2. Academic Validation
  3. Pharmacologically targeted NMDA receptor antagonism by NitroMemantine for cerebrovascular disease

Pharmacologically targeted NMDA receptor antagonism by NitroMemantine for cerebrovascular disease

  • Sci Rep. 2015 Oct 19:5:14781. doi: 10.1038/srep14781.
Hiroto Takahashi 1,  Peng Xia 1,  Jiankun Cui 1,  Maria Talantova 1,  Karthik Bodhinathan 1,  Wenjun Li 1,  Sofiyan Saleem 1,  Emily A Holland 1,  Gary Tong 1,  Juan Piña-Crespo 1,  Dongxian Zhang 1,  Nobuki Nakanishi 1,  James W Larrick 2,  Scott R McKercher 1,  Tomohiro Nakamura 1,  Yuqiang Wang 3,  Stuart A Lipton 1 4
Affiliations

Affiliations

  • 1 Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92307, USA.
  • 2 Panorama Research, Inc., Sunnyvale, California 94089, USA.
  • 3 Institute of New Drug Research, Jinan University College of Pharmacy, Guangzhou 510632, China.
  • 4 Department of Neurosciences, University of California San Diego School of Medicine, La Jolla, California 92039, USA.
PMID: 26477507 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.

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