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 o f bis(2-pyridylmethylene)-1,4-butanediamine]-(N,N',N '',N'''))-Cu(II)- chloride (Cu-PuPy) and pyridylphenyl)methylene-1,4-butanediamine]-(N,N ',N '',N''')}-Cu(II)-chloride (Cu-PuPhePy) on the multiple catalytic f unctions of rat brain NO synthase (NOS). Both drugs inhibited the form ation 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 par asitic electron acceptor. Our data identify copper complexes with SOD mimicking activity as a novel class of neuronal NOS inhibitors blockin g the reductase (diaphorase) activity of the enzyme.