Memantine binding to a superficial site on NMDA receptors contributes to partial trapping

Abstract

Although many nervous system disorders are associated with N -methyl-d-aspartate (NMDA) receptor overactivation, pharmacological inhibition of NMDA receptors has typically demonstrated limited clinical value due to debilitating psychotomimetic side-effects. Memantine, however, induces far fewer behavioural side-effects than other NMDA receptor channel blockers such as ketamine, and slows the progressive cognitive decline associated with Alzheimer's disease. Memantine and ketamine inhibit NMDA receptors with similar affinity and kinetics. A prominent mechanistic difference between memantine and ketamine is the degree to which they are 'trapped' within the closed channel of NMDA receptors following removal of agonist: ketamine becomes trapped in nearly all NMDA receptors to which it was bound before agonist removal, whereas some bound memantine molecules dissociate after agonist removal, a phenomenon called partial trapping. Here we investigated the mechanism underlying partial trapping of memantine by recombinant NR1/2A NMDA receptors. We found that memantine dissociation from NR1/2A receptors after agonist removal (the process that results in partial trapping) followed an exponential time course with τ = 0.79 ± 0.32 s. Neither membrane voltage depolarization nor maintained presence of memantine after agonist removal affected partial trapping, suggesting that partial trapping does not result from memantine escape through open channels. We tested the hypothesis that partial trapping results from binding of memantine to two sites, a superficial 'non-trapping' site and a deep 'trapping' site, which cannot be occupied simultaneously. This hypothesis was supported by the lack of ketamine binding to the superficial site, the voltage dependence of partial trapping, and the effect on partial trapping of a mutation near the deep site. The superficial binding site for memantine may, by causing partial trapping, contribute to memantine's unique therapeutic utility.

Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses

“…However, given that the clinical studies used chronic memantine treatment yet memantine lacked antidepressant properties, it seems unlikely that the clinical differences between these two drugs are due to differences in pharmacokinetics and/ or affinity. The clinical findings demonstrating differences between ketamine and memantine in triggering rapid antidepressant responses are rather surprising, because both drugs are noncompetitive NMDAR antagonists that block the receptor when it is in an open configuration (16,20). Importantly, the two compounds do not show significant differences in their ability to block NMDAR-mediated synaptic or extrasynaptic currents in the absence of physiological Mg 2+ (16).…”

Chronic Administration of the N-Methyl-D-Aspartate Receptor Antagonist Ketamine Improves Rett Syndrome Phenotype

“…Memantine, a weak NMDAR blocker, partially reverses short-term plasticity in hippocampal slices of Mecp2-null mice but fails to halt the progression of RTT phenotypes (44). It is noteworthy that there are several differences in the way memantine and ketamine interact with NMDAR, including their ability to change glutamate binding at rest (69), the trapping properties of the drugs (70), and their unique effects on synaptic and extrasynaptic receptors (71). Moreover, ketamine and memantine activate different downstream intracellular pathways, as memantine does not inhibit the phosphorylation of eukaryotic elongation factor 2, nor does it augment subsequent expression of BDNF (69).…”

Effect of Memantine on Cough Reflex Sensitivity: Translational Studies in Guinea Pigs and Humans

“…Memantine, a use-dependent NMDA receptor/channel blocker, would appear to have such properties. With its open channel-blocking actions and rapid dissociation rates from the channel complex (Kotermanski et al, 2009), memantine displays the peculiar in vitro characteristic of being more effective at preventing receptor/channel gating by high concentrations of NMDA receptor agonists as compared with its actions on threshold NMDA receptor activation (Chen et al, 1992). With these highly specific actions and absence of sigma receptor engagement, memantine has no significant psychotropic effects and failed to demonstrate abuse liability in animal studies or in clinical use (Kornhuber et al, 1993;Parsons et al, 1999;Vosburg et al, 2005;Chen and Lipton, 2006).…”

“…Regarding the latter, in vitro assessments of memantine potency have produced IC 50 values that vary widely but have generally been upwards of 0.1 mM (Chen et al, 1992;Kotermanski et al, 2009). In our pharmacokinetic analyses, peak plasma levels of memantine ranged between 1 and 10 mM when dosed orally at 3-10 mg/kg.…”