title: 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.
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92307, USA.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92307, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Xia
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92307, USA.
authors.forename: Jiankun
authors.initials: J
authors.lastname: Cui
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92307, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Talantova
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92307, USA.
authors.forename: Karthik
authors.initials: K
authors.lastname: Bodhinathan
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92307, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Li
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92307, USA.
authors.forename: Sofiyan
authors.initials: S
authors.lastname: Saleem
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92307, USA.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Holland
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92307, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Tong
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92307, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Piña-Crespo
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92307, USA.
authors.forename: Dongxian
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92307, USA.
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nakanishi
authors.affiliation: Panorama Research, Inc., Sunnyvale, California 94089, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Larrick
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92307, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: McKercher
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92307, USA.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Institute of New Drug Research, Jinan University College of Pharmacy, Guangzhou 510632, China.
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92307, USA.|Department of Neurosciences, University of California San Diego School of Medicine, La Jolla, California 92039, USA.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
mesh_terms: D000818:Animals; D001001:Anura; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002561:Cerebrovascular Disorders / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017774:Long-Term Potentiation / Q000187:drug effects; D018782:Maze Learning / Q000187:drug effects; D008559:Memantine / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D008564:Membrane Potentials / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D008559:Memantine