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.
Highlights
The strategies applied to develop effective and well tolerated neuroprotective drugs are based on the principle that drugs should interact with their targets only during states of pathological and not physiological activation
We demonstrate that this dimer is an uncompetitive NMDA receptor antagonist with moderate affinity, fast off-rate, effective neuroprotective activities against glutamate-induced neuronal cell death without obvious cytotoxicity in vitro and middle cerebral artery occlusion (MCAO)-induced brain damage in vivo, and enhancement of long term potentiation (LTP)
Bis(propyl)-cognitin Selectively Inhibits inhibited NMDA-activated currents (INMDA) in an Agonistdependent Manner—We further examined the selectivity of bis(propyl)-cognitin inhibition among ionotropic glutamate receptors
Summary
Blockade of N-Methyl-D-aspartate Receptors with Fast Off-rate by Novel Multifunctional Dimer Bis(propyl)-cognitin*. By comparison of their actions on NMDA receptors, bis(propyl)-cognitin emerges as a promising neuroprotective drug candidate among these novel dimers We demonstrate that this dimer is an uncompetitive NMDA receptor antagonist with moderate affinity, fast off-rate, effective neuroprotective activities against glutamate-induced neuronal cell death without obvious cytotoxicity in vitro and middle cerebral artery occlusion (MCAO)-induced brain damage in vivo, and enhancement of LTP. These findings strongly suggest that this dimer may be developed to a PAT drug possessing considerable therapeutic potential for various associated neurodegenerative disorders
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