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 ␥-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 M, 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 longterm 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.Neurodegenerative disorders are among the leading cause of death in the elderly, and this medical problem is expected to become more serious as the population continues to age.
N-Methyl-D-aspartate (NMDA)3 receptor overactivation-induced excitotoxicity is clearly implicated in a variety of acute and chronic neurodegenerative disorders (1-4). Thus, the NMDA receptor has been considered an attractive therapeutic target for the development of neuroprotectants. However, the NMDA receptor, as the major excitatory neurotransmitter receptor in the central nervous system, mediates many important physiological processes, such as excitatory neurotransmission, synaptic plasticity, learning and memory, and cell survival (5-8). The therapeutic potential of many NMDA receptor antagonists, therefore, was limited, and they failed in clinical trials because of their psychotropic side effects and memoryimpairing effects resulting from the blockade of NMDA receptor-mediated physiological activities (9, 10). Clinically well tolerated and effective NMDA receptor antagonists for the therapy of neurodegenerative disorders have been pursued over the past several decades.The strategies applie...
