title: Tacrine-melatonin hybrids as multifunctional agents for Alzheimer's disease, with cholinergic, antioxidant, and neuroprotective properties.
abstract: Tacrine-melatonin hybrids were designed and synthesized as new multifunctional drug candidates for Alzheimer's disease. These compounds may simultaneously palliate intellectual deficits and protect the brain against both beta-amyloid (A beta) peptide and oxidative stress. They show improved cholinergic and antioxidant properties, and are more potent and selective inhibitors of human acetylcholinesterase (hAChE) than tacrine. They also capture free radicals better than melatonin. Molecular modeling studies show that these hybrids target both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. At sub-micromolar concentrations they efficiently displace the binding of propidium iodide from the PAS and could thus inhibit A beta peptide aggregation promoted by AChE. Moreover, they also inhibit A beta self-aggregation and display neuroprotective properties in a human neuroblastoma line against cell death induced by various toxic insults, such as A beta(25-35), H(2)O(2), and rotenone. Finally, they exhibit low toxicity and may be able to penetrate the central nervous system according to an in vitro parallel artificial membrane permeability assay for the blood-brain barrier (PAMPA-BBB).
authors.affiliation: Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Fernández-Bachiller
authors.forename: Concepción
authors.initials: C
authors.lastname: Pérez
authors.forename: Nuria Eugenia
authors.initials: NE
authors.lastname: Campillo
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Páez
authors.forename: Gema Cristina
authors.initials: GC
authors.lastname: González-Muñoz
authors.forename: Paola
authors.initials: P
authors.lastname: Usán
authors.forename: Esther
authors.initials: E
authors.lastname: García-Palomero
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.forename: Mercedes
authors.initials: M
authors.lastname: Villarroya
authors.forename: Antonio G
authors.initials: AG
authors.lastname: García
authors.forename: Ana
authors.initials: A
authors.lastname: Martínez
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Rodríguez-Franco
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001812:Blood-Brain Barrier; D020134:Catalytic Domain; D002460:Cell Line; D018678:Cholinergic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008550:Melatonin / Q000138:chemical synthesis / Q000737:chemistry*; D008956:Models, Chemical; D008969:Molecular Sequence Data; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016415:Sequence Alignment; D013619:Tacrine / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D018678:Cholinergic Agents; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D013619:Tacrine; D000110:Acetylcholinesterase; D008550:Melatonin