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Optimization of Bicyclic Lactam Derivatives as NMDA Receptor Antagonists
Author(s) -
Espadinha Margarida,
Dourado Jorge,
LajarinCuesta Rocio,
HerreraArozamena Clara,
Gonçalves Lidia M. D.,
RodríguezFranco María Isabel,
de los Rios Cristobal,
Santos Maria M. M.
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700037
Subject(s) - nmda receptor , pharmacology , receptor , memantine , epilepsy , phencyclidine , schizophrenia (object oriented programming) , chemistry , bicyclic molecule , neuroscience , medicine , biology , stereochemistry , biochemistry , psychiatry
N ‐Methyl‐ d ‐aspartate (NMDA) receptors are fundamental for the normal function of the central nervous system (CNS), and play an important role in memory and learning. Over‐activation of these receptors leads to neuronal loss associated with major neurological disorders such as Parkinson's disease, Alzheimer's disease, schizophrenia, and epilepsy. In this study, 22 novel enantiopure bicyclic lactams were designed, synthesized, and evaluated as NMDA receptor antagonists. Most of the new compounds displayed NMDA receptor antagonism, and the most promising compound showed an IC 50 value on the same order of magnitude as that of memantine, an NMDA receptor antagonist in clinical use for the treatment of Alzheimer's disease. Further biological evaluation indicated that this compound is brain permeable (determined by an in vitro assay) and non‐hepatotoxic. All these results indicate that (3 S ,7a S )‐7a‐(4‐chlorophenyl)‐3‐(4‐hydroxybenzyl)tetrahydropyrrolo[2,1‐ b ]oxazol‐5(6 H )‐one (compound 5 b ) is a potential candidate for the treatment of pathologies associated with the over‐activation of NMDA receptors.