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

Margarida Espadinha, Lucía Viejo, Ricardo M.R.M. Lopes, Clara Herrera-Arozamena, Elies Molins, Daniel J.V.A. dos Santos, Lídia Gonçalves, María Isabel Rodríguez-Franco, Cristóbal de los Ríos, Maria M.M. Santos

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number112242
JournalEuropean Journal of Medicinal Chemistry
Volume194
DOIs
Publication statusPublished - 15 May 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 Elsevier Masson SAS

Keywords

  • 1-Aminoindan-2-ol
  • Antagonism
  • CNS
  • Enantiomerically pure lactams
  • NMDA receptor

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