Dipeptides containing L-arginine analogs: New isozyme-selective inhibitorsof nitric oxide synthase

Several L-arginine analogs are known as potent inhibitors of nitric oxide s ynthase (NOS). We recently synthesized dipeptides containing such amino aci ds, and found that they are potent and isozyme-selective NOS inhibitors. Fo r example, S-methyl-L-isothiocitrullinyl-L-phenylalanine showed 66-fold sel ectivity for iNOS over nNOS, while S-methyl-L-isothiocitrullinyl-L-leucine and N-G-nitro-L-argininyl-L-phenylalanine showed 20- and 14-fold selectivit y, respectively, Interestingly, S-methyl-L-isothiocitrullinyl-L-phenylalani ne showed no selectivity add S-methyl-L-isothiocitrullinyl-L-phenylalanine showed competitive inhibition. These results suggest that each NOS isozyme has a cavity of different size near the C-terminal of the L-arginine bindin g site, and that the selectivity of inhibitors is due to the differences in the size of the cavity.