Acetamidine Lysine Derivative, <i>N</i>-(5(<i>S</i>)-amino-6,7-dihydroxyheptyl)ethanimidamide Dihydrochloride:  A Highly Selective Inhibitor of Human Inducible Nitric Oxide Synthase

Ea, Hallinan; Tsymbalov, Sofya; Finnegan, Patrick M.; Wm, Moore; Gm, Jerome; Mg, Currie; Bs, Pitzele

doi:10.1021/jm9706675

Cited by 27 publications

(7 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with the observation that NOS is active with both L-arginine and L-homoarginine, homoarginine analogs can also be effective NOS inhibitors (45,46). Whereas L-VNIO and L-ENIPO are analogs of arginine, L-VNIL and L-ENIPL are the corresponding analogs of homoarginine (Fig.…”

Section: Crystal Structure Of Rat Nnos With Bound L-vnio-supporting

confidence: 82%

Structural Characterization and Kinetics of Nitric-oxide Synthase Inhibition by Novel N5-(Iminoalkyl)- and N5-(Iminoalkenyl)-ornithines

Bretscher

Poulos

2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

Isoform-specific nitric-oxide synthase (NOS) inhibitors may prove clinically useful in reducing the pathophysiological effects associated with increased neuronal NOS (nNOS) or inducible NOS (iNOS) activity in a variety of neurological and inflammatory disorders. Analogs of the NOS substrate L-arginine are pharmacologically attractive inhibitors because of their stability, reliable cell uptake, and good selectivity for NOS over other heme proteins. Some inhibitory arginine analogs show significant isoform selectivity although the structural or mechanistic basis of such selectivity is generally poorly understood. In the present studies, we determined by x-ray crystallography the binding interactions between rat nNOS and N 5 -(1-imino-3-butenyl)-L-ornithine (L-VNIO), a previously identified mechanismbased, irreversible inactivator with moderate nNOS selectivity. We have also synthesized and mechanistically characterized several L-VNIO analogs and find, surprisingly, that even relatively minor structural changes produce inhibitors that are either iNOS-selective or nonselective. Furthermore, derivatives having a methyl group added to the butenyl moiety of L-VNIO and L-VNIO derivatives that are analogs of homoarginine rather than arginine display slow-on, slow-off kinetics rather than irreversible inactivation. These results elucidate some of the structural requirements for isoform-selective inhibition by L-VNIO and its related alkyl-and alkenyl-imino ornithine and lysine derivatives and may provide information useful in the ongoing rational design of isoform-selective inhibitors. Nitric oxide (NO)1 is a freely diffusible, moderately reactive free radical with diverse biological actions. Three distinct nitric-oxide synthase (NOS) isoforms catalyze the NADPH-and O 2 -dependent conversion of L-arginine to L-citrulline and NO in a wide range of mammalian tissues. Each isoform is associated mainly, but not exclusively, with a specific physiological role, such as neurotransmission or neuromodulation (nNOS) (1, 2), immune response (iNOS) (3), or blood pressure regulation (eNOS) (4). For each isoform, the monomers of the NOS homodimer are comprised of a heme-and tetrahydrobiopterin (BH 4 )-containing oxygenase domain, which binds the substrate arginine, and an FAD-and FMN-containing reductase domain, which binds the substrate NADPH. A calmodulin (CaM)-binding region connects the oxygenase and reductase domains. For nNOS and eNOS, which are constitutively expressed, increases in cellular Ca 2ϩ levels cause Ca 2ϩ -CaM to bind to NOS and activate NO production. In contrast, iNOS is fully active at basal intracellular Ca 2ϩ concentrations and is instead regulated mainly by transcriptional control of enzyme expression.Overproduction of NO or uncoupled reduction of O 2 to superoxide by NOS has been implicated in the morbidity or mortality of cytokine-induced hypotension (5), cardiogenic and septic shock (6 -8), chronic inflammation (9), migraine headache (10 -12), several neurodegenerative diseases (13-15), and the reperfusion inj...

show abstract

Section: Crystal Structure Of Rat Nnos With Bound L-vnio-supporting

confidence: 82%

Structural Characterization and Kinetics of Nitric-oxide Synthase Inhibition by Novel N5-(Iminoalkyl)- and N5-(Iminoalkenyl)-ornithines

Bretscher

Poulos

2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…This single amino acid difference has no effect on the binding affinity of the substrate since the K M of Arg is in the low micromolar range for all isoforms [21]. The only inhibitor selective for iNOS and nNOS over eNOS that might be due to this single amino acid difference is an acetamidine lysine derivative [22]. However, whether or not the vicinal diol moiety of the compound really fits into the carboxylate binding pocket is unknown.…”

Section: Substrate Binding Pocket and Inhibitor-enzyme Interactionsmentioning

confidence: 99%

Structure?function studies on nitric oxide synthases

Poulos

2005

Journal of Inorganic Biochemistry

269

203

View full text Add to dashboard Cite

“…Likewise, in the amidine class of inhibitors (see section 3.7) replacement of the carboxyl moiety of an amidine inhibitor with a vicinal glycol gives a compound that is still potent, but iNOS selective [75].…”

Section: Modification Of the Amino Acid Moiety Of Largininementioning

confidence: 99%

Selective Neuronal Nitric Oxide Synthase Inhibitors

Erdal¹,

Litzinger²,

Seo³

et al. 2005

CTMC

View full text Add to dashboard Cite

This review includes the non-patent literature up to October 2004 that deals with selective neuronal nitric oxide synthase inhibitors (highest potency is for the neuronal isozyme). Some non-selective inhibitors or selective inducible nitric oxide synthase inhibitors are mentioned if they are related to compounds that are discussed; structures of these compounds generally are not given. In vitro inhibition constants are given either as IC(50) values or as K(i)values. An IC(50) value, the inhibitor concentration that produces 50% inhibition in the presence of a constant concentration of substrate, is obtained by extrapolation of several rate data points to 50% inhibition. K(i) values are derived from several types of plots that relate the concentration of inhibitor with enzyme velocity in the presence of a variety of substrate concentrations [1]. The K(i) value can be estimated from the IC(50) value [2]. Although the two inhibition constants are related, they are not the same; generally, the reported K(i) values tend to be lower than the IC(50) values. If specifics are desired about how the data were collected, then the reader will have to look in the literature cited. No attempt was made to be exhaustive in citing all references related to specific inhibitors; rather, examples of literature references are given for each inhibitor described.

show abstract

Acetamidine Lysine Derivative, N-(5(S)-amino-6,7-dihydroxyheptyl)ethanimidamide Dihydrochloride: A Highly Selective Inhibitor of Human Inducible Nitric Oxide Synthase

Cited by 27 publications

References 14 publications

Structural Characterization and Kinetics of Nitric-oxide Synthase Inhibition by Novel N5-(Iminoalkyl)- and N5-(Iminoalkenyl)-ornithines

Structural Characterization and Kinetics of Nitric-oxide Synthase Inhibition by Novel N5-(Iminoalkyl)- and N5-(Iminoalkenyl)-ornithines

Structure?function studies on nitric oxide synthases

Selective Neuronal Nitric Oxide Synthase Inhibitors

Contact Info

Product

Resources

About