Synthesis of 6-amino-1,4-dihydropyridines that prevent calcium overload and neuronal death.
The synthesis and pharmacology of 6-amino-1,4-dihydropyridines, such as ethyl 6-amino-4-aryl-5-cyano-1,4-dihydro-2-methyl-3-pyridinecarboxylic acids (3-16) and 2-amino-4-aryl-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydro-3-quinolinenitriles (17-21) are described. Compounds 18 and 21, at the concentration of 0.3 microM, proved to be the best blockers of the [Ca(2+)] overload induced by depolarization with high [K(+)] of SH-SY5Y neuroblastoma cells, with values of 63.8% and 50.4%, respectively. Most of the compounds induced a remarkable neuroprotective effect against toxicity caused by high [K(+)]-elicited [Ca(2+)] overload, and against H(2)O(2)-generated free radicals, in SH-SY5Y cells.
León
Rafael
R
Laboratorio de Radicales Libres (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
de Los Ríos
Cristóbal
C
Marco-Contelles
José
J
López
Manuela G
MG
García
Antonio G
AG
Villarroya
Mercedes
M
D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010088:Oxidoreductases / Q000378:metabolism; D011188:Potassium / Q000378:metabolism
D015220:Calcium Channels; D004095:Dihydropyridines; D018696:Neuroprotective Agents; D019344:Lactic Acid; C038806:1,4-dihydropyridine; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; D011188:Potassium; D002118:Calcium