title: Synthesis, inhibitory activity of cholinesterases, and neuroprotective profile of novel 1,8-naphthyridine derivatives.
abstract: 1,8-Naphthyridine derivatives related to 17 (ITH4012), a neuroprotective compound reported by our research group, have been synthesized. In general, they have shown better inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) than most tacrine derivatives previously synthesized in our laboratory. The compounds presented an interesting neuroprotective profile in SH-SY5Y neuroblastoma cells stressed with rotenone/oligomycin A. Moreover, compound 14 (ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridine-3-carboxylate) also caused protection in cells stressed with okadaic acid (OA) or amyloid beta 1-42 peptide (Abeta(1-42)). Interestingly, compound 14 prevented the OA-induced PP2A inhibition, one of the enzymes implicated in tau dephosphorylation. This compound also exhibited neuroprotection against neurotoxicity elicited by oxygen and glucose deprivation in hippocampal slices. Because these stressors caused neuronal damage related to physiopathological hallmarks found in the brain of Alzheimer's disease (AD) patients, we conclude that compound 14 deserves further in vivo studies in AD models to test its therapeutic potential in this disease.
authors.affiliation: Departamento de Farmacologia y Terapeutica, Facultad de Medicina, Instituto Teofilo Hernando, Universidad Autonoma de Madrid, C/Arzobispo Morcillo 4, 28029 Madrid, Spain. cristobal.delosrios@uam.es
authors.forename: Cristóbal
authors.initials: C
authors.lastname: de Los Ríos
authors.forename: Javier
authors.initials: J
authors.lastname: Egea
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
authors.forename: Rafael
authors.initials: R
authors.lastname: León
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: Samadi
authors.forename: Isabel
authors.initials: I
authors.lastname: Iriepa
authors.forename: Ignacio
authors.initials: I
authors.lastname: Moraleda
authors.forename: Enrique
authors.initials: E
authors.lastname: Gálvez
authors.forename: Antonio G
authors.initials: AG
authors.lastname: García
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.forename: Mercedes
authors.initials: M
authors.lastname: Villarroya
authors.forename: Alejandro
authors.initials: A
authors.lastname: Romero
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry; D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D002091:Butyrylcholinesterase / Q000737:chemistry; D002118:Calcium / Q000378:metabolism; D020134:Catalytic Domain; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003603:Cytotoxins / Q000494:pharmacology; D045222:Electron Transport Chain Complex Proteins / Q000037:antagonists & inhibitors; D004593:Electrophorus; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007536:Isomerism; D008958:Models, Molecular; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019319:Okadaic Acid / Q000494:pharmacology; D009840:Oligomycins / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D003603:Cytotoxins; D045222:Electron Transport Chain Complex Proteins; D009287:Naphthyridines; D018696:Neuroprotective Agents; D009840:Oligomycins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C551006:ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo(b)(1,8)naphthyridine-3-carboxylate; D012402:Rotenone; C031004:oligomycin A; D019319:Okadaic Acid; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D054648:Protein Phosphatase 2; D005947:Glucose; D010100:Oxygen; D002118:Calcium