Pharmacologically targeted NMDA receptor antagonism by NitroMemantine for cerebrovascular disease

Abstract

Stroke and vascular dementia are leading causes of morbidity and mortality. Neuroprotective therapies have been proposed but none have proven clinically tolerated and effective. While overstimulation of N-methyl-d-aspartate-type glutamate receptors (NMDARs) is thought to contribute to cerebrovascular insults, the importance of NMDARs in physiological function has made this target, at least in the view of many in ‘Big Pharma,’ ‘undruggable’ for this indication. Here, we describe novel NitroMemantine drugs, comprising an adamantane moiety that binds in the NMDAR-associated ion channel that is used to target a nitro group to redox-mediated regulatory sites on the receptor. The NitroMemantines are both well tolerated and effective against cerebral infarction in rodent models via a dual allosteric mechanism of open-channel block and NO/redox modulation of the receptor. Targeted S-nitrosylation of NMDARs by NitroMemantine is potentiated by hypoxia and thereby directed at ischemic neurons. Allosteric approaches to tune NMDAR activity may hold therapeutic potential for cerebrovascular disorders.

Novel conjugates of aminoadamantanes with carbazole derivatives as potential multitarget agents for AD treatment

“…No other blockers, apart from nitromemantine, functioning similarly to memantine and having therapeutic prospects have currently been registered67. It is known that NMDA receptors play an important role in the mammalian brain, being involved not only in the brain development and cognitive processes, but also in the development of some acute and chronic neurodegenerative diseases, including stroke, AD, and depression.…”

Protein S -Nitrosylation as a Therapeutic Target for Neurodegenerative Diseases

“…In this manner, a NitroMemantine drug can provide increased blockade of hyperactivated NMDARs through S-nitrosylation in addition to channel block, thus affording more neuroprotection that that offered by memantine [15,81] (Figure 3). Consistent with this notion, NitroMemantine protected neurons more efficiently than memantine in cellular and animal models of AD and cerebrovascular disease [15,82]. The lead NitroMemantine candidate developed to date, designated YQW-036/NMI-6979, has shown a favorable pharmacokinetic profile, excellent CNS penetration, and good safety index in early preclinical studies [81,82].…”

“…Consistent with this notion, NitroMemantine protected neurons more efficiently than memantine in cellular and animal models of AD and cerebrovascular disease [15,82]. The lead NitroMemantine candidate developed to date, designated YQW-036/NMI-6979, has shown a favorable pharmacokinetic profile, excellent CNS penetration, and good safety index in early preclinical studies [81,82]. The NitroMemantines are currently being evaluated for clinical trials for AD and other neurological disorders.…”

A beacon of hope in stroke therapy—Blockade of pathologically activated cellular events in excitotoxic neuronal death as potential neuroprotective strategies

“…S-nitrosylation maintains inhibition of the extrasynaptic NMDA receptor even after the remaining memantine moiety dissociates from the modified receptor [reviewed in (Nakamura and Lipton, 2016)]. In a recent report, Takahashi, et al demonstrated that NitroMemantines selectively S-nitrosylated ischemic neurons and in turn reduced brain damage in a rat model of ischemic stroke (Takahashi et al, 2015). Besides…”