Indolalkylamines derivatives as antioxidant and neuroprotective agents in an experimental model of Parkinson's disease.
BACKGROUND
The neuroprotective effect of N-(2-propynyl)2-(5-benzyloxy-indol)methylamine (PF 9601N), a novel MAO B inhibitor, and its metabolite FA 72 on the human neuroblastoma SHSY5Y cell line lesioned with (300 microM) dopamine was assessed and compared with that of 1-deprenyl assayed at identical experimental conditions.


METHODS
Using this experimental model, PF 961N showed a neuroprotective effect in a dose-dependent manner, and at a concentration of 10 pM a 20% recovery of cell viability was observed. However, the metabolite FA72 assayed under the same experimental conditions showed an increase in cell viability of nearly 50%. In the case of l-deprenyl, a concentration of 100 microM was necessary to recover only 10% of cell viability.


RESULTS
This neuroprotective effect could be explained in terms of the antioxidant capacity of PF 9601N. In this context, the antioxidant capacities of the novel series of MAO inhibitors, PF 9601N and its analogues, were evaluated by their inhibition of the auto-oxidation of dopamine to melanin and by the dichlorofluorescein and 2-deoxyribose methods.


CONCLUSIONS
All of these compounds have the basic structure of an indole ring in common, but show different substituents at different positions in it. The corresponding structure-activity relationship studies allowed us to conclude that the presence of a benzyloxy group, or a hydroxy or methoxy group, at position 5 of the indol ring enhanced these antioxidant characteristics, presenting a decreasing order of antioxidant activity of the primary > secondary > tertiary amines. The antioxidant properties of PF 9601 N would explain its neuroprotective effect observed in SHSY5Y cells lesioned with dopamine.
Sanz
Elisenda
E
Departament de Bioquimca i Biologia Molecular, Facultad de Medicina, Institut de Neurociencies, Universitat Autónoma de Barcelona, Campus Universitari de Bellaterra, Barcelona, Spain.
Romera
Manuel
M
Bellik
Lydia
L
Marco
J I
JI
Unzeta
Mercedes
M
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000978:Antiparkinson Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001923:Brain Chemistry; D045744:Cell Line, Tumor; D004298:Dopamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008543:Melanins / Q000096:biosynthesis; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D009447:Neuroblastoma; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism; D012642:Selegiline / Q000494:pharmacology; D014363:Tryptamines / Q000494:pharmacology
D000975:Antioxidants; D000978:Antiparkinson Agents; D007211:Indoles; D008543:Melanins; D008996:Monoamine Oxidase Inhibitors; C470996:N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D014363:Tryptamines; D012642:Selegiline; C030820:tryptamine; D004298:Dopamine