Dipeptides containing L-arginine analogs: new isozyme-selective inhibitors of nitric oxide synthase.
Several L-arginine analogs are known as potent inhibitors of nitric oxide synthase (NOS). We recently synthesized dipeptides containing such amino acids, and found that they are potent and isozyme-selective NOS inhibitors. For example, S-methyl-L-isothiocitrullinyl-L-phenylalanine showed 66-fold selectivity for iNOS over nNOS, while S-methyl-L-isothiocitrullinyl-L-leucine and N(G)-nitro-L-argininyl-L-phenylalanine showed 20- and 14-fold selectivity, respectively. Interestingly, S-methyl-L-isothiocitrullinyl-D-phenylalanine showed no selectivity, and 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 binding site, and that the selectivity of inhibitors is due to the differences in the size of the cavity.
Kobayashi
N
N
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan.
Higuchi
T
T
Urano
Y
Y
Kikuchi
K
K
Hirobe
M
M
Nagano
T
T
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology*; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D051379:Mice; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019335:Nitroarginine / Q000138:chemical synthesis / Q000494:pharmacology; D009952:Ornithine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats
D004151:Dipeptides; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D019335:Nitroarginine; C065027:N(G)-iminoethylornithine; D001120:Arginine; D009952:Ornithine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; C496315:Nos3 protein, mouse; C496316:Nos3 protein, rat