1-Benzyl-1,2,3,4-tetrahydro-β-carboline as channel blocker of N-methyl-D-aspartate receptors.

N-methyl-d-aspartate (NMDA) receptors belong to the family of ligand-gated ion channels and are important for synaptic plasticity and memory function. The NMDA receptor consists of a voltage-dependent channel permeable to Ca(2+) and Na(+) . In Alzheimer's disease, neuronal degeneration is thought to cause an excessive release of glutamate to the extracellular space, which may in turn mediate prolonged stimulation of the NMDA receptor complex and, as a consequence, excessive calcium influx into neuronal cells, leading to subsequent cell death. This process is called glutamate-induced excitotoxicity, and its inhibition may present an effective antidementive therapy. We found that 1-benzyl-1,2,3,4-tetrahydro-β-carboline (1a) blocked NMDA receptor-mediated, glutamate-induced excitotoxicity with an IC(50) value of 27.4 μm, whereas the closely related 1-phenyl-1,2,3,4-tetrahydro-β-carboline (1b) had no effect. The binding modes of the reported compounds were studied by in silico docking simulations. We demonstrate that compounds (S)-1a and (R)-1a, but not (S)-1b and (R)-1b, have the same characteristics of potent NMDA receptor blockers, because they establish the main interactions inside the vestibule region of the receptor described previously for the high-affinity NMDA receptor blocker, MK-801.