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Identification of tetracyclic lactams as NMDA receptor antagonists with potential application in neurological disorders
Publication . Espadinha, Margarida; Viejo, Lucía; Lopes, Ricardo M. R. M.; Herrera-Arozamena, Clara; Molins, Elies; Santos, Daniel J. V. A. dos; Gonçalves, Lídia; Rodríguez-Franco, María Isabel; Ríos, Cristobal de los; Santos, Maria M. M.
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.
2020-05Artigo científico Acesso restrito Ver mais

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Fundação para a Ciência e a Tecnologia

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CEEC IND 2017

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CEECIND/01772/2017/CP1476/CT0003

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