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Article: Pathologically activated neuroprotection via uncompetitive blockade of N-methyl-D-aspartate receptors with fast off-rate by novel multifunctional dimer bis(propyl)-cognitin

TitlePathologically activated neuroprotection via uncompetitive blockade of N-methyl-D-aspartate receptors with fast off-rate by novel multifunctional dimer bis(propyl)-cognitin
Authors
Issue Date2010
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal Of Biological Chemistry, 2010, v. 285 n. 26, p. 19947-19958 How to Cite?
AbstractUncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists with fast off-rate (UFO) may represent promising drug candidates for various neurodegenerative disorders. In this study, we report that bis(propyl)-cognitin, a novel dimeric acetylcholinesterase inhibitor and γ-aminobutyric acid subtype A receptor antagonist, is such an antagonist of NMDA receptors. In cultured rat hippocampal neurons, we demonstrated that bis-(propyl)-cognitin voltage-dependently, selectively, and moderately inhibited NMDA-activated currents. The inhibitory effects of bis(propyl)-cognitin increased with the rise in NMDA and glycine concentrations. Kinetics analysis showed that the inhibition was of fast onset and offset with an off-rate time constant of 1.9 s. Molecular docking simulations showed moderate hydrophobic interaction between bis(propyl)-cognitin and the MK-801 binding region in the ion channel pore of the NMDA receptor. Bis(propyl)-cognitin was further found to compete with [ 3H]MK-801 with a K i value of 0.27 μM, and the mutation of NR1(N616R) significantly reduced its inhibitory potency. Under glutamate-mediated pathological conditions, bis(propyl)-cognitin, in contrast to bis(heptyl)-cognitin, prevented excitotoxicity with increasing effectiveness against escalating levels of glutamate and much more effectively protected against middle cerebral artery occlusion-induced brain damage than did memantine. Moreinterestingly, under NMDA receptor-mediated physiological conditions, bis(propyl)-cognitin enhanced long-term potentiation in hippocampal slices, whereas MK-801 reduced and memantine did not alter this process. These results suggest that bis(propyl)-cognitin is a UFO antagonist of NMDA receptors with moderate affinity, which may provide a pathologically activated therapy for various neurodegenerative disorders associated with NMDA receptor dysregulation. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/168464
ISSN
2015 Impact Factor: 4.258
2015 SCImago Journal Rankings: 3.151
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLuo, Jen_US
dc.contributor.authorLi, Wen_US
dc.contributor.authorZhao, Yen_US
dc.contributor.authorFu, Hen_US
dc.contributor.authorMa, DLen_US
dc.contributor.authorTang, Jen_US
dc.contributor.authorLi, Cen_US
dc.contributor.authorPeoples, RWen_US
dc.contributor.authorLi, Fen_US
dc.contributor.authorWang, Qen_US
dc.contributor.authorHuang, Pen_US
dc.contributor.authorXia, Jen_US
dc.contributor.authorPang, Yen_US
dc.contributor.authorHan, Yen_US
dc.date.accessioned2012-10-08T03:19:17Z-
dc.date.available2012-10-08T03:19:17Z-
dc.date.issued2010en_US
dc.identifier.citationJournal Of Biological Chemistry, 2010, v. 285 n. 26, p. 19947-19958en_US
dc.identifier.issn0021-9258en_US
dc.identifier.urihttp://hdl.handle.net/10722/168464-
dc.description.abstractUncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists with fast off-rate (UFO) may represent promising drug candidates for various neurodegenerative disorders. In this study, we report that bis(propyl)-cognitin, a novel dimeric acetylcholinesterase inhibitor and γ-aminobutyric acid subtype A receptor antagonist, is such an antagonist of NMDA receptors. In cultured rat hippocampal neurons, we demonstrated that bis-(propyl)-cognitin voltage-dependently, selectively, and moderately inhibited NMDA-activated currents. The inhibitory effects of bis(propyl)-cognitin increased with the rise in NMDA and glycine concentrations. Kinetics analysis showed that the inhibition was of fast onset and offset with an off-rate time constant of 1.9 s. Molecular docking simulations showed moderate hydrophobic interaction between bis(propyl)-cognitin and the MK-801 binding region in the ion channel pore of the NMDA receptor. Bis(propyl)-cognitin was further found to compete with [ 3H]MK-801 with a K i value of 0.27 μM, and the mutation of NR1(N616R) significantly reduced its inhibitory potency. Under glutamate-mediated pathological conditions, bis(propyl)-cognitin, in contrast to bis(heptyl)-cognitin, prevented excitotoxicity with increasing effectiveness against escalating levels of glutamate and much more effectively protected against middle cerebral artery occlusion-induced brain damage than did memantine. Moreinterestingly, under NMDA receptor-mediated physiological conditions, bis(propyl)-cognitin enhanced long-term potentiation in hippocampal slices, whereas MK-801 reduced and memantine did not alter this process. These results suggest that bis(propyl)-cognitin is a UFO antagonist of NMDA receptors with moderate affinity, which may provide a pathologically activated therapy for various neurodegenerative disorders associated with NMDA receptor dysregulation. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.en_US
dc.languageengen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/en_US
dc.relation.ispartofJournal of Biological Chemistryen_US
dc.subject.meshAnimalsen_US
dc.subject.meshBinding Sitesen_US
dc.subject.meshBinding, Competitiveen_US
dc.subject.meshCell Lineen_US
dc.subject.meshCell Survival - Drug Effectsen_US
dc.subject.meshCells, Cultureden_US
dc.subject.meshDimerizationen_US
dc.subject.meshExcitatory Amino Acid Agonists - Pharmacologyen_US
dc.subject.meshExcitatory Amino Acid Antagonists - Chemistry - Pharmacologyen_US
dc.subject.meshHumansen_US
dc.subject.meshKineticsen_US
dc.subject.meshMaleen_US
dc.subject.meshMembrane Potentials - Drug Effectsen_US
dc.subject.meshModels, Molecularen_US
dc.subject.meshNeurons - Drug Effects - Metabolism - Physiologyen_US
dc.subject.meshNeuroprotective Agents - Chemistry - Pharmacologyen_US
dc.subject.meshPatch-Clamp Techniquesen_US
dc.subject.meshRadioligand Assayen_US
dc.subject.meshRatsen_US
dc.subject.meshRats, Sprague-Dawleyen_US
dc.subject.meshReceptors, N-Methyl-D-Aspartate - Agonists - Antagonists & Inhibitors - Geneticsen_US
dc.subject.meshTacrine - Analogs & Derivatives - Chemistry - Metabolism - Pharmacologyen_US
dc.subject.meshTransfectionen_US
dc.subject.meshAlpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid - Pharmacologyen_US
dc.titlePathologically activated neuroprotection via uncompetitive blockade of N-methyl-D-aspartate receptors with fast off-rate by novel multifunctional dimer bis(propyl)-cognitinen_US
dc.typeArticleen_US
dc.identifier.emailMa, DL:edmondma@hku.hken_US
dc.identifier.authorityMa, DL=rp00760en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1074/jbc.M110.111286en_US
dc.identifier.pmid20404346-
dc.identifier.scopuseid_2-s2.0-77953753022en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77953753022&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume285en_US
dc.identifier.issue26en_US
dc.identifier.spage19947en_US
dc.identifier.epage19958en_US
dc.identifier.isiWOS:000279012000028-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridLuo, J=8720127800en_US
dc.identifier.scopusauthoridLi, W=8853055600en_US
dc.identifier.scopusauthoridZhao, Y=7407397602en_US
dc.identifier.scopusauthoridFu, H=8853053900en_US
dc.identifier.scopusauthoridMa, DL=7402075538en_US
dc.identifier.scopusauthoridTang, J=16239759500en_US
dc.identifier.scopusauthoridLi, C=7501675842en_US
dc.identifier.scopusauthoridPeoples, RW=7006043956en_US
dc.identifier.scopusauthoridLi, F=36463873000en_US
dc.identifier.scopusauthoridWang, Q=10046090600en_US
dc.identifier.scopusauthoridHuang, P=7403658576en_US
dc.identifier.scopusauthoridXia, J=35265628200en_US
dc.identifier.scopusauthoridPang, Y=7201686083en_US
dc.identifier.scopusauthoridHan, Y=8527680500en_US

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