Neu2000, an NR2B-selective, moderate NMDA receptor antagonist and potent spin trapping molecule for stroke

Abstract

Excess activation of ionotropic glutamate receptors, primarily N-methyl-D-aspartate (NMDA) receptors and free radicals, evoke nerve cell death following hypoxic-ischemic brain injury in various animal models. However, clinical trials in stroke patients using NMDA receptor antagonists have failed to show efficacy primarily due to the limited therapeutic time window for neuroprotection and a narrow therapeutic index. In comparison, antioxidants prolonged the time window for neuroprotection in animal models of ischemic stroke and showed greater therapeutic potential in clinical trials for ischemic stroke. Excess activation of NMDA receptors and free radicals mediate the two separate pathways of nerve cell death in stroke and a safe and multifunctional drug that can block both routes in the brain will likely provide a better therapeutic outcome in patients with stroke. Derivatives of the lead structures of sulfasalazine and aspirin have led to the discovery of a new molecule, Neu2000, that has demonstrated excellent neuroprotection against NMDA- and free radical-induced cell death. Neu2000 is an NR2B-selective, moderate NMDA receptor antagonist with potent cell-permeable, spin trapping antioxidant action even at nanomolar concentrations. Nonclinical and human phase I studies demonstrated that Neu2000 can be translated to treat patients with stroke with better efficacy and therapeutic time window.

The neuroprotective effect of praeruptorin C against NMDA-induced apoptosis through down-regulating of GluN2B-containing NMDA receptors

“…Most investigators agree that the pathologic activation of subtype NMDARs contributes to neuronal death after acute excitotoxic trauma, such as brain ischemia (Arundine and Tymianski, 2004; Guo et al, 2011) and acts as a major mediator. NMDARs consist of a GluN2A subunit that promotes neuron protection, whereas GluN2B-containing NMDARs mediate excitotoxicity (Cho et al, 2010). In the present study, the data showed that Pra-C reverses the upregulation of GluN2B induced by NMDA, implying that the neuroprotection of Pra-C is likely to antagonize a particular NMDAR subunit.…”

“…Overactivated NMDA receptors are permeable to Na + , K + , and Ca 2+ ions, among which excess Ca 2+ ions is linearly correlated with neuronal cell death triggered by intracellular Ca 2+ -dependent cascades. Many researchers have focused on the extensive studies of GluN2B antagonists because of the ability to potentially cure various CNS diseases (Brown et al, 2011;Cho et al, 2010).…”

Neuroprotective Effects of Flax Lignan Against NMDA‐Induced Neurotoxicity In Vitro

“…Most investigators agree that pathologic activation of subtype NMDAR contributes to neuronal death after acute excitotoxic trauma, such as brain ischemia and acts as the major mediator . NMDAR consists of GluN2A subunit that promotes neuron protection, whereas GluN2B‐containing NMDAR mediates excitotoxicity . In the present study, the data showed that FLL reverses the upregulation of GluN2B induced by NMDA, implicating the neuroprotection of FLL is likely to antagonize a particular NMDAR subunit.…”

Pharmacological modulation of NMDA receptor activity and the advent of negative and positive allosteric modulators

“…In the area of NMDA receptors, development of allosteric modulators, other than the NTD-binding GluN2B-selective agents, has been lagging. Individual compounds such as felbamate (Figure 4) (Chang and Kuo, 2008; Kleckner et al, 1999) and neu2000 (Figure 4) (Cho et al, 2010) appear to also represent NAMs and further work is necessary to better define their sites of action. In the past year, however, three new classes of drugs have emerged that can negatively modulate NMDA receptor function.…”