title: New tacrine-dihydropyridine hybrids that inhibit acetylcholinesterase, calcium entry, and exhibit neuroprotection properties.
abstract: In this communication, we describe the synthesis and biological evaluation of tacripyrimedones 1-5, a series of new tacrine-1,4-dihydropyridine hybrids bearing the general structure of 11-amino-12-aryl-3,3-dimethyl-3,4,5,7,8,9,10,12-octahydrodibenzo[b,g][1,8]naphthyridine-1(2H)-one. These multifunctional compounds are moderately potent and selective AChEIs, with no activity toward BuChE. Kinetic analysis and molecular modeling studies point out that the new compounds preferentially bind the peripheral anionic site of AChE. In addition, compounds 1-5 show an excellent neuroprotective profile, and a moderate blocking effect of L-type voltage-dependent calcium channels due to the mitigation of [Ca(2+)] elevation elicited by K(+) depolarization. Therefore, they represent a new family of molecules with potential therapeutic application for the treatment of Alzheimer's disease.
authors.affiliation: Laboratorio de Radicales Libres (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: León
authors.forename: Cristóbal
authors.initials: C
authors.lastname: de los Ríos
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
authors.forename: Oscar
authors.initials: O
authors.lastname: Huertas
authors.forename: Xavier
authors.initials: X
authors.lastname: Barril
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Luque
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.forename: Antonio G
authors.initials: AG
authors.lastname: García
authors.forename: Mercedes
authors.initials: M
authors.lastname: Villarroya
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D013055:Spectrophotometry, Infrared; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002800:Cholinesterase Inhibitors; D004095:Dihydropyridines; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D013619:Tacrine; D000110:Acetylcholinesterase; D002118:Calcium