Espinoza-Moraga et al.
Docking simulations of the reported compounds explain why com-
pound 1a is a NMDA receptor blocker and compound 1b does not
have this activity. The results suggest that rational modifications of
the phenyl group in the scaffold 1-methyl-1,2,3,4-tetrahydro-b-carbo-
line based on the described NMDA receptor model provide a basis
for the development of NMDA receptor blockers with advantage
over the described bivalent structures (20) in having a smaller size
and no permanent charge, and thus a reasonable bioavailability.
is bad, too much is even worse. Neuropharmacology;53:699–
723.
11. Benveniste M., Mayer M.L. (1993) Multiple effects of spermine
on N-methyl-D-aspartic acid receptor responses of rat cultured
hippocampal neurones. J Physiol;464:131–163.
12. Cowburn R.F., Wiehager B., Trief E., Li-Li M., Sundstrom E.
(1997) Effects of beta-amyloid-(25–35) peptides on radioligand
binding to excitatory amino acid receptors and voltage-depen-
dent calcium channels: evidence for a selective affinity for the
glutamate and glycine recognition sites of the NMDA receptor.
Neurochem Res;22:1437–1442.
Acknowledgments
1
3. Benveniste H., Drejer J., Schousboe A., Diemer N.H. (1984) Ele-
vation of the extracellular concentrations of glutamate and
aspartate in rat hippocampus during transient cerebral ischemia
monitored by intracerebral microdialysis. J Neurochem;43:1369–
1374.
M.E.M. and J.C. are grateful to the Universidad de Talca for finan-
cial support. M.E.M. is also thankful to the German Academic
Exchange Service (DAAD) for fellowship. L.S.S. thanks FONDECYT
(
1110022) for supporting research activity. We are grateful to the
expert technical assistance by Heidemarie Graf.
14. Dingledine R., McBain C.J., McNamara J.O. (1990) Excitatory
amino acid receptors in epilepsy. Trends Pharmacol Sci;11:334–
338.
References
15. Lipton S.A. (2006) Paradigm shift in neuroprotection by NMDA
receptor blockade: memantine and beyond. Nat Rev Drug Dis-
cov;5:160–170.
1
. Traynelis S.F., Wollmuth L.P., McBain C.J., Menniti F.S., Vance
K.M., Ogden K.K., Hansen K.B., Yuan H., Myers S.J., Dingledine
R. (2010) Glutamate receptor ion channels: structure, regulation,
and function. Pharmacol Rev;62:405–496.
16. Turski L., Bressler K., Rettig K.J., Loschmann P.A., Wachtel H.
(1991) Protection of substantia nigra from MPP+ neurotoxicity by
N-methyl-D-aspartate antagonists. Nature;349:414–418.
17. DiFiglia M. (1990) Excitotoxic injury of the neostriatum: a model
for Huntington's disease. Trends Neurosci;13:286–289.
18. Jimenez J., Riveron-Negrete L., Abdullaev F., Espinosa-Aguirre
J., Rodriguez-Arnaiz R. (2008) Cytotoxicity of the beta-carboline
alkaloids harmine and harmaline in human cell assays in vitro.
Exp Toxicol Pathol;60:381–389.
19. Brahmbhatt K.G., Ahmed N., Sabde S., Mitra D., Singh I.P., Bhu-
tani K.K. (2010) Synthesis and evaluation of beta-carboline deriv-
atives as inhibitors of human immunodeficiency virus. Bioorg
Med Chem Lett;20:4416–4419.
2
3
4
. Cull-Candy S., Brickley S., Farrant M. (2001) NMDA receptor
subunits: diversity, development and disease. Curr Opin Neuro-
biol;11:327–335.
. Childers W.E. Jr, Baudy R.B. (2007) N-methyl-D-aspartate antago-
nists and neuropathic pain: the search for relief. J Med
Chem;50:2557–2562.
. Collingridge G.L., Lester R.A. (1989) Excitatory amino acid recep-
tors in the vertebrate central nervous system. Pharmacol
Rev;41:143–210.
5
. Reynolds I.J., Miller R.J. (1988) Multiple sites for the regulation of
the N-methyl-D-aspartate receptor. Mol Pharmacol;33:581–584.
. Hu L.Y., Guo J., Magar S.S., Fischer J.B., Burke-Howie K.J., Du-
rant G.J. (1997) Synthesis and pharmacological evaluation of N-
20. Rook Y., Schmidtke K.U., Gaube F., Schepmann D., Wunsch B.,
Heilmann J., Lehmann J., Winckler T. (2010) Bivalent beta-carbo-
lines as potential multitarget anti-Alzheimer agents. J Med
Chem;53:3611–3617.
6
(2,5-disubstituted phenyl)-N'-(3-substituted phenyl)-N'-methylgua-
nidines as N-methyl-D-aspartate receptor ion-channel blockers. J
Med Chem;40:4281–4289.
. Grauert M., Bechtel W.D., Ensinger H.A., Merz H., Carter A.J.
21. Shankaraiah N., da Silva W.A., Andrade C.K.Z., Santos L.S.
(2008) Enantioselective total synthesis of (S)-())-quinolactacin B.
Tetrahedron Lett;49:4289–4291.
22. Espinoza-Moraga M., Petta T., Vasquez-Vasquez M., Laurie V.F.,
Moraes L.A.B., Santos L.S. (2010) Bioreduction of b-carboline
imines to amines employing Saccharomyces bayanus. Tetrahe-
dron Asymm;21:1988–1992.
23. Espinoza-Moraga M., Caceres A.G., Santos L.S. (2009) Palladium
asymmetric reduction of b-carboline imines mediated by chiral
auxiliaries assisted by microwave irradiation. Tetrahedron
Lett;50:7059–7061.
24. da Silva W.A., Rodrigues M.T., Shankaraiah N., Ferreira R.B.,
Andrade C.K.Z., Pilli R.A., Santos L.S. (2009) Novel supramolecu-
lar palladium catalyst for the asymmetric reduction of imines in
aqueous media. Org Lett;11:3238–3241.
7
8
(1997) Synthesis and structure-activity relationships of 6,7-ben-
zomorphan derivatives as antagonists of the NMDA receptor-
channel complex. J Med Chem;40:2922–2930.
. Warncke T., Stubhaug A., Jorum E. (1997) Ketamine, an NMDA
receptor antagonist, suppresses spatial and temporal properties
of burn-induced secondary hyperalgesia in man: a double-blind,
cross-over comparison with morphine and placebo. Pain;72:99–
1
06.
. Burket J.A., Cannon W.R., Jacome L.F., Deutsch S.I. (2010) MK-
01, a noncompetitive NMDA receptor antagonist, elicits circling
9
8
behavior in the genetically inbred Balb ⁄ c mouse strain. Brain
Res Bull;83:337–339.
1
0. Parsons C.G., Stoffler A., Danysz W. (2007) Memantine: a NMDA
receptor antagonist that improves memory by restoration of
homeostasis in the glutamatergic system – too little activation
25. Arnold K., Bordoli L., Kopp J., Schwede T. (2006) The SWISS-
MODEL workspace: a web-based environment for protein struc-
ture homology modelling. Bioinformatics;22:195–201.
5
98
Chem Biol Drug Des 2012; 79: 594–599