title: Pathologically activated neuroprotection via uncompetitive blockade of N-methyl-D-aspartate receptors with fast off-rate by novel multifunctional dimer bis(propyl)-cognitin.
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 gamma-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 [(3)H]MK-801 with a K(i) value of 0.27 mum, 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. More interestingly, 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.
authors.affiliation: Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Jialie
authors.initials: J
authors.lastname: Luo
authors.forename: Wenming
authors.initials: W
authors.lastname: Li
authors.forename: Yuming
authors.initials: Y
authors.lastname: Zhao
authors.forename: Hongjun
authors.initials: H
authors.lastname: Fu
authors.forename: Dik-Lung
authors.initials: DL
authors.lastname: Ma
authors.forename: Jing
authors.initials: J
authors.lastname: Tang
authors.forename: Chaoying
authors.initials: C
authors.lastname: Li
authors.forename: Robert W
authors.initials: RW
authors.lastname: Peoples
authors.forename: Fushun
authors.initials: F
authors.lastname: Li
authors.forename: Qinwen
authors.initials: Q
authors.lastname: Wang
authors.forename: Pingbo
authors.initials: P
authors.lastname: Huang
authors.forename: Jun
authors.initials: J
authors.lastname: Xia
authors.forename: Yuanping
authors.initials: Y
authors.lastname: Pang
authors.forename: Yifan
authors.initials: Y
authors.lastname: Han
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019281:Dimerization; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics; D013619:Tacrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; C000609450:bis(heptyl)cognitin; C551529:bis(propyl)cognitin; D013619:Tacrine; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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