TY - JOUR
T1 - Identification of tetracyclic lactams as NMDA receptor antagonists with potential application in neurological disorders
AU - Espadinha, Margarida
AU - Viejo, Lucía
AU - Lopes, Ricardo M.R.M.
AU - Herrera-Arozamena, Clara
AU - Molins, Elies
AU - dos Santos, Daniel J.V.A.
AU - Gonçalves, Lídia
AU - Rodríguez-Franco, María Isabel
AU - Ríos, Cristóbal de los
AU - Santos, Maria M.M.
N1 - Publisher Copyright:
© 2020 Elsevier Masson SAS
PY - 2020/5/15
Y1 - 2020/5/15
N2 - N-Methyl-D-aspartate receptors (NMDARs) are crucial for the normal function of the central nervous system (CNS), and fundamental in memory and learning-related processes. The overactivation of these receptors is associated with numerous neurodegenerative and psychiatric disorders. Therefore, NMDAR is considered a relevant therapeutic target for many CNS disorders. Herein, we report the synthesis and pharmacological evaluation of a new scaffold with antagonistic activity for NMDAR. Specifically, a chemical library of eighteen 1-aminoindan-2-ol tetracyclic lactams was synthesized and screened as NMDAR antagonists. The compounds were obtained by chiral pool synthesis using enantiomerically pure 1-aminoindan-2-ols as chiral inductors, and their stereochemistry was proven by X-ray crystallographic analysis of two target compounds. Most compounds reveal NMDAR antagonism, and eleven compounds display IC50 values in a Ca2+ entry-sensitive fluo-4 assay in the same order of magnitude of memantine, a clinically approved NMDAR antagonist. Docking studies suggest that the novel compounds can act as NMDAR channel blockers since there is a compatible conformation with MK-801 co-crystallized with NMDAR channel. In addition, we show that the tetracyclic 1-aminoindan-2-ol derivatives are brain permeable and non-toxic, and we identify promising hits for further optimization as modulators of the NMDAR function.
AB - N-Methyl-D-aspartate receptors (NMDARs) are crucial for the normal function of the central nervous system (CNS), and fundamental in memory and learning-related processes. The overactivation of these receptors is associated with numerous neurodegenerative and psychiatric disorders. Therefore, NMDAR is considered a relevant therapeutic target for many CNS disorders. Herein, we report the synthesis and pharmacological evaluation of a new scaffold with antagonistic activity for NMDAR. Specifically, a chemical library of eighteen 1-aminoindan-2-ol tetracyclic lactams was synthesized and screened as NMDAR antagonists. The compounds were obtained by chiral pool synthesis using enantiomerically pure 1-aminoindan-2-ols as chiral inductors, and their stereochemistry was proven by X-ray crystallographic analysis of two target compounds. Most compounds reveal NMDAR antagonism, and eleven compounds display IC50 values in a Ca2+ entry-sensitive fluo-4 assay in the same order of magnitude of memantine, a clinically approved NMDAR antagonist. Docking studies suggest that the novel compounds can act as NMDAR channel blockers since there is a compatible conformation with MK-801 co-crystallized with NMDAR channel. In addition, we show that the tetracyclic 1-aminoindan-2-ol derivatives are brain permeable and non-toxic, and we identify promising hits for further optimization as modulators of the NMDAR function.
KW - 1-Aminoindan-2-ol
KW - Antagonism
KW - CNS
KW - Enantiomerically pure lactams
KW - NMDA receptor
UR - http://www.scopus.com/inward/record.url?scp=85082848924&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2020.112242
DO - 10.1016/j.ejmech.2020.112242
M3 - Article
C2 - 32248004
AN - SCOPUS:85082848924
SN - 0223-5234
VL - 194
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 112242
ER -