Progress in the Development of Selective Nitric Oxide Synthase (NOS) Inhibitors

Some 40 years ago it was recognized by Furchgott and colleagues that the endothelium releases a vasodilator, endothelium-derived relaxing factor (EDRF). Later on, several groups identified EDRF to be a gas, nitric oxide (NO). Since then, NO was identified as one of the most versatile and unique molecules in animal and human biology. Nitric oxide mediates a plethora of physiological functions, for example, maintenance of vascular tone and inflammation. Apart from these physiological functions, NO is also involved in the pathophysiology of various disorders, specifically those in which regulation of blood flow and inflammation has a key role. The aim of the current review is to summarize the role of NO in cerebral ischemia, the most common cause of stroke.

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“…The development of highly specific inhibitors of NOS subtypes might make this therapeutic approach feasible (Salerno et al, 2002).…”

Section: Nitric Oxide Synthase Inhibitorsmentioning

confidence: 99%

Nitric Oxide: Considerations for the Treatment of Ischemic Stroke

Terpolilli¹,

Moskowitz

Plesnila³

2012

J Cereb Blood Flow Metab

128

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“…The nonselective NOS inhibitor, N G -nitro-L-arginine methyl ester (L-NAME), was administered in drinking water at a concentration of 0.5 mg/ml (16). Water was replaced every other day.…”

Section: Enzyme Inhibitorsmentioning

confidence: 99%

“…The NOS1-selective inhibitor, 7-nitroindazole (7-NI), was dissolved in DMSO and injected i.p. at a dose of 25 mg/kg (16). The NOS2-selective inhibitor, N-iminoethyl-L-lysine (L-NIL), was dissolved in PBS and injected i.p.…”

Section: Enzyme Inhibitorsmentioning

confidence: 99%

Neuronal Nitric Oxide Synthase Is Necessary for Elimination of Giardia lamblia Infections in Mice

Zhou

Singer

2006

The Journal of Immunology

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NO produced by inducible NO synthase (NOS2) is important for the control of numerous infections. In vitro, NO inhibits replication and differentiation of the intestinal protozoan parasite Giardia lamblia. However, the role of NO against this parasite has not been tested in vivo. IL-6-deficient mice fail to control Giardia infections, and these mice have reduced levels of NOS2 mRNA in the small intestine after infection compared with wild-type mice. However, NOS2 gene-targeted mice and wild-type mice treated with the NOS2 inhibitor N-iminoethyl-l-lysine eliminated parasites as well as control mice. In contrast, neuronal NOS (NOS1)-deficient mice and wild-type mice treated with the nonspecific NOS inhibitor NG-nitro-l-arginine methyl ester and the NOS1-specific inhibitor 7-nitroindazole all had delayed parasite clearance. Finally, Giardia infection increased gastrointestinal motility in wild-type mice, but not in SCID mice. Furthermore, treatment of wild-type mice with NG-nitro-l-arginine methyl ester or loperamide prevented both the increased motility and the elimination of parasites. Together, these data show that NOS1, but not NOS2, is necessary for clearance of Giardia infection. They also suggest that increased gastrointestinal motility contributes to elimination of the parasite and may also contribute to parasite-induced diarrhea. Importantly, this is the first example of NOS1 being involved in the elimination of an infection.

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“…Sodium sulfate was used to dry organic layers during work up. 1 H NMR spectra were recorded on a Gemini 2000, Mercury 400 or Inova 500 spectrometers (75.4, 100.6, or 125.7 MHz, for 13 C NMR spectra) in CDCl 3 . Chemical shifts are reported as δ values in parts per million with the CDCl 3 (TMS), (CD 2 H) 2 SO, CD 2 HOD, and HOD resonance peaks set at 0 ppm, 2.50 ppm, 3.31 ppm, and 4.80 ppm respectively.…”

Section: Experimental General Methods Reagents and Materialsmentioning

confidence: 99%

Conformationally Restricted Dipeptide Amides as Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors

Gómez-Vidal

Martásek

et al. 2006

J. Med. Chem.

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Four new conformationally-restricted analogues of the 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 4N-(L-Arg NO 2 )-trans-4-amino-Lprolineamide (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 and eNOS, respectively. 3-N-(L-Arg NO 2 )-trans-3-amino-L-prolineamide (6) is as potent an inhibitor of nNOS as is 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.Nitric oxide (NO) is a ubiquitous biological messenger involved in a variety of physiological processes that acts as a signal transducer but also exerts a variety of regulatory and cytostatic functions. In most instances NO mediates its biological effects by activating guanylate cyclase and increasing cyclic GMP synthesis. However, effects of nitric oxide that are independent of cyclic GMP are also known. 1 Nitric oxide synthase (NOS, EC 1.14.13.39) isoforms 2 are homodimers that catalyze the oxidation of L-arginine to L-citrulline and nitric oxide in a NADPH-and O 2 -dependent process. 3 There are at least three distinct isoforms of NOS. The constitutive endothelial isoform (eNOS) is involved in the regulation of smooth muscle relaxation and blood pressure and in the inhibition of platelet aggregation. A second constitutive isoform is the neuronal NOS (nNOS), which is important for neurotransmission. A third isozyme is the inducible NOS (iNOS), which is located in activated macrophage cells and acts as a cytotoxic agent in normal immune responses. All of the isoforms utilize NADPH, FAD, FMN, tetrahydrobiopterin, and heme as cofactors. The constitutive isoforms also require Ca 2+ and calmodulin for activity, while the inducible isoform has tightly bound Ca 2+ and calmodulin. The crystal structures of the oxygenase domains of murine iNOS monomer, 4 murine and human iNOS dimer, 5,6,7,8 human and bovine endothelial NOS dimers, 9 and rat neuronal NOS dimer 10 indicate a high degree *Address correspondence to this author at the Department of Chemistry Phone: 1−847−491−5653 Email: Agman@chem.northwestern.edu. § Northwestern University ¶ University of Texas † Present address: Departamento de Quimica Farmaceutica y Organica, Facultad de Farmacia, Universidad de Granada, 18071 Granada, Spain # Developed the eNOS overexpression system in E. coli and the purification of eNOS. ± Developed the overexpression system for nNOS in E. coli and the purification of the nNOS. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of structural similarity within the catalytic center and the dimer interface regions between NOS isoforms. They share only approximately 50% ...

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Progress in the Development of Selective Nitric Oxide Synthase (NOS) Inhibitors

Cited by 208 publications

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Nitric Oxide: Considerations for the Treatment of Ischemic Stroke

Nitric Oxide: Considerations for the Treatment of Ischemic Stroke

Neuronal Nitric Oxide Synthase Is Necessary for Elimination of Giardia lamblia Infections in Mice

Conformationally Restricted Dipeptide Amides as Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors

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