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Identification of tetracyclic lactams as NMDA receptor antagonists with potential application in neurological disorders

AuthorsEspadinha, M.; Viejo, L.; Lopes, R. M. R. M.; Herrera-Arozamena, Clara; Molins, E.; dos Santos, D. J. V. A.; Gonçalves, L.; Rodríguez-Franco, María Isabel ; Ríos, C. d. l.; Santos, M. M. M.
Enantiomerically pure lactams
NMDA recept
Issue Date2020
CitationEuropean Journal of Medicinal Chemistry 194 (2020)
AbstractN-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 IC values in a Ca 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.
Publisher version (URL)http://dx.doi.org/10.1016/j.ejmech.2020.112242
Identifiersdoi: 10.1016/j.ejmech.2020.112242
issn: 1768-3254
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