The neuroprotective activity of 8-alkylamino-1,4-benzoxazine antioxidants.
Antioxidant 8-alkylamino-1,4-benzoxazines, (R,S)-(3-tert-butyl-8-phenylethylamino-3,4-dihydro-2H-1,4-benzoxazin-5-yl) (phenyl) methanone (S 24429) and (R,S)-(3-cyclopentyl-8-benzylamino-3,4-dihydro-2H-1,4-benzoxazin-5-yl) (phenyl) methanone (S 24718), were prepared according to a two-step one-pot electrochemical procedure. These compounds had been selected from a previous study of structure/activity. Both compounds (1-100 microM) prevented the fall in ATP levels caused by 24 h of hypoxia in astrocytes. Both compounds (1 and 10 mg/kg i.p.) were powerful neuroprotective agents in protecting against the lesions induced by 15 microg S-bromo-willardiine injected into the cortex or white matter of 5-day old mice pups. In contrast, exifone, an antioxidant compound, was inactive at these doses. S 24429 and S 24718 appear to be novel neuroprotective agents, which are effective in a model of brain damage mimicking the lesions underlying cerebral palsy.
Largeron
M
M
Laboratoire de Chimie Analytique et Electrochimie, Faculté des Sciences Pharmaceutiques et Biologiques, UMR 8638 CNRS-Université René Descartes, 4, Avenue de l'Observatoire, 75270 Paris Cedex 06, France. largeron@pharmacie.univ-paris5.fr
Mesples
B
B
Gressens
P
P
Cecchelli
R
R
Spedding
M
M
Le Ridant
A
A
Fleury
M
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology*; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001577:Benzophenones / Q000494:pharmacology; D048588:Benzoxazines; D001921:Brain / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010078:Oxazines / Q000494:pharmacology*; D010100:Oxygen / Q000494:pharmacology; D051381:Rats
C438832:(3-cyclopentyl-8-benzylamino-3,4-dihydro-2H-1,4-benzoxazin-5-yl)phenylmethanone; C438833:(3-tert-butyl-8-phenylethylamino-3,4-dihydro-2H-1,4-benzoxazin-5-yl)phenylmethanone; D000975:Antioxidants; D001577:Benzophenones; D048588:Benzoxazines; D018696:Neuroprotective Agents; D010078:Oxazines; C068592:5-bromowillardiine; C052932:exifone; D000255:Adenosine Triphosphate; D000409:Alanine; D010100:Oxygen