Inhibition of 6-hydroxydopamine-induced oxidative damage by 4,5-dihydro-3H-2-benzazepine N-oxides.
A number of new analogs of 3,3-dimethyl-4,5-dihydro-3H-2-benzazepine 2-oxide, structurally related to the nitrone spin trap alpha-phenyl-N-tert-butylnitrone (PBN), were synthesized and evaluated for their activity in vitro as protectants against oxidative stress induced in rat brain mitochondria by 6-hydroxydopamine (6-OHDA), a neurotoxin producing experimental model of Parkinson's disease (PD). As assessed by a fluorimetric assay, all 2-benzazepine-based nitrones were shown to decrease hydroxyl radicals (OH) generated during 6-OHDA autoxidation. The inhibition effects on the OH formation shown by the 5-gem-dimethyl derivatives, 2-4 times higher than those of the corresponding 5-methyl derivatives, were attributed to the flattening effect of the 5-gem-dimethyl group on the azepine ring, which should enhance nitrone reactivity and/or increase stability of the radical adducts. In contrast, owing to steric hindrance, a methyl group to C-1 diminishes the OH-scavenging activity of the nitrone group. All the assayed compounds were more potent than PBN as inhibitors of 6-OHDA-induced lipid peroxidation (LPO) and protein carbonylation (PCO), taken as an indicator of mitochondrial protein oxidative damage. The most promising antioxidant (compound 11), bearing 5-gem-dimethyl and spiro C-3 cyclohexyl groups, highlighted in this study as the best features, inhibited LPO and PCO with IC50 values of 20 and 48 microM, respectively, showing a potency improvement over PBN of two order magnitude. Both LPO and PCO inhibition potency data were found primarily related to the OH-scavenging activities, whereas lipophilicity plays a role in improving the LPO (but not PCO) inhibition, as a statistically valuable two-parameter equation proved.
Soto-Otero
Ramón
R
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Santiago de Compostela, Santiago de Compostela, Spain.
Méndez-Alvarez
Estefanía
E
Sánchez-Iglesias
Sofía
S
Zubkov
Fedor I
FI
Voskressensky
Leonid G
LG
Varlamov
Alexey V
AV
de Candia
Modesto
M
Altomare
Cosimo
C
D000818:Animals; D001552:Benzazepines / Q000737:chemistry / Q000494:pharmacology*; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals / Q000037:antagonists & inhibitors / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology*; D016627:Oxidopamine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D001552:Benzazepines; D003497:Cyclic N-Oxides; D005609:Free Radicals; D016627:Oxidopamine