Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/11430
Title: Pathologically activated neuroprotection via uncompetitive blockade of N-methyl-D-aspartate receptors with fast off-rate by novel multifunctional dimer bis(propyl)-cognitin
Authors: Luo, J
Li, W
Zhao, Y
Fu, H
Ma, DL
Tang, J
Li, C
Peoples, RW
Li, F
Wang, Q
Huang, P
Xia, J
Pang, Y
Han, Y 
Issue Date: 2010
Publisher: Amer Soc Biochemistry Molecular Biology Inc
Source: Journal of biological chemistry, 2010, v. 285, no. 26, p. 19947-19958 How to cite?
Journal: Journal of Biological Chemistry 
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 Ki 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.
URI: http://hdl.handle.net/10397/11430
DOI: 10.1074/jbc.M110.111286
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