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 Ca(2+) 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 Ca(2+) overload and oxidative stress models. Their selectivity ratio makes them highly interesting for the treatment of neurological disorders where Ca(2+) dyshomeostasis and high levels of oxidative stress have been demonstrated. Furthermore, their low potency towards 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 post-incubation model that simulates the real clinical situation of ictus patients, offering a therapeutic window 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.