New 5‑Unsubstituted Dihydropyridines with Improved Ca_V1.3 Selectivity as Potential Neuroprotective Agents against Ischemic Injury

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 Ca_v1.3/Ca_v1.2 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.