Research

Design, synthesis and evaluation of new polycyclic antagonists of the NMDA receptors

Within this project we designed, synthesized and evaluated novel polycyclic compounds as analogs of the clinically approved NMDA receptor antagonists amantadine and memantine. We were the first to report that oxa-analogs of amantadine were also antagonists of the NMDA receptors (a), and that novel polycyclic scaffolds, were also endowed with potent NMDA receptor antagonism (b) and (c). Recently, in a collaboration with the group of Prof. D. Muñoz-Torrero, we disclosed a family of dual acetylcholinesterase inhibitors and NMDA receptor antagonists, of interest for Alzheimer’s disease (d).

Duque, M. D.; Camp, P.; Profire, L.; Montaner, S.; Vázquez, S.; Sureda, F. X.; Mallol, J.; López-Querol, M.; Naesens, L.; DeClercq, E.; Prathalingam, S. R.; Kelly, J. M. (2009). Synthesis and pharmacological evaluation of (2-oxaadamant-1-yl)amines. Bioorg. Med. Chem. 17, 3198-3206.
Valverde, E.; Sureda, F. X.; Vázquez, S. (2014). Novel benzopolycyclic amines with NMDA receptor antagonist activity. Bioorg. Med. Chem. 22, 2678-2683.
Leiva, R.; Phillips, M. B.; Turcu, A. L.; Gratacòs-Batlle, E.; León-García, L.; Sureda, F. X.; Soto, D.; Johnson, J. W.; Vázquez S. (2018). Pharmacological and electrophysiological characterization of novel NMDA receptor antagonists. ACS Chem. Neurosci. 9, 2722-2730.
Pérez-Areales, F. J.; Turcu, A. L.; Barniol-Xicota, M.; Pont, C.; Pivetta, D.; Espargaró, A.; Bartolini, M.; De Simone, A.; Andrisano, V.; Pérez, B.; Sabate, R.; Sureda, F. X.; Vázquez, S.; Muñoz-Torrero, D. (2019). A novel class of multitarget anti-Alzheimer benzohomoadamantane chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors. Eur. J. Med. Chem. 180, 613-626.
Companys-Alemany, J.; Turcu, A. L.; Bellver-Sanchi, A.; Loza M. I.; Brea, J.; Canudas, A. M.; Leiva, R.; Vázquez, S.; Pallàs, M.; Griñán-Ferré C. A Novel NMDA Receptor Antagonist Protects against Cognitive Decline Presented by Senescent Mice. Pharmaceutics. 2020, 12, 284.
Turcu, A. L.; Companys-Alemany, J.; Philips, M. B.; Patel, D. S.; Griñán-Ferré, C.; Loza, I.; Brea, J. M.; Pérez, B.; Soto, D.; Sureda, F. X.; Kurnikova, M. G.; Johnson, J. W.; Pallàs, P; Vázquez, S. Design, synthesis, and in vitro and in vivo characterization of new memantine analogs for Alzheimer’s Disease. Eur. J. Med. Chem., 2022, 236, 114354.
Wilcox, M. R.; Nigam, A.; Glasgow, N. G.; Narangoda, C.; Philips, M. B.; Patel, D.; Mesbahi-Vasey, S.; Turcu, A. L.; Vázquez, S.; Kurnikova, M. G.; Johnson, J. W. Inhibition of NMDA Receptors Through a Membrane-to-Channel Path. Nat. Commun. 2022, 13, 4114
Companys-Alemany J, Turcu AL, Schneider M, Müller CE, Vázquez S, Griñán-Ferré C, Pallàs M. NMDA receptor antagonists reduce amyloid-β deposition by modulating calpain-1 signaling and autophagy, rescuing cognitive impairment in 5XFAD mice. Cell. Mol. Life. Sci. 2022, 9;79(8):408.
Companys-Alemany J, Roig-Soriano J, Turcu AL, Chillón M, Vázquez S, Pallàs M, Griñán-Ferré C. Optimized N-methyl-D-aspartate receptor antagonist exhibits hippocampal proneurogenic effects in aged senescence-accelerated mouse prone 8 mice. Neuroreport. 2022, 5;33(14):623-628
Companys-Alemany, J., Turcu, A.L., Vázquez, S. et al. Glial cell reactivity and oxidative stress prevention in Alzheimer’s disease mice model by an optimized NMDA receptor antagonist. Sci Rep. 2022, 12, 17908.