Structure activity relationships of peroxynitrite scavengers an approach to nitric oxide neurotoxicity.
Nitric oxide (NO) is made by NO synthase during the conversion of arginine to citrulline. Researchers have found that they can block the actions of excitotoxins by inhibiting NO synthase. Released from excitable cells during trauma, NO may react with superoxide to form peroxynitrite. Once formed, peroxynitrite and its products can then react with proteins, lipids and nucleic acids resulting in cell injury and death. The present study was undertaken to investigate analogs of cysteine as scavengers of peroxynitrite. Peroxynitrite scavengers were assayed by Attoflo, an automated radioimmunoassay. Briefly, peroxynitrite, in a dose-dependent manner (0.1 to 10 mM), inhibited the binding of I125 cAMP to a polyclonal antibody used in the assay of cAMP. Drugs were tested for blockade of the inhibition (90%) caused by peroxynitrite at 10 mM. Cysteine blocked the inhibition of ligand/antibody binding in a dose-dependent manner (EC50 = 3 mM). Cysteine, cysteine esters, penicillamine, penicillamine esters and cysteamine were the most effective peroxynitrite scavengers. Analogs of cysteine may thereby protect cells from nitric oxide toxicity.
Althaus
J S
JS
Upjohn Company, Kalamazoo, MI 49001.
Oien
T T
TT
Fici
G J
GJ
Scherch
H M
HM
Sethy
V H
VH
VonVoigtlander
P F
PF
D000818:Animals; D000937:Antigen-Antibody Reactions / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers; D007074:Immunoglobulin G / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism* / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D011863:Radioimmunoassay; D013329:Structure-Activity Relationship
D016166:Free Radical Scavengers; D007074:Immunoglobulin G; D009566:Nitrates; C039642:peroxynitric acid; D009569:Nitric Oxide; D000242:Cyclic AMP; D003545:Cysteine