Structural and functional analogs of CuZn superoxide dismutase inhibit rat brain nitric oxide synthase by interference with the reductase (diaphorase) domain.
Copper complexes with superoxide dismutase (SOD) activity show a wide range of pharmacological activities. We have investigated the effect of ([N,N'-bis(2-pyridylmethylene)-1,4-butanediamine]-(N,N',N", N"')]-Cu(II)-chloride (Cu-PuPy) and ([N,N'-bis(2-pyridyl-phenyl)methylene-1,4-butanediamine]-(N,N',N", N"'))-Cu(II)-chloride (Cu-PuPhePy) on the multiple catalytic functions of rat brain NO synthase (NOS). Both drugs inhibited the formation of L-citrulline as well as the enzymatic reduction of cytochrome c. The uncoupled oxidation of NADPH, catalyzed by neuronal NOS in the absence of L-arginine, was inhibited by Cu-PuPy but stimulated by Cu-PuPhePy, suggesting that the phenyl-substituted compound acts as a parasitic electron acceptor. Our data identify copper complexes with SOD mimicking activity as a novel class of neuronal NOS inhibitors blocking the reductase (diaphorase) activity of the enzyme.
Mayer
B
B
Institut für Pharmakologie und Toxikologie, Karl-Franzens-Universität Graz, Austria. mayer@kfunigraz.ac.at
Pfeiffer
S
S
Leopold
E
E
Müller
J
J
Weser
U
U
Schmidt
K
K
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002147:Calmodulin / Q000378:metabolism; D002956:Citrulline / Q000378:metabolism; D003864:Depression, Chemical; D008058:Dihydrolipoamide Dehydrogenase / Q000037:antagonists & inhibitors*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000494:pharmacology*
D000975:Antioxidants; D002147:Calmodulin; D002956:Citrulline; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D009251:NADPH-Ferrihemoprotein Reductase; D008058:Dihydrolipoamide Dehydrogenase