title: 2-Benzazepine nitrones protect dopaminergic neurons against 6-hydroxydopamine-induced oxidative toxicity.
abstract: A number of C-3 spirocyclic 2-benzazepine analogs of α-phenyl-N-tert-butyl nitrone (PBN) were synthesized and tested for their activity in protecting rat brain mitochondria and dopaminergic (DA) neurons against 6-hydroxydopamine (6-OHDA), a toxin inducing destruction of the DA nigro-striatal pathway in rodent models of Parkinson's disease. The newly synthesized nitrone derivatives were firstly investigated for their activity in decreasing the level of hydroxyl radicals generated during 6-OHDA oxidation, and inhibit lipid peroxidation (TBARS assay) and protein carbonyl content (PCC) in rat brain mitochondria. Most of the studied 2-benzazepine nitrones showed inhibitory potencies in both TBARS and PCC assays at least two magnitude orders higher than that of PBN. The data obtained usefully complemented the known structure-activity relationships. In particular, 5 and 10, bearing C-3 spiro cyclopentyl and tetrahydropyranyl moieties, respectively, at 8 µM concentration proved to be significantly more effective than PBN in protecting cultured DA neurons exposed to 6-OHDA, which alone causes about 45% cell loss in 24 h. In addition, we found that 5 inhibited butyrylcholinesterase with an IC(50)  value of 16.8 µM, which would enhance its potential as neuroprotective agent in Alzheimer's neurodegeneration. These findings extend the utility of benzazepine-based PBN analogs in the treatment of age-related free radical-mediated disorders.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Universidad de Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Soto-Otero
authors.forename: Estefanía
authors.initials: E
authors.lastname: Méndez-Álvarez
authors.forename: Sofía
authors.initials: S
authors.lastname: Sánchez-Iglesias
authors.forename: José Luís
authors.initials: JL
authors.lastname: Labandeira-García
authors.forename: Jannette
authors.initials: J
authors.lastname: Rodríguez-Pallares
authors.forename: Fedor I
authors.initials: FI
authors.lastname: Zubkov
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Zaytsev
authors.forename: Leonid G
authors.initials: LG
authors.lastname: Voskressensky
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Varlamov
authors.forename: Modesto
authors.initials: M
authors.lastname: de Candia
authors.forename: Filomena
authors.initials: F
authors.lastname: Fiorella
authors.forename: Cosimo
authors.initials: C
authors.lastname: Altomare
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020128:Inhibitory Concentration 50; D015227:Lipid Peroxidation / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000737:chemistry / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D050050:Protein Carbonylation / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D001552:Benzazepines; D002800:Cholinesterase Inhibitors; D003497:Cyclic N-Oxides; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; C015388:nitrones; C029217:phenyl-N-tert-butylnitrone; D016627:Oxidopamine