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- Publisher Website: 10.1074/jbc.M110.111286
- Scopus: eid_2-s2.0-77953753022
- PMID: 20404346
- WOS: WOS:000279012000028
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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
Title | Pathologically activated neuroprotection via uncompetitive blockade of N-methyl-D-aspartate receptors with fast off-rate by novel multifunctional dimer bis(propyl)-cognitin |
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Authors | |
Issue Date | 2010 |
Publisher | American 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? |
Abstract | Uncompetitive 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 Identifier | http://hdl.handle.net/10722/168464 |
ISSN | 2020 Impact Factor: 5.157 2023 SCImago Journal Rankings: 1.766 |
ISI Accession Number ID | |
References |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Luo, J | en_US |
dc.contributor.author | Li, W | en_US |
dc.contributor.author | Zhao, Y | en_US |
dc.contributor.author | Fu, H | en_US |
dc.contributor.author | Ma, DL | en_US |
dc.contributor.author | Tang, J | en_US |
dc.contributor.author | Li, C | en_US |
dc.contributor.author | Peoples, RW | en_US |
dc.contributor.author | Li, F | en_US |
dc.contributor.author | Wang, Q | en_US |
dc.contributor.author | Huang, P | en_US |
dc.contributor.author | Xia, J | en_US |
dc.contributor.author | Pang, Y | en_US |
dc.contributor.author | Han, Y | en_US |
dc.date.accessioned | 2012-10-08T03:19:17Z | - |
dc.date.available | 2012-10-08T03:19:17Z | - |
dc.date.issued | 2010 | en_US |
dc.identifier.citation | Journal Of Biological Chemistry, 2010, v. 285 n. 26, p. 19947-19958 | en_US |
dc.identifier.issn | 0021-9258 | en_US |
dc.identifier.uri | http://hdl.handle.net/10722/168464 | - |
dc.description.abstract | Uncompetitive 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.language | eng | en_US |
dc.publisher | American Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/ | en_US |
dc.relation.ispartof | Journal of Biological Chemistry | en_US |
dc.subject.mesh | Animals | en_US |
dc.subject.mesh | Binding Sites | en_US |
dc.subject.mesh | Binding, Competitive | en_US |
dc.subject.mesh | Cell Line | en_US |
dc.subject.mesh | Cell Survival - Drug Effects | en_US |
dc.subject.mesh | Cells, Cultured | en_US |
dc.subject.mesh | Dimerization | en_US |
dc.subject.mesh | Excitatory Amino Acid Agonists - Pharmacology | en_US |
dc.subject.mesh | Excitatory Amino Acid Antagonists - Chemistry - Pharmacology | en_US |
dc.subject.mesh | Humans | en_US |
dc.subject.mesh | Kinetics | en_US |
dc.subject.mesh | Male | en_US |
dc.subject.mesh | Membrane Potentials - Drug Effects | en_US |
dc.subject.mesh | Models, Molecular | en_US |
dc.subject.mesh | Neurons - Drug Effects - Metabolism - Physiology | en_US |
dc.subject.mesh | Neuroprotective Agents - Chemistry - Pharmacology | en_US |
dc.subject.mesh | Patch-Clamp Techniques | en_US |
dc.subject.mesh | Radioligand Assay | en_US |
dc.subject.mesh | Rats | en_US |
dc.subject.mesh | Rats, Sprague-Dawley | en_US |
dc.subject.mesh | Receptors, N-Methyl-D-Aspartate - Agonists - Antagonists & Inhibitors - Genetics | en_US |
dc.subject.mesh | Tacrine - Analogs & Derivatives - Chemistry - Metabolism - Pharmacology | en_US |
dc.subject.mesh | Transfection | en_US |
dc.subject.mesh | Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid - Pharmacology | en_US |
dc.title | Pathologically activated neuroprotection via uncompetitive blockade of N-methyl-D-aspartate receptors with fast off-rate by novel multifunctional dimer bis(propyl)-cognitin | en_US |
dc.type | Article | en_US |
dc.identifier.email | Ma, DL:edmondma@hku.hk | en_US |
dc.identifier.authority | Ma, DL=rp00760 | en_US |
dc.description.nature | link_to_subscribed_fulltext | en_US |
dc.identifier.doi | 10.1074/jbc.M110.111286 | en_US |
dc.identifier.pmid | 20404346 | - |
dc.identifier.scopus | eid_2-s2.0-77953753022 | en_US |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-77953753022&selection=ref&src=s&origin=recordpage | en_US |
dc.identifier.volume | 285 | en_US |
dc.identifier.issue | 26 | en_US |
dc.identifier.spage | 19947 | en_US |
dc.identifier.epage | 19958 | en_US |
dc.identifier.isi | WOS:000279012000028 | - |
dc.publisher.place | United States | en_US |
dc.identifier.scopusauthorid | Luo, J=8720127800 | en_US |
dc.identifier.scopusauthorid | Li, W=8853055600 | en_US |
dc.identifier.scopusauthorid | Zhao, Y=7407397602 | en_US |
dc.identifier.scopusauthorid | Fu, H=8853053900 | en_US |
dc.identifier.scopusauthorid | Ma, DL=7402075538 | en_US |
dc.identifier.scopusauthorid | Tang, J=16239759500 | en_US |
dc.identifier.scopusauthorid | Li, C=7501675842 | en_US |
dc.identifier.scopusauthorid | Peoples, RW=7006043956 | en_US |
dc.identifier.scopusauthorid | Li, F=36463873000 | en_US |
dc.identifier.scopusauthorid | Wang, Q=10046090600 | en_US |
dc.identifier.scopusauthorid | Huang, P=7403658576 | en_US |
dc.identifier.scopusauthorid | Xia, J=35265628200 | en_US |
dc.identifier.scopusauthorid | Pang, Y=7201686083 | en_US |
dc.identifier.scopusauthorid | Han, Y=8527680500 | en_US |
dc.identifier.issnl | 0021-9258 | - |