Pharmacologically targeted NMDA receptor antagonism by NitroMemantine for cerebrovascular disease.

Hiroto Takahashi,Juan Piña-Crespo,Peng Xia,Tomohiro Nakamura,Karthik Bodhinathan,Yuqiang Wang,Jiankun Cui,Dongxian Zhang,Stuart A Lipton,Sofiyan Saleem,Emily A Holland,James W Larrick,Gary Tong,Scott R Mckercher,Wenjun Li,Maria Talantova,Nobuki Nakanishi

doi:10.1038/srep14781

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.

Highlights

Focal cerebral ischemia and vascular dementia represent leading causes of severe cognitive dysfunction and death worldwide[1]
We have previously shown that the N-methyl-d-aspartate-type glutamate receptors (NMDARs) can be antagonized by memantine via open-channel block[10,14] as well as by nitric oxide (NO)-based compounds via an allosteric redox-modulatory site(s) that is subject to S-nitrosylation[20,21,22]
During hypoxia, NO-based compounds preferentially react with allosteric cysteine residues in the NMDAR to limit excessive activity[22]

Summary

Introduction

Focal cerebral ischemia (stroke) and vascular dementia (due to multiple strokes in the microvasculature) represent leading causes of severe cognitive dysfunction and death worldwide[1]. We found that by adding the –ONO2 functional group of nitroglycerin onto memantine (represented by compound YQW-035), we decreased the potency of steady-state channel block during electrophysiological recordings from frog oocytes expressing recombinant NMDARs (Fig. 1b).

Results

Conclusion