Computational Studies of Competitive Inhibitors of Nitric Oxide Synthase (NOS) Enzymes: Towards the Development of Powerful and Isoform-Selective Inhibitors

2006 ◽  
Vol 13 (16) ◽  
pp. 1929-1946 ◽  
Author(s):  
A. Tafi ◽  
L. Angeli ◽  
G. Venturini ◽  
M. Travagli ◽  
F. Corelli ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Computational Studies ◽  
Selective Inhibitors ◽  
Competitive Inhibitors ◽  
Oxide Synthase

scholarly journals Synthesis and enzymatic evaluation of 2- and 4-aminothiazole-based inhibitors of neuronal nitric oxide synthase

2009 ◽  
Vol 5 ◽  
Author(s):  
Graham R Lawton ◽  
Haitao Ji ◽  
Pavel Martásek ◽  
Linda J Roman ◽  
Richard B Silverman
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Blood Brain Barrier ◽  
Neuronal Nitric Oxide Synthase ◽  
Lead Compound ◽  
Selective Inhibitors ◽  
Net Charge ◽  
In Vivo Efficacy ◽  
Oxide Synthase

Highly potent and selective inhibitors of neuronal nitric oxide synthase (nNOS) possessing a 2-aminopyridine group were recently designed and synthesized in our laboratory and were shown to have significant in vivo efficacy. In this work, analogs of our lead compound possessing 2- and 4-aminothiazole rings in place of the aminopyridine were synthesized. The less basic aminothiazole rings will be less protonated at physiological pH than the aminopyridine ring, and so the molecule will carry a lower net charge. This could lead to an increased ability to cross the blood-brain barrier thereby increasing the in vivo potency of these compounds. The 2-aminothiazole-based compound was less potent than the 2-aminopyridine-based analogue. 4-Aminothiazoles were unstable in water, undergoing tautomerization and hydrolysis to give inactive thiazolones.

scholarly journals Contrasting effects of N5-substituted tetrahydrobiopterin derivatives on phenylalanine hydroxylase, dihydropteridine reductase and nitric oxide synthase

2000 ◽  
Vol 348 (3) ◽  
pp. 579-583 ◽  
Author(s):  
Ernst R. WERNER ◽  
Hans-Jörg HABISCH ◽  
Antonius C. F. GORREN ◽  
Kurt SCHMIDT ◽  
Laura CANEVARI ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Phenylalanine Hydroxylase ◽  
Neuronal Nitric Oxide Synthase ◽  
Dihydropteridine Reductase ◽  
Redox Active ◽  
Competitive Inhibitors ◽  
Oxide Synthase ◽  
Active Contribution ◽  
Stimulation Of

Tetrahydrobiopterin [(6R)-5,6,7,8-tetrahydro-L-biopterin, H4biopterin] is one of several cofactors of nitric oxide synthases (EC 1.14.13.39). Here we compared the action of N5-substituted derivatives on recombinant rat neuronal nitric oxide synthase with their effects on dihydropteridine reductase (EC 1.6.99.7) and phenylalanine hydroxylase (EC 1.14.16.1), the well-studied classical H4biopterin-dependent reactions. H4biopterin substituted at N5 with methyl, hydroxymethyl, formyl and acetyl groups were used. Substitution at N5 occurs at a position critical to the redox cycle of the cofactor in phenylalanine hydroxylase/dihydropteridine reductase. We also included N2ʹ-methyl H4biopterin, a derivative substituted at a position not directly involved in redox cycling, as a control. As compared with N5-methyl H4biopterin, N5-formyl H4biopterin bound with twice the capacity but stimulated nitric oxide synthase to a lesser extent. Depending on the substituent used, N5-substituted derivatives were redox-active: N5-methyl- and N5-hydroxylmethyl H4biopterin, but not N5-formyl- and N5-acetyl H4biopterin, reduced 2,6-dichlorophenol indophenol. N5-Substituted H4biopterin derivatives were not oxidized to products serving as substrates for dihydropteridine reductase and, depending on the substituent, were competitive inhibitors of phenylalanine hydroxylase: N5-methyl- and N5-hydroxymethyl H4biopterin inhibited phenylalanine hydroxylase, whereas N5-formyl- and N5-acetyl H4biopterin had no effect. Our data demonstrate differences in the mechanism of stimulation of phenylalanine hydroxylase and nitric oxide synthase by H4biopterin. They are compatible with a novel, non-classical, redox-active contribution of H4biopterin to the catalysis of the nitric oxide synthase reaction.

N-Substituted acetamidines and 2-methylimidazole derivatives as selective inhibitors of neuronal nitric oxide synthase

2010 ◽  
Vol 20 (22) ◽  
pp. 6495-6499 ◽  
Author(s):  
Cristina Maccallini ◽  
Antonia Patruno ◽  
Fabio Lannutti ◽  
Alessandra Ammazzalorso ◽  
Barbara De Filippis ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Neuronal Nitric Oxide Synthase ◽  
Selective Inhibitors ◽  
Oxide Synthase

Nω-Nitroarginine-Containing Dipeptide Amides. Potent and Highly Selective Inhibitors of Neuronal Nitric Oxide Synthase

1999 ◽  
Vol 42 (16) ◽  
pp. 3147-3153 ◽  
Author(s):  
Hui Huang ◽  
Pavel Martasek ◽  
Linda J. Roman ◽  
Bettie Sue Siler Masters ◽  
Richard B. Silverman
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Neuronal Nitric Oxide Synthase ◽  
Selective Inhibitors ◽  
Oxide Synthase
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