Optimization of Bicyclic Lactam Derivatives as NMDA Receptor Antagonists

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 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 (3S,7aS)-7a-(4-chlorophenyl)-3-(4-hydroxybenzyl)tetrahydropyrrolo[2,1-b]oxazol-5(6H)-one (compound 5 b) is a potential candidate for the treatment of pathologies associated with the over-activation of NMDA receptors.This work was supported by the FundaÇao para a Ciência e a Tecnologia (FCT, Portugal) through iMed.ULisboa (UID/DTP/04138/ 2013), and the research project PTDC/QUI-QUI/111664/2009. M.M.M.S. acknowledges FCT “Programa Operacional Potencial Humano” and the European Social Fund for the IF Program (IF/ 00732/2013). The authors also thank FCT fellowship SFRH/BD/ 117931/2016 (M. Espadinha). C.d.l.R. acknowledges financial support from the Instituto de Salud Carlos III, Spanish Ministry of Health (PI13/00789). M.I.R.-F. acknowledges financial support from the Spanish Ministry of Economy and Competitiveness (MINECO, grants SAF2012-31035 and SAF2015-64948-C2-1-R), partially financed by FEDER funds, and Consejo Superior de Investigaciones Cient&ficas (CSIC, grant PIE-201580E109).Peer Reviewe