Medicine and Health Sciences Commons^™

Pathologically Activated Neuroprotection Via Uncompetitive Blockade Of N-Methyl-D-Aspartate Receptors With Fast Off-Rate By Novel Multifunctional Dimer Bis(Propyl)-Cognitin, Jialie Luo, Wenming Li, Yuming Zhao, Hongjun Fu, Dik-Lung Ma, Jing Tang, Chaoying Li, Robert W. Peoples, Fushun Li, Qinwen Wang, Pingbo Huang, Jun Xia, Yuanping Pang, Yifan Han

Biomedical Sciences Faculty Research and Publications

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 …