title: New 5-unsubstituted dihydropyridines with improved CaV1.3 selectivity as potential neuroprotective agents against ischemic injury.
abstract: 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 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.
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense , 28040 Madrid, Spain.
authors.forename: Giammarco
authors.initials: G
authors.lastname: Tenti
authors.forename: Esther
authors.initials: E
authors.lastname: Parada
authors.forename: Rafael
authors.initials: R
authors.lastname: León
authors.forename: Javier
authors.initials: J
authors.lastname: Egea
authors.forename: Sonia
authors.initials: S
authors.lastname: Martínez-Revelles
authors.forename: Ana María
authors.initials: AM
authors.lastname: Briones
authors.forename: Vellaisamy
authors.initials: V
authors.lastname: Sridharan
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Ramos
authors.forename: J Carlos
authors.initials: JC
authors.lastname: Menéndez
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D006624:Hippocampus / Q000098:blood supply; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D018384:Oxidative Stress; D051381:Rats; D011921:Rats, Inbred WKY; D015427:Reperfusion Injury / Q000517:prevention & control*
chemical_list: C472073:CACNA1D protein, human; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D018696:Neuroprotective Agents; D002118:Calcium