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.
Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, Universidad de Talca, P.O. Box 747, Talca, Chile.
Marlene
M
Espinoza-Moraga
Julio
J
Caballero
Friedemann
F
Gaube
Thomas
T
Winckler
Leonardo S
LS
Santos
D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D002243:Carbolines / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
D002243:Carbolines; D016194:Receptors, N-Methyl-D-Aspartate