl-D-aspartate (NMDA) receptor antagonist with high affinity for the glutamate site. The current study evaluated whether perzinfotel would have antinociceptive effects or block thermal hypersensitivity associated with the administration of chemical irritants in rats. Perzinfotel lacked antinociceptive effects but dose- and time-dependently blocked prostaglandin E(2) (PGE(2))- and capsaicin-induced thermal hypersensitivity in a warm-water tail-withdrawal assay in rats. Doses of 10 mg/kg intraperitoneal or 100 mg/kg oral blocked PGE(2)-induced hypersensitivity by 60 to 80%. The magnitude of reversal was greater than other negative modulators of the NMDA receptor studied, such as uncompetitive channel blockers (e.g., memantine, dizocilpine, and ketamine), a NR2B selective antagonist (e.g., ifenprodil), and other glutamate antagonists [e.g., selfotel, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), D,L-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid (CGP-39653)], up to doses that suppressed operant rates of responding. In contrast to other negative modulators of the NMDA receptor studied, which typically decreased operant rates of responding at doses that lacked antinociceptive effects, perzinfotel did not modify response rates at doses that blocked irritant-induced thermal hypersensitivity. Collectively, these studies demonstrate that perzinfotel has therapeutic ratios for effectiveness versus adverse effects superior to those seen with other competitive and uncompetitive NMDA receptor antagonists studied.

Effect of the protein kinase C inhibitor, staurosporine, on the high dose of methamphetamine-induced behavioral sensitization to dizocilpine (MK-801)

In our 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). We hypothesize 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. The effects of METH on extracellular glutamate levels in the NAc were studied using in vivo microdialysis. Locomotor activity was measured by using an infrared sensor. 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.

Memantine

Memantine (Ebixa, Namenda, Axura) is an uncompetitive NMDA receptor antagonist used in the management of patients with moderate-to-severe Alzheimer's disease. It is currently the only drug approved for use in these more advanced stages of the disease. Significant reductions in functional and cognitive decline have been demonstrated with memantine relative to placebo in randomised, double-blind trials in this patient population. Clinical trial and postmarketing surveillance data indicate that the drug is generally well tolerated. Two fully published modelled cost-effectiveness analyses of memantine in moderate-to-severe Alzheimer's disease have been conducted in the UK and Finland, in which patient progression was simulated through health states related to dependency, residential setting and cognitive function. Although the specific costs included in the analyses varied, as did the study perspective and geographical location, results of the base-case analyses consistently showed that memantine was dominant over no pharmacological treatment. In the UK and Finnish analyses, memantine increased the duration of independence by 1.3 and 4.1 months, respectively, and the time to institutionalisation by 0.8 and 1 month. Mean total per-patient costs were reduced by 1963 pounds over 2 years (2003 costs) in the UK analysis and by 1687 eurossover 5 years (2001 costs) in the Finnish analysis. Memantine was also associated with a small gain in quality-adjusted life expectancy in the UK model. In sensitivity analyses, memantine remained dominant for almost all plausible changes to key variables. Memantine reduced total societal costs by $1090 per patient per month (1999 costs) compared with no pharmacological treatment over 28 weeks in a resource utilisation and cost analysis conducted alongside a pivotal US trial in patients with moderate-to-severe Alzheimer's disease. Results were primarily driven by reductions in total caregiver costs, which included the opportunity cost of time spent in caregiving tasks, and in direct nonmedical costs, which included the cost of care in a nursing home or similar institution.In conclusion, in patients with moderate-to-severe Alzheimer's disease, memantine is associated with significant reductions in functional and cognitive decline compared with no pharmacological treatment. Available pharmacoeconomic data from Europe and the US, despite some inherent limitations, support the use of memantine as a cost-effective treatment in this patient population, although definitive conclusions are not feasible because of limited data.

ADENOSINE RECEPTOR LIGANDS AND DIZOCILPINE-INDUCED ANTINOCICEPTION IN MICE

Interactions between adenosine receptor ligands and dizocilpine (uncompetitive NMDA receptor antagonist) was studied in antinociceptive, writhing test in mice. Minimal effective, antinociceptive doses of adenosine receptor agonists were: 0.1 mg/kg (CPAAl receptor agonist), 0.05 mg/kg (CUS 21680A2 receptor agonist), and 0.005 mg/kg (NECAA1/A2 agonist). Generally, these agonists did not potentiate the subthreshold dose of dizocilpine (0.05 mg/kg). Of all adenosine receptor antagonists used, only caffeine (A1 and A2 antagonist) reversed dizocilpine-induced (0.1 mg/kg) antinociception dose-dependently. These findings indicate that dizocilpine-induced antinociception in the writhing test is only partly influenced by adenosine receptor ligands.

P.5.032 Basal metabolism in panic patients during a treatment with paroxetine

It has been repeatedly reported that NMDA receptors may contribute to ethanol-induced discriminative stimulus effects and withdrawal syndrome. However, the role of NMDA receptors in the reinforcing properties of ethanol remains unclear. The aim of the present study was to evaluate effects of the novel low-affinity, uncompetitive NMDA receptor antagonist, 1-amino-1,3,3,5,5-pentamethyl-cyclohexane hydrochloride (MRZ 2/579), on ethanol self-administration and ethanol withdrawal-associated seizures in rats. Both an operant (lever pressing for ethanol) and non-operant two-bottle choice setups were employed to initiate ethanol self-administration. In another procedure, forced treatment with high doses (9–15 g/kg/day) was used to induce physical dependence on ethanol. MRZ 2/579 delivered chronically by osmotic minipumps (9.6 mg/day, s.c.) did not alter either operant or non-operant ethanol drinking behaviour in a maintenance phase of ethanol self-administration. In contrast, repeated daily injections of the drug (5 mg/kg, i.p.) led to a progressive decrease in operant responding for ethanol. MRZ 2/579 (0.5–7.5 mg/kg, i.p.) and another low-affinity NMDA receptor antagonist, memantine (1–10 mg/kg, i.p.) dose-dependently suppressed ethanol withdrawal seizures with efficacies comparable with that of a standard benzodiazepine derivative, diazepam. The results of the present study indicate that: (i) intermittent administration of MRZ 2/579 may lead to a gradual decrease of operant responding for ethanol; and (ii) the group of low-affinity uncompetitive NMDA receptor antagonists may be an interesting alternative to benzodiazepines in the treatment of alcohol withdrawal.

Effects of distinct classes of N-methyl- d-aspartate receptor antagonists on seizures, axonal sprouting and neuronal loss in vitro: suppression by NR2B-selective antagonists

Chronic treatment with high-affinity, competitive N-methyl- d-aspartate receptor (NMDAR) antagonists can promote axonal sprouting, induce neuronal loss and exacerbate seizures associated with temporal lobe epilepsy. Whether moderate-affinity uncompetitive and NR2B subunit-selective NMDAR antagonists elicit similar responses remains largely unexplored. We directly compared the effects of distinct classes of NMDAR antagonists on electrographic seizures, axonal sprouting and neuronal survival using electrophysiological recordings and histology in hippocampal slice cultures treated chronically with vehicle, D-APV (high-affinity competitive), Ro 25-6981 or ifenprodil (NR2B-selective), or memantine (moderate-affinity uncompetitive). Granule cell layer field potential recordings revealed multiple spontaneous electrographic seizures in vehicle-treated cultures following GABA A receptor blockade. Compared to vehicle, seizures were dramatically reduced in cultures treated with NR2B selective antagonists and slightly increased in cultures treated with moderate-affinity uncompetitive or high-affinity competitive antagonists. In general, compared to vehicle, cultures treated with NR2B selective antagonists exhibited less sprouting of granule cell mossy fiber axons (MFS) and more granule cell layer neurons. Cultures treated with high-affinity competitive or moderate-affinity uncompetitive NMDAR antagonists showed increased MFS and fewer granule cell layer neurons. These data reveal differential effects of distinct classes of NMDAR antagonists on seizure expression, axonal sprouting and neuronal survival and suggest an association between these responses.

P.1.066 The interaction between selective sigmaligands and uncompetitive NMDA receptor antagonists in the forced swimming test in rats

P.1.066 The interaction between selective sigmaligands and uncompetitive NMDA receptor antagonists in the forced swimming test in rats

Effect of neramexane on ethanol dependence and reinforcement

It has been suggested that drugs modulating the glutamate/ N-methyl- d-aspartate (NMDA) receptor system may be useful in the treatment of alcohol dependence. The effect of neramexane, a low-to-moderate affinity uncompetitive NMDA receptor antagonist, was examined on the development and expression of ethanol dependence (withdrawal-associated audiogenic seizures) and ethanol-induced conditioned place preference. Neramexane hydrochloride (3.5 mg/kg and higher) inhibited both the development and expression of ethanol dependence. Neramexane hydrochloride also inhibited the acquisition (1.75 mg/kg and higher) and expression (3.5 mg/kg and higher) of ethanol-induced place preference. Our data support therapeutic potential of neramexane as a treatment for alcohol abuse.

Memantine: a therapeutic drug for Alzheimer's disease and the comparison with MK-801

Memantine is agreed officially as a therapeutic drug for moderate-to-severe Alzheimer's disease (AD) in EU and USA. Memantine is a similar uncompetitive NMDA-receptor antagonist to MK-801 and phencyclidine (PCP), and it prevents nerve cell death induced by the ischemia which induces as excessive release of glutamate. These medicines act on an ion channel binding site similar to the magnesium ion binding site. However, MK-801 and PCP cause schizophrenic symptoms, so they are not being used as a therapeutic drug for AD. Memantine does not have those toxicities and does not stimulate acetylcholine release in the cerebral cortex. Although the mechanism of the difference from memantine and MK-801 has not been made clear yet, it seems that memantine is combined and released with the ion channel depending on electric potential in the same way as the magnesium ion. Basic and clinical research will clarify the control mechanism of memantine.

Evaluation of memantine for the treatment of Alzheimer’s disease

Increasing evidence suggests that disturbances in glutamatergic activity play an important role in Alzheimer’s disease (AD). Excessive glutamate-mediated activation of NMDA receptors, for example, may contribute to the neuronal death that characterises AD. On the other hand, physiological activation of the NMDA receptor appears necessary for normal cognitive function. Therefore, compounds that finely modulate NMDA receptor activity hold promise as treatments for AD. Memantine (Namenda™, Axura®, Ebixa®; Forest Laboratories, Inc., Merz Pharmaceuticals GmbH, H. Lundbeck A/S) is a low-moderate affinity, uncompetitive NMDA-receptor antagonist that appears to block pathological, but not physiological, activation of the NMDA receptor. Consequently, therapeutic doses of the drug are well-tolerated and do not seem to interfere with the acquisition or processing of cognitive information. Memantine has been shown to improve symptoms and reduce the rate of clinical deterioration among patients with moderate-to-severe AD and was approved in the US for this indication in October 2003. This review provides a brief rationale for the development of memantine as a therapy for AD, as well as an overview of the pharmacology, clinical efficacy, safety and tolerability of this novel therapeutic agent.

The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease.

Memantine has been demonstrated to be safe and effective in the symptomatic treatment of Alzheimer's disease (AD). While the neurobiological basis for the therapeutic activity of memantine is not fully understood, the drug is not a cholinesterase inhibitor and, therefore, acts differently from current AD therapies. Memantine can interact with a variety of ligand-gated ion channels. However, NMDA receptors appear to be a key target of memantine at therapeutic concentrations. Memantine is an uncompetitive (channel blocking) NMDA receptor antagonist. Like other NMDA receptor antagonists, memantine at high concentrations can inhibit mechanisms of synaptic plasticity that are believed to underlie learning and memory. However, at lower, clinically relevant concentrations memantine can under some circumstances promote synaptic plasticity and preserve or enhance memory in animal models of AD. In addition, memantine can protect against the excitotoxic destruction of cholinergic neurons. Blockade of NMDA receptors by memantine could theoretically confer disease-modifying activity in AD by inhibiting the "weak" NMDA receptor-dependent excitotoxicity that has been hypothesized to play a role in the progressive neuronal loss that underlies the evolving dementia. Moreover, recent in vitro studies suggest that memantine abrogates beta-amyloid (Abeta) toxicity and possibly inhibits Abeta production. Considerable attention has focused on the investigation of theories to explain the better tolerability of memantine over other NMDA receptor antagonists, particularly those that act by a similar channel blocking mechanism such as dissociative anesthetic-like agents (phencyclidine, ketamine, MK-801). A variety of channel-level factors could be relevant, including fast channel-blocking kinetics and strong voltage-dependence (allowing rapid relief of block during synaptic activity), as well as reduced trapping (permitting egress from closed channels). These factors may allow memantine to block channel activity induced by low, tonic levels of glutamate--an action that might contribute to symptomatic improvement and could theoretically protect against weak excitotoxicity--while sparing synaptic responses required for normal behavioral functioning, cognition and memory.

Role of group I metabotropic glutamate receptors and NMDA receptors in homocysteine-evoked acute neurodegeneration of cultured cerebellar granule neurones

Hyperhomocysteinemia is a risk factor in neurodegeneration. It has been suggested that apart from disturbances in methylation processes, the mechanisms of this effect may include excitotoxicity mediated by the N-methyl-d-aspartate (NMDA) receptors. In this study we demonstrate that apart from NMDA receptors, also group I metabotropic glutamate receptors participate in acute homocysteine (Hcy)-induced neurotoxicity in cultured rat cerebellar granule neurones. Primary neuronal cultures were incubated for 30min in the Mg2+-free ionic medium containing homocysteine and other ligands, and neurodegenerative changes were assessed 24h later using propidium iodide staining. d,l-Homocysteine given alone appeared to be a weak neurotoxin, with EC50 of 17.4mM, whereas EC50 for l-glutamate was 0.17mM. Addition of 50μM glycine enhanced homocysteine neurotoxicity, and only that portion of neurotoxicity was abolished by 0.5μM MK-801, an uncompetitive NMDA receptor antagonist. The net stimulation of 45Ca uptake by granule cells incubated in the presence of 25mM d,l-homocysteine with 50μM glycine was only 3% of the net uptake evoked by 1mM glutamate. Application of an antagonist of group I metabotropic glutamate receptors (mGluRs) LY367385 at 25 and 250μM concentrations, induced a dose-dependent partial neuroprotection, whereas given together with MK-801 completely prevented neurotoxicity. In the absence of glycine, LY367385 and MK-801 given alone failed to induce neuroprotection, while applied together completely prevented homocysteine neurotoxicity. Agonist of group I mGluRs, 10 trans-azetidine-2,3-dicarboxylic acid (t-ADA) induced significant neurotoxicity. This study shows for the first time that acute homocysteine-induced neurotoxicity is mediated both by group I mGluRs and NMDA receptors, and is not accompanied by massive influx of extracellular Ca2+ to neurones.

The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer's disease: preclinical evidence.

There is increasing evidence for the involvement of glutamate-mediated neurotoxicity in the pathogenesis of Alzheimer's disease (AD). We suggest that glutamate receptors of the N-methyl-D-aspartate (NMDA) type are overactivated in a tonic rather than a phasic manner in this disorder. This continuous mild activation may lead to neuronal damage and impairment of synaptic plasticity (learning). It is likely that under such conditions Mg(2+) ions, which block NMDA receptors under normal resting conditions, can no longer do so. We found that overactivation of NMDA receptors using a direct agonist or a decrease in Mg(2+) concentration produced deficits in synaptic plasticity (in vivo: passive avoidance test and/or in vitro: LTP in the CA1 region). In both cases, memantine-an uncompetitive NMDA receptor antagonists with features of an 'improved' Mg(2+) (voltage-dependency, kinetics, affinity)-attenuated this deficit. Synaptic plasticity was restored by therapeutically-relevant concentrations of memantine (1 microM). Moreover, doses leading to similar brain/serum levels provided neuroprotection in animal models relevant for neurodegeneration in AD such as neurotoxicity produced by inflammation in the NBM or beta-amyloid injection to the hippocampus. As such, if overactivation of NMDA receptors is present in AD, memantine would be expected to improve both symptoms (cognition) and to slow down disease progression because it takes over the physiological function of magnesium.

Evaluation of memantine for the treatment of Alzheimer?s disease

Increasing evidence suggests that disturbances in glutamatergic activity play an important role in Alzheimer’s disease (AD). Excessive glutamate-mediated activation of NMDA receptors, for example, may contribute to the neuronal death that characterises AD. On the other hand, physiological activation of the NMDA receptor appears necessary for normal cognitive function. Therefore, compounds that finely modulate NMDA receptor activity hold promise as treatments for AD. Memantine (Namenda™, Axura®, Ebixa®; Forest Laboratories, Inc., Merz Pharmaceuticals GmbH, H. Lundbeck A/S) is a low-moderate affinity, uncompetitive NMDA-receptor antagonist that appears to block pathological, but not physiological, activation of the NMDA receptor. Consequently, therapeutic doses of the drug are well-tolerated and do not seem to interfere with the acquisition or processing of cognitive information. Memantine has been shown to improve symptoms and reduce the rate of clinical deterioration among patients with moderate-to-severe AD and was approved in the US for this indication in October 2003. This review provides a brief rationale for the development of memantine as a therapy for AD, as well as an overview of the pharmacology, clinical efficacy, safety and tolerability of this novel therapeutic agent.

Neuroprotection by memantine against neurodegeneration induced by β-amyloid(1–40)

Progressive neuronal loss and cognitive decline in Alzheimer’s disease (AD) might be aggravated by β-amyloid-enhanced excitotoxicity. Memantine is an uncompetitive NMDA receptor antagonist under clinical development for the treatment of AD. Memantine has neuroprotective actions in several in vitro and in vivo models. In the present study, we determined whether memantine protected against β-amyloid induced neurotoxicity and learning impairment in rats. Twenty Sprague–Dawley rats received vehicle or vehicle plus memantine (steady-state plasma concentrations of 2.34±0.23 μM, n=10) s.c. by osmotic pump for 9 days. After 2 days of treatment, 2 μl of water containing β-amyloid 1–40 [Aβ(1–40)] were injected into the hippocampal fissure. On the ninth day of treatment, animals were sacrificed, and morphological and immunohistochemical techniques were used to determine the extent of neuronal degeneration and astrocytic and microglial activation in the hippocampus. Psychomotor activity and spatial discrimination were tested on the eighth day of treatment. Aβ(1–40), but not water, injections into hippocampus led to neuronal loss in the CA1 subfield, evidence of widespread apoptosis, and astrocytic and microglial activation and hypertrophy. Memantine treated animals had significant reductions in the amount of neuronal degeneration, pyknotic nuclei, and GFAP immunostaining as compared with vehicle treated animals. These data suggest that memantine, at therapeutically relevant concentrations, can protect against neuronal degeneration induced by β-amyloid.

Attenuation of the stimulant and convulsant effects of cocaine by 17-substituted-3-hydroxy and 3-alkoxy derivatives of dextromethorphan

Pharmacological evidence has suggested a role for both sigma and N-methyl- d-aspartate (NMDA) receptors in the behavioral stimulant effects of cocaine and its convulsant effects observed at higher doses. A series of dextromethorphan (DM) analogs with a range of affinities for sigma-1 binding sites and for the NMDA receptor ion channel were used to explore the contribution of these two mechanisms in controlling the stimulant and convulsant effects of cocaine. These compounds were potent and efficacious blockers of both stimulant and convulsant effects produced by acute cocaine administration in mice (cocaine 10 or 75 mg/kg ip for locomotor activity or convulsions, respectively). Generally, the DM analogs blocked these effects of cocaine at doses that did not display ataxic and sedative side effects as measured in the inverted screen test. In contrast to the high-affinity NMDA blockers, (+)-MK-801 (dizocilpine) and dextrorphan (DX), DM and analogs did not stimulate locomotor activity. There was no significant correlation between the affinities of the DM analogs for the sigma-1 or the phencyclidine (PCP) binding site and their potencies to produce behavioral effects on their own or to attenuate the behavioral or toxic effects of cocaine. The present study has identified a series of agents that have cocaine-blocking effects that appear to be distinct from that of classical sigma-1 receptor ligands and that of traditional uncompetitive NMDA receptor antagonists. These findings point to potentially novel pharmacological strategies for blocking cocaine stimulant and toxic effects.

Nefopam, an analogue of orphenadrine, protects against both NMDA receptor-dependent and independent veratridine-induced neurotoxicity.

Nefopam hyghochloride is a potent analgesic compound commercialized in most Western Europe for 20 years, which possesses a profile distinct from that of opioids or anti-inflammatory drugs. Previous evidence suggested a central action of nefopam but the detailed mechanisms remain unclear. While, nefopam structure resembles that of orphenadrine, an uncompetitive NMDA receptor antagonist, here we report that differently from orphenadrine, nefopam (100 microM) failed to protect cultured cerebellar neurons from excitotoxicity following direct exposure of neurons to glutamate. Moreover, nefopam failed to displace MK-801 binding to hippocampal membranes. Nefopam effectively prevented NMDA receptor-mediated early appearance (30 min) of toxicity signs induced by the voltage sensitive sodium channel (VSSC) activator veratridine. The later phase (24 h) of neurotoxicity by veratridine occurring independently from NMDA receptor activation, was also prevented by nefopam. Nefopam effect was not mimicked by the GABA receptor agonist muscimol.

Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats

In spite of intensive research, the problem of treating antidepressant-resistant depressive patients has not yet been solved. The authors previously reported that combined administration of imipramine and the uncompetitive NMDA receptor antagonist amantadine reduced immobility time in the forced swimming test in rats to a much greater extent than either treatment alone. The present paper investigates the possibility of synergistic interactions between three antidepressants (imipramine, venlafaxine, fluoxetine) with three uncompetitive NMDA receptor antagonists (amantadine, memantine and neramexane). Most combinations resulted in synergistic (hyperadditive) antidepressive-like effects in the forced swim test. Most interesting was the observation that fluoxetine, which was inactive when given alone, showed a positive effect when combined with amantadine (10 and 20 mg/kg), memantine (2.5 and 5 mg/kg) or neramexane (2.5 and 5 mg/kg). The specificity of these observations is supported by control open field studies, which demonstrated no significant increase, or even a decrease in general locomotion after coadministration of the compounds. The present results suggest that the combination of traditional antidepressant drugs and NMDA receptor antagonists may produce enhanced antidepressive effects, and this is of particular relevance for antidepressant-resistant patients.

Amino-alkyl-cyclohexanes as a novel class of uncompetitive NMDA receptor antagonists.

Because of its widespread involvement in the physiology and pathology of the CNS, the glutamatergic system has gained considerable attention as a potential target for development of new agents for a number of therapeutic indications. In this respect, the glutamate receptor subtype of the NMDA type has been most intensively studied. The present review describes the rational for developing amino-alkyl-cyclohexanes, as new uncompetitive NMDA receptor antagonists based on our positive experience with memantine which has been used clinically for many years for the treatment of neurodegenerative dementia. Many amino-alkyl-cyclohexane derivatives have been evaluated in vitro and in animal models, and in turn, one structure, namely neramexane HCl (MRZ 2/579) was selected for further development. This agent shows some similarity to memantine e.g. channel blocking kinetics, voltage dependency, and affinity. Preclinical tests indicated particularly good activity in animal models of alcoholism (self-administration, withdrawal-induced audiogenic seizures etc.) and pain (chronic pain, inhibition of tolerance to the analgesic effects of morphine). It turn, this agent has recently entered phase II of clinical trials in alcoholism after a favourable profile seen in phase I studies.

The in vivo relevance of the varied channel-blocking properties of uncompetitive NMDA antagonists: tests on spinal neurones

The voltage dependence and channel-blocking kinetics of uncompetitive NMDA receptor antagonists have been well-described using in vitro techniques, but there is little evidence concerning the functional significance of these properties in vivo. We have now compared the effects of NMDA antagonists that display varied profiles of voltage-dependent block in vitro, on responses of spinal neurones in anaesthetised rats. The compounds examined were the uncompetitive channel blockers memantine, ketamine and MK-801 and, for comparison, an antagonist that acts at the strychnine-insensitive glycine binding site (MRZ 2/502). Using frequency of spike discharge as an indicator of somatic depolarisation, we have compared the effects of these antagonists on responses evoked by iontophoretic NMDA application and on synaptic responses evoked by pinch or electrical stimulation (the latter eliciting “wind-up”). The effectiveness of the antagonists was directly but variably related to the discharge frequency of the test response. The rank order of dependence on firing rate matched the rank order of voltage dependence reported in vitro, namely: memantine > ketamine > MK-801≥ MRZ 2/502. Doses that reduced responses to iontophoretic application of NMDA were less effective at reducing responses to pinch, perhaps due to the major non-NMDA component of the synaptic response. Memantine preferentially reduced “wind-up” relative to responses to pinch, whereas ketamine and MK-801 reduced both types of synaptic responses in parallel. This “filtering” by low affinity, voltage-dependent NMDA antagonists such as memantine, of non-physiological activity whilst leaving normal synaptic events relatively untouched, may contribute to their more favourable clinical profile.