Conformationally restricted dipeptide amides as potent and selective neuronal nitric oxide synthase inhibitors

Four new conformationally restricted analogues of a potent and selective neuronal nitric oxide synthase inhibitor, L-nitroargininyl-L-2,4- diaminobutyramide (1), have been synthesized. N^α-Methyl and N^α-benzyl derivatives (3 and 4, respectively) of 4-N-(L-Arg^NO2)-trans-4-amino-L-prolineamide (2) are also selective inhibitors, but the potency and selectivity of 3 are weak. Analogue 4 has only one-third the potency and one-half to one-third the selectivity of 2 against iNOS (inducible nitric oxide synthase) and eNOS (endothelial nitric oxide synthase), respectively. 3-N-(L-Arg^NO2)-trans-3-amino-L-prolineamide (6) is as potent an inhibitor of nNOS (neuronal nitric oxide synthase) as 2; selectivity for nNOS over iNOS is half of that for 2, but the selectivity for nNOS over eNOS is almost double that for 2. The corresponding cis-isomer (5) is a weak inhibitor of nNOS. These results are supported by computer modeling.