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(alpha)-Methyl and N(alpha)-benzyl derivatives (3 and 4, respectively) of 4-N-(l-Arg(NO(2))-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(NO)(2))-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.
Ji
Haitao
H
Department of Chemistry, Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, Illinois 60208-3113, USA.
Gómez-Vidal
José A
JA
Martasek
Pavel
P
Roman
Linda J
LJ
Silverman
Richard B
RB
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000737:chemistry; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000737:chemistry; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000737:chemistry; D011392:Proline / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship
D000577:Amides; D004151:Dipeptides; D011392:Proline; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III