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Bicyclic lactams as potential inhibitors of the NMDA receptor
* 1 , 1 , 2, 3 , 4 , 1 , 1 , 4 , 5 , 2, 3 , 1
1  Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal
2  Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autonoma de Madrid, Madrid, Spain
3  Instituto de Investigacion Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain
4  Instituto de Química Médica (IQM-CSIC), Madrid, Spain
5  Faculty of Sciences University of Porto, Porto, Portugal

Published: 03 November 2018 by MDPI in 4th International Electronic Conference on Medicinal Chemistry session ECMC-4

The family of ionotropic glutamate receptors (iGluRs) is localized in the cell membrane of neurons and has crucial roles in the normal development of the central nervous system (CNS). Sustain healthy memory, learning, and cognitive processes are fundamental functions of these receptors. [1] N-Methyl-D-aspartate (NMDA) receptors belong to the family of iGluRs and its over-activation is associated to neuronal loss and, consequently, to major neurological disorders such as Parkinson and Alzheimer’s diseases. Recently, targeting the NMDA receptor was considered a promising strategy in the medicinal chemistry field and the development of effective NMDA receptor antagonists become an attractive therapeutic approach. [2]

In the last years, Santos’ group has been involved in the design and development of potent NMDA receptor antagonists, more precisely enantiopure bicyclic lactams. [3-5] To evaluate the activity of the potential NMDA receptor antagonists, was measured their capacity to inhibit NMDA-induced increase of intracellular Ca2+ levels in in vitro cultures of embryonary rat cortical neurons, using the Ca2+-sensitive fluorescent dye Fluo-4. The first molecule that showed some interesting results was a (S)-phenylalaninol oxazolopyrrolidone. [3] After, based on the oxazolopyrrolidone scaffold, a hit-to-lead optimization was carried out in the search for more potent NMDA receptor antagonists. A new library of enantiopure phenylalaninol bicyclic lactams was developed and most of the new compounds displayed NMDA receptor antagonism. It was even more interesting the significant difference in activities between the two enantiomers. The most promising compound showed an IC50 value of 27 µM, on the same order of magnitude as that of memantine (47 µM), an NMDA receptor antagonist in clinical use for the treatment of Alzheimer’s disease. [5] More recently, we also extended our interest to more rigid molecules, also containing a bicyclic lactam core. Interestingly, this new family of compounds showed to be even more potent as NMDA receptor antagonists (4-fold more active than memantine). Additional biological tests indicated that the promising compounds can cross the blood-brain barrier (determined by an in vitro assay) and non-hepatotoxic, as well. Furthermore, the synthesis of the interesting aminoalchool-based libraries is easy to perform, resulting in moderate to good yields, and excellent stereoselectivities.


We thank the Fundação para a Ciência e Tecnologia for financial support through iMed.ULisboa (UID/DTP/04138/2013), research project PTDC/QUI-QUI/111664/2009 and to FCT fellowship SFRH/BD/117931/2016 (M. Espadinha). We also want to thank for financial support through Instituto de Salud Carlos III, Spanish Ministry of Health (PI13/00789), and Spanish Ministry of Economy and Competitiveness (MINECO, grants SAF2012-31035 and SAF2015-64948-C2-1-R).


[1] Stawski P., Janovjak H., Trauner D. Bioorg. Med. Chem. 2010, 18, 7759-7772.

[2] Morris R. Neuropharmacology, 2013, 74, 32-40.

[3] Pereira N. A. L., Sureda F. X., Turch m., Amat M., Bosch J., Santos M. M. M. Monatsh. Chem. 2013, 144, 473-477.

[4] Pereira N. A. L., Sureda F. X., Pérez M., Amat M., Bosch J., Santos M. M. M. Molecules, 2016, 21, 1027.

[5] Espadinha M., Dourado J., Lajarin-Cuesta R., Herrera-Arozamena C., Gonçalves L., Rodríguez-Franco I., de los Ríos C., Santos M. M. M. ChemMedChem. 2017, 12, 537-545.

Keywords: NMDA receptor, neurological disorders, bicyclic lactams, antagonists