Pharmacologically targeted NMDA receptor antagonism by NitroMemantine for cerebrovascular disease

• Published in: Scientific reports 2015-10, Vol.5 (1), p.14781-14781, Article 14781
• Main Authors: Takahashi, Hiroto, Xia, Peng, Cui, Jiankun, Talantova, Maria, Bodhinathan, Karthik, Li, Wenjun, Saleem, Sofiyan, Holland, Emily A., Tong, Gary, Piña-Crespo, Juan, Zhang, Dongxian, Nakanishi, Nobuki, Larrick, James W., McKercher, Scott R., Nakamura, Tomohiro, Wang, Yuqiang, Lipton, Stuart A.
• Format: Article
• Language: English
• Subjects: 13/106; 631/378/2586; 631/443/376; 64; 9/74; Allosteric properties; Animal models; Animals; Anura; Apoptosis - drug effects; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Brain Ischemia - pathology; Brain Ischemia - physiopathology; Cerebral infarction; Cerebrovascular diseases; Cerebrovascular Disorders - drug therapy; Cerebrovascular Disorders - metabolism; Cerebrovascular Disorders - pathology; Dementia disorders; Glutamic acid receptors (ionotropic); Humanities and Social Sciences; Hypoxia; Ischemia; Long-Term Potentiation - drug effects; Maze Learning - drug effects; Memantine - analogs & derivatives; Memantine - pharmacology; Memantine - therapeutic use; Membrane Potentials - drug effects; Morbidity; multidisciplinary; N-Methyl-D-aspartic acid receptors; Neuroprotection; Nitric Oxide - metabolism; Oxidation-Reduction - drug effects; Pharmaceutical industry; Rats; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Rodents; Science; Stroke; Synaptic Transmission - drug effects; Vascular dementia
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep14781

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.