American Chemical Society
jm500263v_si_001.pdf (2.2 MB)

New 5‑Unsubstituted Dihydropyridines with Improved CaV1.3 Selectivity as Potential Neuroprotective Agents against Ischemic Injury

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journal contribution
posted on 2014-05-22, 00:00 authored by Giammarco Tenti, Esther Parada, Rafael León, Javier Egea, Sonia Martínez-Revelles, Ana María Briones, Vellaisamy Sridharan, Manuela G. López, María Teresa Ramos, J. Carlos Menéndez
C5-unsubstituted-C6-aryl-1,4-dihydropyridines were prepared by a CAN-catalyzed multicomponent reaction from chalcones, β-dicarbonyl compounds, and ammonium acetate. These compounds were able to block Ca2+ entry after a depolarizing stimulus and showed an improved Cav1.3/Cav1.2 selectivity in comparison with nifedipine. Furthermore, they were able to protect neuroblastoma cells against Ca2+ overload and oxidative stress models. Their selectivity ratio makes them highly interesting for the treatment of neurological disorders where Ca2+ dyshomeostasis and high levels of oxidative stress have been demonstrated. Furthermore, their low potency toward the cardiovascular channel subtype makes them safer by reducing their probable side effects, in comparison to classical 1,4-dihydropyridines. Some compounds afforded good protective profile in a postincubation model that simulates the real clinical situation of ictus patients, offering a therapeutic window of opportunity of great interest for patient recovery after a brain ischemic episode. Good activities were also found in acute ischemia/reperfusion models of oxygen and glucose deprivation.